Clinica - Pécsi Tudományegyetem



PÉCSI TUDOMÁNYEGYETEM

Orvostudományi és Egészségtudományi Centrum

Szak- és Továbbképző Központ

H-7624 Pécs, Szigeti út 12.

Tel.: (72) 512-643

Fax: (72) 512-683

IGAZGATÓ: PROF. DR. ERTL TIBOR

SZAKORVOSI TOVÁBBKÉPZÉS

TÉMA: CLINICAL NEPHROLOGY

SZERKESZTETTE: DR. NÉMETH LÁSZLÓ

CÍM: PETZ ALADÁR MEGYEI OKTATÓ KÓRHÁZ – RENDELŐINTÉZET

I.SZ. BELGYÓGYÁSZATI SZAKRENDELÉS

9024 Győr, Szent Imre u. 41. Tel.: (96) 418-244/1494

IRODALOM: 2007. JANUÁR 1 – MÁRCIUS 31.

GYŐR, 2007. ÁPRILIS 1.

C O N T E N T S

Part One

SECTIONS

I. EPIDEMIOLOGY

II. ETIOPATHOGENESIS

III. CLINCAL PRESENTATION

IV. TREATMENT

V. TRANSPLANTATION

TITLE OF PUBLICATIONS – AUTHORS – PUBLICATIONS

Part One

I. EPIDEMILOGY

1. Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese.

Hayakawa T, Takamura T, Abe T, Kaneko S.

Metabolism. 2007 56 (1): 44-8.

2. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans.

Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, Rich SS, Xu J, McDonough C, Janssen B, Yard BA, van der Woude FJ, Bowden DW.

Nephrol Dial Transplant. 2007 Jan 5; [Epub ahead of print].

3. Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy.

Ma J, Mollsten A, Falhammar H, Brismar K, Dahlquist G, Efendic S, Gu HF.

J Diabetes Complications. 2007 21 (1): 28-33.

4. Asssociation of adiponectin and resistin with cardiovascular events in Korean patients with type 2 diabetes: The Korean atherosclerosis study (KAS). A 42-month prospective study.

Lim S, Koo BK, Cho SW, Kihara S, Funahashi T, Cho YM, Kim SY, Lee HK, Shimomura I, Park KS.

Atherosclerosis. 206 Dec 16; [Epub ahead of print].

5. Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy.

Li GS, Zhang H, Lv JC, Shen Y, Wang HY.

Kidney Int. 2007 Jan 17; [Epub ahead of print].

6. Characterization of a large Lebanese family segregating IgA nephropathy.

Karnib HH, Sanna-Cherchi S, Zalloua PA, Medawar W, D’Agati VD, Lifton RP, Badr K, Gharavi AG.

Nephrol Dial Transplant. 2007 Jan 4; [Epub ahead of print].

7. Seroprevalence of hepatitis B and C viruses in patients with chronic kidney disease in the predialysis stage at a University Hospital in Turkey.

Sit D, Kadiroglu AK, Kayabasi H, Yilmaz ME, Goral V.

Intervirology. 2006 50 (2): 133-7.

8. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis.

Roccatello D, Fornasieri A, Giachino O, Rossi D, Beltrame A, Banfi G, Confalonieri R, Tarantino A, Pasquali S, Amoroso A, Savoldi S, Colombo V, Manno C, Ponzetto A, Moriconi L, Pani A, Rustichelli R, Di Belgiojoso GB, Comotti C, Quarenghi MI.

Am J Kidney Dis. 2007 49 (1): 69-82.

9. Malaria-induced renal damage: Facts and myths.

Ehrich JH, Eke FU.

Pediatr Nephrol. 2007 Jan 5; [Epub ahead of print].

10. Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: A standardized mortality ratio analysis.

Meliker JR, Wahl RL, Cameron LL, Nriagu JO.

Environ Health. 2007 Feb 2; [Epub ahead of print].

11. Chronic kidney disease in children: The global perspective.

Warady BA, Chadha V.

Pediatr Nephrol. 2007 Feb 20; [Epub ahead of print].

12. Epidemiological features of CKD in Taiwan.

Kuo HW, Tsai SS, Tiao MM, Yang CY.

Am J Kidney Dis. 2007 49 (1): 46-55.

13. Octogenarians and nonagenarians starting dialysis in the United States.

Kurella M, Covinsky KE, Collins AJ, Chertow GM.

Ann Intern Med. 2007 146 (3): 177-83.

14. Risk factors for chronic kidney disease in a community-based population: A 10-year follow-up study.

Yamagata K, Ishida K, Sairenchi T, Takahashi H, Ohba S, Shiigai T, Narita M, Koyama A.

Kidney Int. 2006 Nov 22; [Epub ahead of print].

15. Kidney disease in life-course socioeconomic context: The Atherosclerosis Risk in Communities (ARIC) Study.

Shoham DA, Vupputuri S, Diez Roux AV, Kaufman JS, Coresh J, Kshirsagar AV, Zeng D, Heiss G.

Am J Kidney Dis. 2007 49 (2): 217-26.

16. Confounding effect of comorbidity in survival studies in patients on renal replacement therapy.

van Manen JG, van Dijk PC, Stel VS, Dekker FW, Cleries M, Conte F, Feest T, Kramar R, Leivestad T, Briggs JD, Stengel B, Jager KJ.

Nephrol Dial Transplant. 2007 22 (1): 187-95.

17. Obesity-hypertension: An ongoing pandemic.

Francischetti EA, Genelhu VA.

Int J Clin Pract. 2007 61 (2): 269-80.

18. Diabetes, kidney disease and anaemia: Time to tackle a troublesome triad?

Al-Khoury S, Afzali B, Shah N, Thomas S, Gusbeth-Tatomir P, Goldsmith D, Covic A.

Int J Clin Pract. 2007 61 (2): 281-9.

19. Prevalence and implications of isolated microscopic hematuria in asymptomatic Chinese pregnant women.

Szeto CC, To KF, Lai FM, Chow KM, Tam WH, Chung KY, Leung CB, Lui SF, Li PK, Lau TK.

Nephron Clin Pract. 2007 105 (4): c147-52.

20. Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice.

New JP, Middleton RJ, Klebe B, Farmer CK, de Lusignan S, Stevens PE, O’donoghue DJ.

Diabet Med. 2007 Feb 28; [Epub ahead of print].

21. Relationship between inflammatory markers, metabolic and anthropometric variables in the Caribbean type 2 diabetic patients with and without microvascular complications.

Nayak BS, Roberts L.

J Inflamm (Lond). 2006 Dec 22; [Epub ahead of print].

22. Association between the metabolic syndrome and chronic kidney disease in Chinese adults.

Chen J, Gu D, Chen CS, Wu X, Hamm LL, Muntner P, Batuman V, Lee CH, Whelton PK, He J.

Nephrol Dial Transplant. 2007 Feb 1; [Epub ahead of print].

23. Prevalence of chronic kidney disease and associated risk factors - - United States, 1999-2004.

Centers for Disease Control and Prevention [CDC].

MMWR Morb Mortal Wkly Rep. 2007 56 (8): 161-5.

24. Epidemiology of renal recovery after acute renal failure.

Bagshaw SM.

Curr Opin Crit Care. 2006 12 (6): 544-50.

II. ETIOPATHOGENESIS

1. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease.

Mittal RD, Manchanda PK.

Immunogenetics. 2007 59 (2): 159-65.

2. Interleukin-1 receptor antagonist gene polymorphism affects the progression of chronic renal failure.

Buraczynska M, Ksiazek P, Kubit P, Zaluska W.

Cytokine. 2007 Jan 13; [Epub ahead of print].

3. Induction of TRPC6 channel acquired forms of proteinuric kidney disease.

Moller CC, Wei C, Altinants MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J.

J Am Soc Nephrol. 2007 18 (1): 29-36.

4. DEC-205-mediated internalization of HIV-1 results in the establishment of silent infection in renal tubular cells.

Hatsukari I, Singh P, Hitosugi N, Messmer D, Valderrama E, Teichberg S, Chaung W, Gross E, Schmidtmayerova H, Singhal PC.

J Am Soc Nephrol. 2007 18 (3): 780-7.

5. Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway.

He JC, Lu TC, Fleet M, Sunamoto M, Husain M, Fang W, Neves S, Chen Y, Shankland S, Iyengar R, Klotman PE.

J Am Soc Nephrol. 2007 18 (1): 93-102.

6. HIV-1 Tat reduces nephrin in human podocytes: A potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy.

Doublier S, Zennaro C, Spatola T, Lupia E, Bottelli A, Deregibus MC, Carraro M, Conaldi PG, Camussi G.

AIDS. 2007 21 (4): 423-32.

7. Eosinophilic glomerulonephritis in chidren in Southwestern Uganda.

Walker A, Ellis J, Irama M, Senkungu J, Nansera D, Axton J, Coward RJ, Peat DS, Bode HH, Mathieson PW.

Kidney Int. 2007 Jan 17, [Epub ahead of print].

8. The simple design of complement factor H: Looks can be deceiving.

Alexander JJ, Quigg RJ.

Mol Immunol. 2007 44 (1-3): 123-32.

9. The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect.

Wolf MT, Beck BB, Zaucke F, Kunze A, Misselwitz J, Ruley J, Ronda T, Fischer A, Eifinger F, Licht C, Otto E, Hoppe B, Hildebrandt F.

Kidney Int. 2007 Jan 24; [Epub ahead of print].

10. Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.

Bernhardt WM, Wiesener MS, Weidemann A, Schmitt R, Weichert W, Lechler P, Campean V, Ong AC, Willam C, Gretz N, Eckardt KU.

Am J Pathol. 2007 170 (3): 830-42.

11. A novel Cys1638Tyr NC1 domain substitution in {alpha} 5 (IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities.

Wilson JC, Yoon HS, Walker RJ, Eccles MR.

Nephrol Dial Transplant. 2007 Feb 3; [Epub ahead of print].

12. Role of matrix metalloproteinases in renal pathophysiologies.

Catania JM, Chen G, Parrish AR.

Am J Physiol Renal Physiol. 2006 Dec 26; [Epub ahead of print].

13. The expression of matrix metalloproteinase-11 protein in various types of glomerulonephritis.

Nakopoulou L, Lazaris AC, Boletis I, Michail S, Iatrou C, Papadikis G, Athanassiadou S, Stathakis C.

Nephrol Dial Transplant. 2007 22 (1): 109-17.

14. Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-{beta}1 in patients with distinct types of primary glomerulonephritis.

Bauvois B, Mothu N, Nguyen J, Nguyen-Khoa T, Noel LH, Jungers P.

Nephrol Dial Transplant. 2007 Jan 5; [Epub ahead of print].

15. Chemokines and chemokine receptors in glomerulonephritis and renal allograft rejection.

Stasikowska O, Wagrowska-Danilewicz M.

Med Sci Monit. 2007 13 (2): RA31-6.

16. Expression and targeting of CX3CL1 (fractalkine) in renal tubular epithelial cells.

Durkan AM, Alexander RT, Liu GY, Rui M, Femia G, Robinson LA.

J Am Soc Nephrol. 2007 18 (1): 74-83.

17. Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state.

Lai KN, Leung JC, Chan LY, Guo H, Tang SC.

Kidney Int. 2007 Jan 24; [Epub ahead of print].

18. The role played by endocytosis in albumin induced secretion of TGF {beta}-1 by proximal tubular epithelial cells.

Diwakar R, Pearson AD, Colville-Nash P, Brunskill NJ, Dockrell ME.

Am J Physiol Renal Physiol. 2007 Jan 16; [Epub ahead of print].

19. DNA fragmentation in chronic glomerulonephritis: An immunohistological analysis.

Ott U, Aschoff A, Pocock J, Funfstuck R, Jirikowski G, Stein G, Wolf G.

Nephron Clin Pract. 2007 105 (1): c18-28.

20. Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: Evidence for role of P2X4.

Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, Falzoni S, Lupi R, Ferraninni E, Pugliese G, Di Virgilio F.

Am J Physiol Renal Physiol. 2007 Jan 30; [Epub ahead of print].

21. Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis.

Turner CM, Tam FW, Lai PC, Tarzi RM, Burnstock G, Pusey CD, Cook HT, Unwin RJ.

Nephrol Dial Transplant. 2007 22 (2): 386-95.

22. The contribution of B cells to renal interstitial inflammation.

Heller F, Lindenmeyer MT, Cohen CD, Brandt U, Draganovici D, Fischereder M, Kretzler M, Anders HJ, Sitter T, Mosberger I, Kerjaschki D, Regele H, Schlondorff D, Segerer S.

Am J Pathol. 2007 170 (2): 457-68.

23. Mast cell, a promising therapeutic target in tubulointerstitial fibrosis.

Li Y, Liu FX, Peng YM, Li J, Chen J.

Med Hypotheses. 2007 Jan 24; [Epub ahead of print].

24. Smooth muscle alpha-actin deficiency in myofibroblasts leads to enhanced renal tissue fibrosis.

Takeji M, Moriyama T, Oseto S, Kawada N, Hori M, Imai E, Miwa T.

J Biol Chem. 2006 281 (52): 40193-200.

25. A comparison of pathomolecular markers of fibrosis and morphology in kidney from autopsies of African Americans and whites.

Pat B, Hughson MD, Nicol JL, Hoy WE, Gobe GC.

Virchows Arch. 2006 Nov 23; [Epub ahead of print].

26. Oxidants in chronic kidney disease.

Shah SV, Baliga R, Rajapurkar M, Fonseca VA.

J Am Soc Nephrol. 2007 18 (1): 16-28.

27. Red blood cell and plasma glutathione peroxidase activities and selenium concentration in patients with chronic kidney disease: A review.

Zachara BA, Gromadzinksa J, Wasowicz W, Zbrog Z.

Acta Biochim Pol. 2006 Dec 11; [Epub ahead of print].

28. Angiotensin II-induced genomic damage in renal cells can be prevented by angiotensin II type 1 receptor blockade or radical scavenging.

Schupp N, Schmid U, Rutkowski P, Lakner U, Kanase N, Heidland A, Stopper H.

Am J Physiol Renal Physiol. 2007 Jan 16; [Epub ahead of print].

29. Associations between the CYBA 242C/T and the MPO -463/A polymorphisms, oxidative stress and cardiovascular disease in chronic kidney disease patients.

Grahl DA, Axelsson J, Nordfors L, Heimburger O, Barany P, Qureshi AR, Kato S, Watanabe M, Suliman M, Riella MC, Lindholm B, Stenvinkel P, Pecoits-Filho R.

Blood Purif. 2007 25 (2): 210-8.

30. Is inflammation the link between atherosclerosis and vascular calcification in chronic kidney disease?

Tsirpanlis G.

Blood Purif. 2007 25 (2): 179-82.

31. Vascular calcifications: Pathogenesis, management, and impact on clinical outcomes.

Cannata-Andia JB, Rodriguez-Garcia M, Carrillo-Lopez N, Naves-Diaz M, Diaz-Lopez B.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S267-73.

32. Vitamin D and vascular calcification.

Zittermann A, Schleithoff SS, Koerfer R.

Curr Opin Lipidol. 2007 18 (1): 41-6.

33. Expression of nestin in the podocytes of normal and diseased human kidneys.

Su W, Chen J, Yang H, You L, Xu L, Wang X, Li R, Gao L, Lin S, Xu H, Breyer MD, Hao CM.

Am J Physiol Regul Integr Comp Physiol. 2007 Jan 25; [Epub ahead of print].

34. Mechanisms of renal damage in plasma cell dyscrasias: An overview.

Merlini G, Pozzi C.

Contrib Nephrol. 2007 (153): 66-86.

35. Paraproteinemic renal diseases that involve the tubulo-interstitium.

Herrera GA, Sanders PW.

Contrib Nephrol. 2007 (153): 105-15.

36. The not so ’mighty chondrion’: Emergence of renal disease due to mitochondrial dysfunction.

Hall AM, Unwin RJ.

Nephron Physiol. 2007 105 (1): p1-10.

37. Cachexia in chronic kidney disease: Role of inflammation and neuropeptide signaling.

Mak RH, Cheung W.

Curr Opin Nephrol Hypertens. 2007 16 (1): 27-31.

38. Pathology and immunology of lupus glomerulonephritis: Can we bridge the two?

Liapis H, Tsokos GC.

Int Urol Nephrol. 2007 Jan 12; [Epub ahead of print].

39. Pathogenic role of anti-C1q autoantibodies in the development of lupus nephritis--a hypothesis.

Flierman R, Daha MR.

Mol Immunol. 2007 44 (1-3): 133-8.

40. Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis.

Matsuura K, Uesugi N, Hijiya N, Uchida T, Moriyama M.

Hum Pathol. 2007 Jan 18; [Epub ahead of print].

41. Does renal function influence plasma levels of advanced glycation and oxidation protein products in patients with chronic rheumatic diseases complicated by secondary amyloidosis?

Rysava R, Kalousova M, Zima T, Dostal C, Merta M, Tesar V.

Kidney Blood Press Res. 2006 30 (1): 1-7.

42. Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.

Kallenberg CG.

Curr Opin Rheumatol. 2007 19 (1): 17-24.

43. Antineutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis.

Chen M, Yu F, Wang SX, Zou WZ, Zhao MH, Wang HY.

J Am Soc Nephrol. 2007 18 (2): 599-605.

44. Churg-Strauss syndrome.

Pagnoux C, Guilpain P, Guillevin L.

Curr Opin Rheumatol. 2007 19 (1): 25-32.

45. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet.

Rodriguez-Iturbe B, Batsford S.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

46. Significance of glomerular cell apoptosis in the resolution of acute post-streptococcal glomerulonephritis.

Oda T, Yoshizawa N, Yamakami K Ishida A, Hotta O, Suzuki S, Miura S.

Nephrol Dial Transplant. 2007 22 (3): 740-8.

47. Is IgA nephropathy induced by abnormalities of CD4 (+) CD25 (+) Treg cells in the tonsils?

Huang H, Peng Y, Liu F, Lei H.

Med Hypotheses. 2007 Feb 24; [Epub ahead of print].

48. Involvement of transglutaminase-2 in pathological changes in renal disease.

Ikee R, Kobayashi S, Hemmi N, Saigusa T, Namikoshi T, Yamada M, Imakiire T, Kikuchi Y, Suzuki S, Miura S.

Nephron Clin Pract. 2007 105 (3): c139-46.

49. Is hypertension a tissue perfusion disorder? Implications for renal and myocardial perfusion.

Mourad JJ, Laville M.

J Hypertens. 2006 24 (Suppl 5): S10-6.

50. Disorders in high-density metabolism with insulin resistance and chronic kidney disease.

Kaysen GA.

J Ren Nutr. 2007 17 (1): 4-8.

51. Adiponectin and chronic kidney disease.

Guebre-Egziabher F, Drai J, Fouque D.

J Ren Nutr. 2007 (1): 9-12.

52. Expression pattern of genes in peripheral blood mononuclear cells in diabetic nephropathy.

Moczulski DK, Fojcik H, Wielgroecki A, Trautsolt W, Gawlik B, Kosiorz-Gorczynska S, Oczko-Wojciechowska M, Wiench M, Strojek K, Zukowska-Szczechowska E, Grzeszczak W.

Diabet Med. 2007 Jan 29; [Epub ahead of print].

53. Common polymorphisms of the PAI1 gene do not play a major role in the development of diabetic nephropathy in type 1 diabetes.

Martin RJ, Savage DA, Patterson CC, Brady HR, Maxwell AP.

Diabet Med. 2007 Jan 29; [Epub ahead of print].

54. Altered chaperone and protein turnover regulators expression in cultured skin fibroblasts from type 1 diabetes mellitus with nephropathy.

Tessari P, Puricelli L, Iori E, Arrigoni G, Vadovato M, James P, Coracina A, Millioni R.

J Proteome Res. 2007 6 (3): 976-86.

55. Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy.

Osawa N, Koya D, Araki SI, Uzu T, Tsunoda T, Kashiwagi A, Nakamura Y, Maeda S.

J Hum Genet. 2006 Dec 2; [Epub ahead of print].

56. Phenotypic transitions and fibrosis in diabetic nephropathy.

Simonson MS.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

57. Dysregulated intracellular signaling impairs CTGF stimulated responses in human mesangial cells exposed to high extracellular glucose.

Furlong FM, Crean J, Thornton L, O’leary R, Murphy M, Martin F.

Am J Physiol Renal Physiol. 2007 Feb 27; [Epub ahead of print].

58. Investigation of the estrogen receptor-{alpha} gene with type 2 diabetes and/or nephropathy in African-American and European-American populations.

Gallagher CJ, Keene KL, Mychaleckyj JC, Langefeld CD, Hirschhorn JN, Henderson BE, Gordon CJ, Freedman BI, Rich SS, Bowden DW, Sale M.

Diabetes. 2007 56 (3): 675-84.

59. Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss.

Baelde HJ, Eikmans M, Lappin DW, Doran PP, Hohenadel D, Brinkkoetter PT, van der Woude FJ, Waldherr R, Rabelink TJ, de Heer E, Bruijn JA.

Kidney Int. 2007 Jan 31; [Epb ahead of print].

60. Norepinephrine transporter gene (NET) polymorphism in patients with type 2 diabetes.

Ksiazek P, Buraczynska K, Buraczynska M.

Kidney Blood Press Res. 2006 29 (6): 338-43.

61. A genome-wide search for linkage to renal function phenotypes in west africans with type 2 diabetes.

Chen G, Adeymo AA, Zhou J, Chen Y, Doumatey A, Lashley K, Huang H, Amoah A, Agyenim-Boateng K, Eghan BA, Okafor G, Acheampong J, Oli J, Fasanmade O, Johnson T, Rotimi C.

Am J Kidney Dis. 2007 49 (3): 394-400.

62. Inflammation and diabetic nephropathy.

Mora C, Navarro JF.

Curr Diab Rep. 2006 6 (6): 463-8.

63. The role of TNF-alpha in diabetic nephropathy: Pathogenic and therapeutic implications.

Navarro JF, Mora-Fernandez C.

Cytokine Growth Factor Rev. 2006 17 (6): 441-50.

64. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications.

Nishikawa T, Araki E.

Antioxid Redox Signal. 2007 Jan 1; [Epub ahead of print].

65. Renal microvascular injury in diabetes: RAGE and redox signaling.

Coughlan MT, Cooper ME, Forbes JM.

Antioxid Redox Signal. 2007 Jan 1; [Epub ahead of print].

66. Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes.

Mostafa AA, Randell EW, Vasdev SC, Gill VD, Han Y, Gadag V, Raouf AA, El Said H.

Mol Cell Biochem. 2007 Feb 21; [Epub ahead of print].

67. Lipids and diabetic nephropathy.

Rosario RF, Prabhakar S.

Curr Diab Rep. 2006 6 (6): 455-62.

68. Identification of the glomerular podocyte as a target for growth hormone action.

Reddy GR, Pushpanathan MJ, Ransom RF, Holzman LB, Brosius FC, Diakonova M, Mathieson P, Saleem MA, List EO, Kopchick JJ, Frank SJ, Menon RK.

Endocrinology. 2007 Feb 1; [Epub ahead of print].

69. Homocysteine induces mesangial apoptosis via activation of p38-mitogen-activated protein kinase.

Shastry S, Ingram AJ, Scholey JW, James LR.

Kidney Int. 2006 Dec 6; [Epub ahead of print].

70. Membrane targeting and secretion of mutant uromodulin in familial juvenile hyperuricemic nephropathy.

Jennings P, Aydin S, Kotanko P, Lechner J, Lhotta K, Williams S, Thakker RV, Pfaller W.

J Am Soc Nephrol. 2007 18 (1): 264-73.

71. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome.

Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP.

Mol Immunol. 2007 44 (1-3): 111-22.

72. Thin basement membrane nephropathy cannot be diagnosed reliably in deparaffinized, formalin-fixed tissue.

Nasr SH, Markowitz GS, Valeri AM, Yu Z, Chen L, D’Agati VD.

Nephrol Dial Transplant. 2007 Feb 3; [Epub ahead of print].

III. CLINICAL PRESENTATION

1. Advances in urinary proteome analysis and biomarker discovery.

Fliser D, Novak J, Thongboonkerd V, Argiles A, Jankowski V, Girolami MA, Jankowski J, Mischak H.

J Am Soc Nephrol. 2007 Feb 28; [Epub ahead of print].

2. Diagnostic potential for urinary proteomics.

Hortin GL, Sviridov D.

Pharmacogenomics. 2007 8 (3): 237-55.

3. Circulating levels of visfatin/pre-B-cell colony-enhancing factor 1 in relation to genotype, GFR, body composition, and survival in patients with CKD.

Axelsson J, Witasp A, Carrero JJ, Qureshi AR, Suliman ME, Heimburger O, Barany P, Lindholm B, Alvestrand A, Schalling M, Nordfors L, Stenvinkel P.

Am J Kidney Dis. 2007 49 (2): 237-44.

4. Kidney function and risk of peripheral arterial disease: Results from the Atherosclerosis Risk in Communities (ARIC) Study.

Wattanakit K, Folsom AR, Selvin E, Coresh J, Hirsch AT, Weatherley BD.

J Am Soc Nephol. 2007 18 (2): 629-36.

5. Spectrum of renal failure in elderly patients.

Kohli S, Bhat A, Aravindan, Sud K, Jha V, Gupta KL, Sakhuja V.

Int Urol Nephrol. 2007 Jan 23; [Epub ahead of print].

6. Derivation and validation of a clinical index for prediction of rapid progression of kidney dysfunction.

Hemmelgarn BR, Culleton BF, Ghali WA.

QJM. 2007 100 (2): 87-92.

7. Effect of organic solvent exposure on chronic kidney disease progression: The GN-PROGRESS Cohort Study.

Jacob S, Hery M, Protois JC, Rossert J, Stengel B.

J Am Soc Nephrol. 2007 18 (1): 274-81.

8. The association of anemia and hypoalbuminemia with accelerated decline in GFR among adolescents with chronic kidney disease.

Furth SL, Cole SR, Fadrowski JJ, Gerson A, Pierce CB, Chandra M, Weiss R, Kaskel F; The Council of Pediatric Nephrology and Urology, New York/New Jersey; The Kidney and Urology Foundation of America.

Pediatr Nephrol. 2006 Nov 21; [Epub ahead of print].

9. Functional impairment of monocyte-derived dendritic cells in patients with severe chronic kidney disease.

Verkade MA, van Druningen CJ, Vaessen LM, Hesselink DA, Weimar W, Betjes MG.

Nephrol Dial Transplant. 2007 22 (1): 128-38.

10. Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD.

Axelsson J, Moller HJ, Witasp A, Qureshi AR, Carrero JJ, Heimburger O, Barany P, Alvestrand A, Lindholm B, Moestrup SK, Stenvinkel P.

Am J Kidney Dis. 2006 48 (6): 916-25.

11. Adiponectin and renal function, and implication as a risk of cardiovascular disease.

Iwashima Y, Horio T, Kumada M, Suzuki Y, Kihara S, Rakugi H, Kawano Y, Funahashi T, Ogihara T.

Am J Cardiol. 2006 98 (12): 1603-8.

12. Insulin resistance, inflammation, and blood pressure determine vascular dysfunction in CKD.

Dogra G, Irish A, Chan D, Watts G.

Am J Kidney Dis. 2006 48 (6): 926-34.

13. Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: Study based on an enzyme-linked assay and immunohistochemical staining.

Endo T, Nakabayashi K, Sekiuchi M, Kuroda T, Soejima A, Yamada A.

Clin Exp Nephrol. 2006 10 (4): 253-61.

14. Oxidized low-density lipoproteins active CD4+ T cell apoptosis in patients with end-stage renal disease through Fas engagement.

Meier P, Spertini F, Blanc E, Burnier M.

J Am Soc Nephrol. 2007 18 (1): 331-42.

15. Tissue factor and its inhibitor in human non-crescentic glomerulonephritis--immunostaining vs plasma and urinary levels.

Naumnik B, Borawski J, Chyczewski L, Pawlak K, Mysliwiec M.

Nephrol Dial Transplant. 2006 21 (12): 3450-7.

16. Chronic kidney disease-mineral-bone disorder: A new paradigm.

Moe SM, Drueke T, Lameire N, Eknoyan G.

Adv Chronic Kidney Dis. 2007 14 (1): 3-12.

17. Bone health in chronic kidney disease-mineral and bone disease.

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Adv Chronic Kidney Dis. 2007 14 (1): 27-36.

18. Mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of K/DOQI target ranges.

Craver L, Marco MP, Martinez I, Rue M, Borras M, Martin ML, Sarro F, Valdivielso JM, Fernandez E.

Nephrol Dial Transplant. 2007 Jan 5; [Epub ahead of print].

19. Interpretation of serologic tests in an HIV-infected patient with kidney disease.

Hernandez GT, Critchfield JM, Rodriguez RA.

Nat Clin Pract Nephrol. 2006 2 (12): 708-12.

20. A history of the kidney in plasma cell disorders.

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Contrib Nephrol. 2007 (153): 5-24.

21. Quality of life in chronic kidney disease: Effects of treatment modality, depression, malnutrition and inflammation.

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Int J Clin Pract. 2007 Jan 29; [Epub ahead of print].

22. Health-related quality of life of predialysis patients with chronic renal failure.

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Nephron Clin Pract. 2007 105 (1): c1-8.

23. Growth impairment shows an age-dependent pattern in boys with chronic kidney disease.

Zivicnjak M, Franke D, Filler G, Haffner D, Froede K, Nissel R, Haase S, Offner G, Ehrich JH, Querfeld U.

Pediatr Nephrol. 2006 Nov 28; [Epub ahead of print].

24. Clinical predictors of neurocognitive deficits in children with chronic kidney disease.

Slickers J, Duquette P, Hooper S, Gipson D.

Pediatr Nephrol. 2006 Dec 16; [Epub ahead of print].

25. Alport syndrome and pregnancy.

Matsuo K, Tudor EL, Baschat AA.

Obstet Gynecol. 2007 109 (2 Pt2): 531-2.

26. Reduced systolic myocardial function in children with chronic renal insufficiency.

Chinali M, de Simone G, Matteucci MC, Picca S, Mastrostefano A, Anarat A, Caliskan S, Jeck N, Neuhaus TJ, Peco-Antic A, Peruzzi L, Testa S, Mehls O, Wuhl E, Schaefer F.

J Am Soc Nephrol. 2007 18 (2): 593-8.

27. Nephrotic syndrome after bevacizumab: Case report and literature review.

George BA, Zhou XJ, Toto R.

Am J Kidney Dis. 2007 49 (2): e23-9.

28. Systemic lupus erythematosus.

D’Cruz DP, Khamashta MA, Hughes GR.

Lancet. 2007 369 (9561): 587-96.

29. Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis.

Matsuura K, Uesugi N, Hijiya N, Uchida T, Moriyama M.

Hum Pathol. 2007 38 (3): 410-9.

30. Severe lupus nephritis: Racial differences in presentation and outcome.

Korbet SM, Schwartz MM, Evans J, Lewis EJ.

J Am Soc Npehrol. 2007 18 (1): 244-54.

31. Acute amphotericin G overdose.

Burke D, Lal R, Finkel KW, Samuels J, Foringer JR.

Ann Pharmacother. 2006 40 (12): 2254-9.

32. Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid syndrome.

Mora CS, Segami MI, Hidalgo JA.

Semin Arthritis Rheum. 2006 36 (3): 135-43.

33. Antigen and epitope specificity of anti-glomerular basement membrane antibodies in patients with Goodpasture disease with or without anti-neutrophil cytoplasmic antibodies.

Yang R, Hellmark T, Zhao J, Cui Z, Segelmark M, Zhao MH, Wang HY.

J Am Soc Nephrol. 2007 Feb 28; [Epub ahead of print].

34. Life-threatening cryoglobulinemia: Clinical and immunological characterization of 29 cases.

Ramos-Casals M, Robles A, Brito-Zeron P, Nardi N, Nicolas JM, Forns X, Plaza J, Yague J, Sanchez-Tapias JM, Font J.

Semin Arthritis Rheum. 2006 36 (3): 189-96.

35. Cytoplasmic antineutrophil cytoplasmic antibody positive pauci-immune glomerulonephritis associated with infectious endocarditis.

Kishimoto N, Mori Y, Yamahara H, Kijima Y, Nose A, Uchiyama-Tanaka Y, Tokoro T, Nagata T, Umeda Y, Takahashi N, Yoshida H, Matsubara H.

Clin Nephrol. 2006 66 (6): 447-54.

36. Thrombopoietin and interleukin-6 levels in Henoch-Schonlein purpura.

Lin CY, Yang YH, Lee CC, Huang CL, Wang LC, Chiang BL.

J Microbiol Immunol Infect. 2006 39 (6): 476-82.

37. Henoch-Schonlein purpura nephritis complicated by reversible posterior leukoencephalopathy syndrome.

Sasayama D, Shimojima Y, Gono T, Kaneko K, Matsuda M, Ikeda SI.

Clin Rheumatol. 2007 Jan 5; [Epub ahead of print].

38. Minimal change nephrotic syndrome in association with strongyloidiasis.

Hsieh YP, Wen YK, Chen ML.

Clin Nephrol. 2006 66 (6): 459-63.

39. Membraneous glomerulonephritis and non-Hodgkin’s lymphoma in a patient with primary Sjogren’s syndrome.

Iwanaga N, Kamachi M, Fujikawa K, Aramaki T, Izumi Y, Arima K, Tamai M, Aratake K, Nakamura H, Origuchi T, Ida H, Kawakami A, Taguchi T, Eguchi K.

Intern Med. 2007 46 (4): 191-4.

40. Membranous nephropathy associated with fluconazole treatment.

Shin GT, Yim H, Park J, Kim H.

Am J Kidney Dis. 2007 49 (2): 318-22.

41. Is paraoxonase 192 gene polymorphism a risk factor for membranoproliferative glomerulonephritis in children?

Bilge I, Sirin A, Agachan B, Emre S, Sadikoglu B, Yilmaz H, Sucu A, Isbir T.

Cell Biochem Funct. 2007 25 (2): 159-165.

42. Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy.

Li GS, Zhang H, Lv JC, Shen Y, Wang HY.

Kidney Int. 2007 71 (5): 448-53.

43. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels.

Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, Huang WQ, Anreddy SR, Hall S, Hastings MC, Lau KK, Cook WJ, Novak J.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

44. Absence of increased a1-microglobulin in IgA nephropathy proteinuria.

Yokota H, Hiramoto M, Okada H, Kanno Y, Yuri M, Morita S, Naitou M, Ichikawa A, Katoh M, Suzuki H.

Mol Cell Proteomics. 2007 Jan 21; [Epub ahead of print].

45. Insulin resistance and the progression of IgA glomerulonephritis.

Kaartinen K, Syrjanen J, Porsti I, Harmoinen A, Pasternack A, Huhtala H, Niemela O, Mustonen J.

Nephrol Dial Transplant. 2007 22 (3): 778-83.

46. Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy.

Myllymaki JM, Honkanen TT, Syrjanen JT, Helin HJ, Rantala IS, Pasternack AI, Mustonen JT.

Kidney Int. 2006 Dec 27; [Epub ahead of print].

47. Long-term efficacy of tonsillectomy in Chinese patients with IgA nephropathy.

Chen Y, Tang Z, Wang Q, Yu Y, Zeng C, Chen H, Liu ZH, Li LS.

Am J Nephrol. 2007 27 (2): 170-5.

48. Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed by immunosuppression for acute lymphocytic leukemia.

Iwata Y, Wada T, Uchiyama A, Miwa A, Nakaya I, Tohyama T, Yamada Y, Kurokawa T, Yoshida T, Ohta S, Yokoyama H, Iida H.

Intern Med. 2006 45 (22): 1291-5.

49. IgA nephropathy associated with Hodgkin’s disease in children: A case report, literature review and urinary proteome analysis.

Khositseth S, Kanitsap N, Warnnissorn N, Thongoboonkerd V.

Pediatr Nephrol. 2006 Dec 2, [Epub ahead of print].

50. Relationship between ankle-brachial index and chronic kidney diseaase in hypertensive patients with no known cardiovascular disease.

Mostaza JM, Suarez C, Manzano L, Cairols M, Garcia-Iglesias F, Sanchez-Alvarez J, Ampuero J, Godoy D, Rodriguez-Samaniego A, Sanchez-Zamorano MA.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S201-5.

51. Role of pulse pressure on cardiovascular risk in chronic kidney disease.

Fernandez-Fresnedo G, Rodrigo E, de Francisco AL, de Castro SS, Castaneda O, Arias M.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S246-9.

52. Insulin induces renal vasodilation, increases plasma renin activity, and senzitizes the renal vasculature to angiotensin receptor blockade in healthy subjects.

Perlstein TS, Gerhard-Herman M, Hollenberg NK, Williams GH, Thomas A.

J Am Soc Nephrol. 2007 18 (3): 944-51.

53. A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.

Mollsten A, Marklund SL, Wessman M, Svensson M, Forsblom C, Parkkonen M, Brismar K, Groop PH, Dahlquist G.

Diabetes. 2007 56 (1): 265-9.

54. Association between haptoglobin gene variants and diabetic nephropathy: Haptoglobin polymorphism in nephropathy susceptibility.

Conway BR, Savage DA, Brady HR, Maxwell AP.

Nephron Exp Nephrol. 2007 105 (3): e75-9.

55. Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy - a natonwide 5-year-study in Japan.

Murase Y, Imagawa A, Hanafusa T, Iwahashi H, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Maruyama T, Makino H.

Diabetologia. 2007 50 (3): 531-7.

56. Maternal history of type 2 diabetes is associated with diabetic nephropathy in type 1 diabetic patients.

Hadjadj S, Duengler F, Torremocha F, Faure-Gerard G, Bridoux F, Boissonnot M, Mauco G, Guilhot J, Marechaud R.

Diabetes Metab. 2007 Jan 25; [Epub ahead of print].

57. Renal and retinal microangiopathy after 15 years of follow-up in a sample of type 1 diabetes mellitus patients.

Romero P, Salvat M, Fernandez J, Baget M, Martinez I.

J Diabetes Complications. 2007 21 (2): 93-100.

58. Kidney function after islet transplant alone in type 1 diabetes: Impact of immunosuppressive therapy on progression of diabetic nephropathy.

Maffi P, Bertuzzi F, De Taddeo F, Magistretti P, Nano R, Fiorina P, Caumo A, Pozzi P, Socci C, Venturini M, Del Maschio A, Secchi A.

Diabetes Care. 2007 Jan 26; [Epub ahead of print].

59. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: ’’Double diabetes’’ in the Diabetes Control and Complications Trial.

Kilpatrick ES, Rigby AS, Atkin SL.

Diabetes Care. 2007 30 (3): 707-12.

60. Pre-eclampsia but not pregnancy-induced hypertension is a risk factor for diabetic nephropathy in type 1 diabetic women.

Gordin D, Hiilesmaa V, Fagerudd J, Ronnback M, Forsblom C, Kaaja R, Teramo K, Groop PH; FinnDiane Study group.

Diabetologia. 2007 50 (3): 516-22.

61. SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes.

Lin HY, Wang CL, Hsiao PJ, Yung-Chuan L, Chen SY, Lin KD, Hsin SC, Hsieh MC, Shin SJ.

Diabetes. 2007 Jan 17; [Epub ahead of print].

62. Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.

Calle R, McCarthy MI, Banerjee P, Zeggini E, Cull CA, Thorne KI, Wiltshire S, Terra S, Meyer D, Richmond J, Mancuso J, Milos P, Fryburg D, Holman RR.

Diabetologia. 2006 49 (12): 2892-9.

63. Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients.

Buraczynska M, Kisazek P, Baranowicz-Gaszczyk I, Jozwiak L.

Nephrol Dial Transplant. 2006 Nov 22; [Epub ahead of print].

64. Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy.

Boger CA, Stubanus M, Haak T, Gotz AK, Christ J, Hoffman U, Riegger GA, Kramer BK.

Nephrol Dial Transplant. 2007 22 (1): 154-62.

65. Proteome analysis of serum from type 2 diabetcs with nephropathy.

Kim HJ, Cho EH, Yoo JH, Kim PK, Shin JS, Kim MR, Kim CW.

J Proteome Res. 2007 6 (2): 735-43.

66. Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: An observational follow-up study.

Araki S, Haneda M, Koya D, Sugimoto T, Isshiki K, Chin-Kanasaki M, Uzu T, Kashiwagi A.

Diabetologia. 2007 Jan 16; [Epub ahead of print].

67. Proteomic identification of urinary biomarkers of diabetic nephropathy.

Rao PV, Lu X, Standley M, Pattee P, Neelima G, Girisesh G, Dakshinamurthy KV, Roberts CT, Nagalla SR.

Diabetes Care. 2007 30 (3): 629-37.

68. Prediction of diabetic nephropathy using urine proteomic profiling 10 years prior to development of nephropathy.

Otu HH, Can H, Spentzos D, Nelson RG, Hanson RL, Looker HC, Knowler WC, Monroy M, Libermann TA, Karumanchi SA, Thadhani R.

Diabetes Care. 2007 30 (3): 638-43.

69. Relationship between total oxidant status and severity of diabetic nephropathy in type 2 diabetic patients.

Aslan M, Sabuncu T, Kocyigit A, Celik H, Selek S.

Nutr Metab Cardiovasc Dis. 2007 Feb 21; [Epub ahead of print].

70. Cortisol secretion in patients with type 2 diabetes: Relationship with chronic complications.

Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, Epaminoda P, Masserini B, Beck-Peccoz P, Orsi E, Ambrosi B, Arosio M.

Diabetes Care. 2007 30 (1): 83-8.

71. Anemia in diabetes: Marker or mediator of microvascular disease?

Thomas MC.

Nat Clin Pract Nephrol. 2007 3 (1): 20-30.

72. Diagnosing diabetic nephropathy by (1) H NMR metabonomics of serum.

Makinen VP, Soininen P, Forsblom C, Parkkonen M, Ingman P, Kaski K, Groop PH, Ala-Korpela M; On behalf of the FinnDiane Study Group.

MAGMA. 2006 Dec 15; [Epub ahead of print].

73. The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: Results from Metascreen, a multicenter diabetes clinic-based survey.

[No authors listed].

Diabetes Care. 2006 29 (12): 2701-7.

74. The new KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and CKD.

Nelson RG, Tuttle KR.

Blood Purif. 2007 25 (1): 112-4.

75. Inverse association between lipid levels and mortality in men with chronic kidney disease who are not yet on dialysis: Effects of case mix and the malnutrition-inflammation-cachexia syndrome.

Kovesdy CP, Anderson JE, Kalantar-Zadeh K.

J Am Soc Nephrol. 2007 18 (1): 304-11.

76. The outcome of heart transplant recipients following the development of end-stage renal disease: Analysis of the Canadian Organ Replacement Register (CORR).

Alam A, Badovinac K, Ivis F, Trpeski L, Cantarovich M.

Am J Transplant. 2007 7 (2): 461-5.

77. Poor prognosis of heart transplant patients with end-stage renal failure.

Villar E, Boissonnat P, Sebbag L, Hendawy A, Cahen R, Trolliet P, Labeeuw M, Ecochard R, Pouteil-Noble C.

Nephrol Dial Transplant. 2007 Jan 31; [Epub ahead of print].

78. Determinants of renal function in pediatric heart transplant recipients: Long-term follow-up study.

Sachdeva R, Blaszak RT, Ainley KA, Parker JG, Morrow WR, Frazier EA.

J Heart Lung Transplant. 2007 26 (2): 108-13.

79. The impact of renal function on the long-term clinical course of patients who underwent percutaneous coronary intervention.

Papafaklis MI, Naka KK, Papamichael ND, Kolios G, Sioros L, Sclerou V, Katsouras CS, Michalis LK.

Catheter Cardiovasc Interv. 2007 69 (2): 189-97.

IV. TREATMENT

1. Clinical trials in nephrology: Success or failure.

Garcia-Donaire JA, Segura J, Ruilope LM.

Curr Opin Nephrol Hypertens. 2007 16 (2): 59-63.

2. Transforming growth factor-{beta} in human diabetic nephropathy: Effects of ACE inhibition.

Langham RG, Kelly DJ, Gow RM, Zhang Y, Cordonnier DJ, Pinel N, Zaoui P, Gilbert RE.

Diabetes Care. 2006 29 (12): 2670-5.

3. Dual blockade of the renin-angiotensin system in the progression of renal disease: The need for more clinical trials.

Fernandez-Juarez G, Barrio V, de Vinuesa SG, Goicoechea M, Praga M, Luno J.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S250-4.

4. Prescription of drugs blocking the renin-angiotensin system in Italian children.

Bianchetti MG, Ammenti A, Avolio L, Bettinelli A, Bosio M, Fossali E, La Manna A, Maringhini S, Pela I, Ratsch IM, Vigano S, Ardissino G; Italkid Project; CHILD Project.

Pediatr Nephrol. 2007 22 (1): 144-8.

5. Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment.

Neumann J, Ligtenberg G, Klein IH, Boer P, Oey PL, Koomans HA, Blankestijn PJ.

Hypertension. 2007 Jan 15; [Epub ahead of print].

6. Insulin resistance, inflammatory biomarkers, and adipokines in patients with chronic kidney disease: Effects of angiotensin II blockade.

de Vinuesa SG, Goicoechea M Kanter J, Puerta M, Cachofeiro V, Lahera V, Gomez-Campdera F, Luno J.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S206-12.

7. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy.

Jin HM, Pan Y.

Nephrol Dial Transplant. 2007 Feb 17; [Epub ahead of print].

8. Health economic implications of irbesartan treatment versus standard blood pressure control in patients with type 2 diabetes, hypertension and renal disease: A Hungarian analysis.

Palmer AJ, Valentine WJ, Ray JA, Roze S, Muszbek N.

Eur J Health Econ. 2007 Jan 20; [Epub ahead of print].

9. Irbesartan treatment reduces biomarkers of inflammatory activity in patients with type 2 diabetes and microalbuminuria: An IRMA 2 Substudy.

Persson F, Rossing P, Hovind P, Stehouwer CD, Schalkwijk C, Tarnow L, Parving HH.

Diabetes. 2006 55 (12): 3550-5.

10. Ca2+ channel subtypes and pharmacology in the kidney.

Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T.

Circ Res. 2007 100 (3): 342-53.

11. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy.

Matsumoto S, Takebayashi K, Aso Y.

Metabolism. 2006 55 (12): 1645-52.

12. Beta blockers in the management of chronic kidney disease.

Bakris GL, Hart P, Ritz E.

Kidney Int. 2006 70 (11): 1905-13.

13. Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease.

Goicoechea M, de Vinuesa SG, Lahera V, Cachofeiro V, Gomez-Campdera F, Vega A, Abad S, Luno J.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S231-5.

14. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: A subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study.

Athyros VG, Mikhailidis DP, Liberopoulos EN, Kakafika AI, Karagiannis A, Papageorgiou AA, Tziomalos K, Ganotakis ES, Elisaf M.

Nephrol Dial Transplant. 2007 22 (1): 118-27.

15. Lipid metabolism in chronic kidney disease: The role of statin in cardiovascular risk.

Wanner C, Drechsler C, Krane V.

J Ren Nutr. 2007 17 (1): 75-8.

16. Lipid changes and statins in chronic renal insufficiency.

Ritz E, Wanner C.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S226-30.

17. Statin therapy in renal disease: Harmful or protective.

Rocher L.

Curr Atheroscler Rep. 2007 9 (1): 18-24.

18. Rosiglitazone prevents advanced glycation endproducts-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1.

Yu X, Li C, Li X, Cai L.

Toxicol Sci. 2007 Jan 29; [Epub ahead of print].

19. An open-label study of darbopoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis.

Agarwal AK, Silver MR, Reed JE, Dhingra RK, Liu W, Varma N, Stehman-Breen C.

J Intern Med. 2006 260 (6): 577-85.

20. Nutritional and inflammatory status influence darbopoetin dose in pre-dialysis elderly patients.

Neves PL, Morgado E, Faisca M, Carrasqueira H, Baptista A, Silva AP.

Int Urol Nephrol. 2006 Dec 7; [Epub ahead of print].

21. Stabilization of glomerular filtration rate in advanced chronic kidney disease: A two-year follow-up of a cohort of chronic kidney disease patients stages 4 and 5.

Serrano A, Huang J, Ghossein C, Nishi L, Gangavathi A, Madhan V, Ramadugu P, Ahya SN, Paparello J, Khosla N, Schlueter W, Batlle D.

Adv Chronic Kidney Dis. 2007 14 (1): 105-12.

22. New approaches to the management of anemia of chronic kidney disease: Beyond Epogen and Infed.

Rastogi A, Nissenson AR.

Kidney Int Suppl. 2006 (104): S14-6.

23. Iron therapy for renal anemia: How much needed, how much harmful?

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Pediatr Nephrol. 2007 Jan 6; [Epub ahead of print].

24. Oxidative stress in uremia: The role of anemia correction.

Lahera V, Goicoechea M, de Vinuesa SG, Oubina P, Cachofeiro V, Gomez-Campdera F, Amann R, Luno J.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S174-7.

25. Target level for hemoglobin correction in patients with diabetes and CKD: Primary results of the Anemia Correction in Diabetes (ACORD) Study.

Ritz E, Laville M, Bilous RW, O’Donoghue D, Scherhag A, Burger U, de Alvaro F; Anemia Correction in Diabetes Investigators.

Am J Kidney Dis. 2007 49 (2): 194-207.

26. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: A meta-analysis.

Phrommintikul A, Haas SJ, Elsik M, Krum H.

Lancet. 2007 369 (9559): 381-8.

27. Thetrapeutic potential of TGF-beta inhibition in chronic renal failure.

Gagliardini E, Benigni A.

Expert Opin Biol Ther. 2007 7 (3): 293-304.

28. CD36 is a novel and potential anti-fibrogenic target in albumin-induced renal proximal tubule fibrosis.

Yang YL, Lin SH, Chuang LY, Guh JY, Liao TN, Lee TC, Chang WT, Chang FR, Hung MY, Chiang TA, Hung CY.

J Cell Biochem. 2007 Jan 16; [Epub ahead of print].

29. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis.

Tan X, Li Y, Liu Y.

J Steroid Biochem Mol Biol. 2007 Jan 4; [Epub ahead of print].

30. Arteriosclerosis and vascular calcification in chronic kidney disease (CKD) patients.

Masho Y, Shigematsu T.

Clin Calcium. 2007 17 (3): 354-9.

31. Drug insight: Vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease.

Brown AJ, Slatopolsky E.

Nat Clin Pract Endocrinol Metab. 2007 3 (2): 134-44.

32. Management of chronic kidney disease mineral-bone disorder.

Fadem SZ, Moe SM.

Adv Chronic Kidney Dis. 2007 14 (1): 44-53.

33. Metabolic bone disease in chronic kidney disease.

Martin KJ, Gonzalez EA.

J Am Soc Nephrol. 2007 18 (3): 875-85.

34. A new era in phosphate binder therapy: What are the options?

Salusky IB.

Kidney Int Suppl. 2006 (105): S10-5.

35. The relationship between Sevelamer HCl and vascular calcification.

Uemura K, Kakuta T, Saito A.

Clin Calcium. 2007 17 (3): 392-8.

36. Pleiotropic effects of the non-calcium phosphate binder sevelamer.

Nikolov IG, Joki N, Maizel J, Lacour B, Drueke TB, Massy ZA.

Kidney Int Suppl. 2006 (105): S16-23.

37. Risedronate, an effective treatment for glucocorticoid-induced bone loss in CKD patients with or without concomitant active vitamin D (PRIUS-CKD).

Fujii N, Hamano T, Mikami S, Nagasawa Y, Isaka Y, Moriyama T, Horio M, Imai E, Hori M, Ito T.

Nephrol Dial Transplant. 2006 Nov 23; [Epub ahead of print].

38. Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function.

Shoji T, Wada A, Inoue K, Hayashi D, Tomida K, Furumatsu Y, Kaneko T, Okada N, Fukuhara Y, Imai E, Tsubakihara Y.

Nephron Clin Pract. 2006 105 (3): c99-107.

39. Effect of dietary protein restriction on the progression of kidney disease: Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study.

Levey AS, Greene T, Sarnak MJ, Wang X, Beck GJ, Kusek JW, Collins AJ, Kopple JD.

Am J Kidney Dis. 2006 48 (6): 879-88.

40. Pharmacological therapy for Wegener’s granulomatosis.

White ES, Lynch JP.

Drugs. 2006 66 (9): 1209-28.

41. Fifteen-year remission of a steroid-resistant nephrotic syndrome sustained by cyclosporine A.

Drube J, Geerlings C, Taylor R, Mengel M, Ehrich JH.

Pediatr Nephrol. 2007 Jan 18; [Epub ahead of print].

42. Efficacy and safety of ’rescue therapy’ with mycophenolate mofetil in resistant primary glomerulonephritis - - A multicenter study.

Segarra A, Amoedo ML, Garcia JM, Pons S, Praga M, Garcia EI, Alonso JC, Gasco JM, Pou L, Piera L.

Nephrol Dial Transplant. 2007 Feb 20; [Epub ahead of print].

43. High-dose therapy in patients with plasma cell dyscrasias and renal dysfunction.

Pineda-Roman M, Tricot G.

Contrib Nephrol. 2007 (153): 182-94.

44. Current and emerging views and treatments of systemic immunoglobulin light-chain (AL) amyloidosis.

Comenzo RL.

Contrib Nephrol. 2007 (153): 195-210.

45. Successful treatment of hepatitis B-associated leukocytoclastic vasculitis with lamivudine treatment in a child patients.

Surmali Onay O, Baskin E, Ozcay F, Melek E, Canan O, Bilezikci B.

Rheumatol Int. 2007 Jan 25; [Epub ahead of print].

46. Meta-analysis of antiplatelet therapy for IgA nephropathy.

Taji Y, Kuwahara T, Shikata S, Morimoto T.

Clin Exp Nephrol. 2006 10 (4): 268-73.

47. Agalsidase-beta therapy for advanced Fabry disease: A randomized trial.

Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ; Fabry Disease Clinical Trial Study Group.

Ann Intern Med. 2007 146 (2): 77-86.

48. Gene therapy targeting kidney disease: Routes and vehicles.

Isaka Y.

Clin Exp Nephrol. 2006 10 (4): 229-35.

49. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL). A randomized comparison of 3 preventive strategies.

Briguori C, Airoldi F, D’Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A.

Circulation. 2007 Feb 19; [Epub ahead of print].

50. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: A meta-analysis of randomized clinical trials.

Landoni G, Biondi-Zoccai GG, Tumlin JA, Bove T, De Luca M, Calabro MG, Ranucci M, Zangrillo A.

Am J Kidney Dis. 2007 49 (1): 56-68.

51. N-acetylcysteine and sodium bicarbonate versus –acetlylcysteine and standard hydration for the prevention of radiocontrast-induced nephropathy following coronary angiography.

Schmidt P, Pang D, Nykamp D, Knowlton G, Jia H.

Ann Pharmacother. 2006 Dec 26; [Epub ahead of print].

V. TRANSPLANTATION

1. Lymphatic neoangiogenesis in human renal allografts: Results from sequential protocol biopsies.

Stuht S, Gwinner W, Franz I, Schwarz A, Jonigk D, Kreipe H, Kerjaschki D, Haller H, Mengel M.

Am J Transplant. 2007 7 (2): 377-84.

2. Heightened expression of the cytotoxicity receptor NKG2D correlates with acute and chronic nephropathy after kidney transplantation.

Seiler M, Brabcova I, Viklicky O, Hribova P, Rosenberger C, Pratschke J, Lodererova A, Matz M, Schonemann C, Reinke P, Volk HD, Kotsch K.

Am J Transplant. 2007 7 (2): 423-33.

3. Role of dendritic cell synthesis of complement in the allospecific T cell response.

Zhou W, Peng Q, Li K, Sacks SH.

Mol Immunol. 2007 44 (1-3): 57-63.

4. Expression of the chemokine receptor CCR1 in human renal allografts.

Mayer V, Hudkins KL, Heller F, Schmid H, Kretzler M, Brandt U, Anders HJ, Regele H, Nelson PJ, Alpers CE, Schlondorff D, Segerer S.

Nephrol Dial Transplant. 2007 Feb 13; [Epub ahead of print].

5. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome.

Worthington JE, McEwen A, McWilliam LJ, Picton ML, Martin S.

Transplantation. 2007 83 (4): 398-403.

6. Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation.

Brandacher G, Cakar F, Winkler C, Schneeberger S, Obrist P, Bosmuller C, Werner-Felmayer G, Werner ER, Bonatti H, Margreiter R, Fuchs D.

Kidney Int. 2007 71 (1): 60-7.

7. Pretransplant soluble CD30 level has limited effect on acute rejection, but affects graft function in living donor kidney transplantation.

Kim MS, Kim HJ, Kim SI, Ahn HJ, Ju MK, Kim HJ, Jeon KO, Kim YS.

Transplantation. 2006 82 (12): 1602-5.

8. Inflammation and endothelial activation are linked to renal function in long-term kidney transplantation.

Cottone S, Palermo A, Vaccaro F, Mule G, Guarneri M, Arsena R, Vadala A, Cerasola G.

Transpl Int. 2007 20 (1): 82-7.

9. Endothelial dysfunction and fetuin A levels before and after kidney transplantation.

Caglar K, Yilmaz MI, Saglam M, Cakir E, Kilic S, Eyileten T, Sonmez A, Oguz Y, Oner K, Ors F, Vural A, Yenicesu M.

Transplantation. 2007 83 (4): 392-7.

10. Renal tubular acidosis after kidney transplantation--incidence, risk factors and clinical implications.

Keven K, Ozturk R, Sengul S, Kutlay S, Ergun I, Erturk S, Erbay B.

Nephrol Dial Transplant. 2007 Jan 8, [Epub ahead of print].

11. Comparison of early renal function parameters for the prediction og 5-year graft survival after kidney transplantation.

Schnuelle P, Gottmann U, Koppel H, Brinkkoetter PT, Krzossok S, Weiss J, Schmitt W, Yard BA, Schwarzbach MH, Post S, van der Woude FJ, Birck R.

Nephrol Dial Transplant. 2007 22 (1): 235-45.

12. Urine cytology screening for polyoma virus infection following renal transplantation: The Oxford experience.

Thamboo TP, Jeffery KJ, Friend PJ, Turner GD, Roberts IS.

J Clin Pathol. 2006 Dec 8; fEpub ahead of print].

13. The older living kidney donor: Part of the solution to the organ shortage.

Gill JS, Gill J, Rose C, Zalunardo N, Landsberg D.

Transplantation. 2006 82 (12): 1662-6.

14. Successful transplantation of kidneys from deceased donors with acute renal failure: Three-year results.

Anil Kumar MS, Khan SM, Jaglan S, Heifets M, Moritz MJ, Saeed MI, Fyfe B, Sustento-Reodica N, Kumar A.

Transplantation. 2006 82 (12): 1640-5.

15. Transplant tourism: Outcomes of United States residents who undergo kidney transplantation overseas.

Canales MT, Kasiske BL, Rosenberg ME.

Transplantation. 2006 82 (12): 1658-61.

16. Surgically relevant normal and variant renal parenchymal and vascular anatomy in preoperative 16-MDCT evaluation of potential laparoscopic renal donors.

Raman SS, Pojchamarnwiputh S, Muangsomboon K, Schulam PG, Gritsch HA, Lu DS.

AJR Am J Roentgenol. 2007 188 (1): 105-14.

17. Stable T-cell reactivity after successful tapering of azathioprine in HLA-identical living-related kidney transplant recipients despite minor histocompatibility antigen mismatches.

Gerrits JH, van de Wetering J, Postma S, Drabbels JJ, Vaessen LM, Ijzermans JN, Rischen J, Claas FH, Weimar W, van Besouw NM.

Nephrol Dial Transplant. 2006 Dec 1; [Epub ahead of print].

18. Living related kidney transplantation without calcineurin inhibitors: Initial experience in a Mexican center.

Martinez-Mier G, Mendez-Lopez MT, Budar-Fernandez LF, Estrada-Oros J, Franco-Abaroa R, George-Micelli E, Rios-Martinez L, Mendez-Machado GF.

Transplantation. 2006 82 (11): 1533-6.

19. Calcineurin inhibitor-free protocols: Risks and benefits.

Barbari AG, Stephan AG, Masri MA.

Saudi J Kidney Dis Transpl. 2007 18 (1): 1-23.

20. Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy?

Courtney AE, McNamee PT, Nelson WE, Maxwell AP.

Nephrol Dial Transplant. 2006 21 (12): 3550-4.

21. Chronic allograft nephropathy in paediatric renal transplantation.

Alexander SI, Fletcher JT, Nankivell B.

Pediatr Nephrol. 2007 22 (1): 17-23.

22. Establishing the molecular pathways involved in chronic allograft nephropathy for testing new noninvasive diagnostic markers.

Mas V, Maluf D, Archer K, Yanek K, Mas L, King A, Gibney E, Massey D, Cotterell A, Fisher R, Posner N.

Transplantation. 2007 83 (4): 448-57.

23. Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab.

Hristea D, Hadaya K, Marangon N, Buhler L, Villard J, Morel P, Martin PY.

Transpl Int. 2007 20 (1): 102-5.

24. Anti-CD20 monoclonal antibody (rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patient.

Gallon L, Chhabra D.

Am J Transplant. 2006 6 (12): 3017-21.

25. Antivirals for the treatment of polyomavirus BK replication.

Rinaldo CH, Hirsch HH.

Expert Rev Anti Infect Ther. 2007 5 (1): 105-15.

26. Inhibitory effect of gamma interferon on BK virus gene expression and replication.

Abend JR, Low JA, Imperiale MJ.

J Virol. 2007 81 (1): 272-9.

27. Cell mediated immunity (CMI) and post transplant viral infections--role of a functional immune assay to titrate immunosuppression.

Gautam A, Fischer SA, Yango AF, Gohh RY, Morrissey PE, Monaco AP.

Int Immunopharmacol. 2006 6 (13-14): 2023-6.

28. Risk factors for development of new-onset diabetes mellitus after kidney transplantation.

Shah T, Kasravi A, Huang E, Hayashi R, Young B, Cho YW, Bunnapradist S.

Transplantation. 2006 82 (12): 1673-6.

29. Cancer incidence before and after kidney transplantation.

Vajdic CM, McDonald SP, McCredie MRE, van Leewuen MT, Stewart JH, Law M, Chapman JR, Webster AC, Kaldor JM, Grulich AE.

JAMA. 2006 (296): 2823-31.

30. KSHV after an organtransplant: Should we screen?

Marcelin AG, Calvez V, Dussaix E.

Curr Top Microbiol Immunol. 2007 (312): 245-62.

.

C O N T E N T S

Part Two

SECTIONS

I. EPIDEMIOLOGY

II. ETIOPATHOGENESIS

III. CLINICAL PRESENTATION

IV. TREATMENT

V. TRANSPLANTATION

SUMMARY OF PUBLICATIONS

.

Part Two

I. EPIDEMIOLOGY

1. Association of the C825T polymorphism of the G-protein beta3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese.

Hayakawa T, Takamura T, Abe T et al.

Metabolism. 2007 56 (1): 44-8.

A C825T polymorphism of the gene encoding the G-protein beta3 subunit (GNB3) is associated with increased intracellular signal transduction. We known that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influence lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies.

2. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans.

Freedman BI, Hicks PJ, Sale MM et al.

Nephrol Dial Transplant. 2007 Jan 5; [Epub ahead of print].

Background Four linkage analyses have identified a region on chromosome 18q22-23 that appears to harbour a diabetic nephropathy (DN) susceptibility locus. A trinucleotide repeat sequence in exon 2 of the carnosinase gene (CNDP1) residing on 18q22.3 was subsequently associated with DN in European Caucasians and Arabs. Methods We evaluated the role of the CNDP1 5 leucine/5 leucine (5-5) polymorphism (CNDP1) Mannheim) in diabetic end-stage renal disease (ESRD) susceptibility in 858 European Americans: 294 with type 2 DN-associated ESRD (DN-ESRD), 258 with diabetes lacking nephropathy and 306 healthy controls. Results Subject with DM lacking nephropathy were significantly more likely to be homozygous for the 5-leucine repeat CNDP1 genotype (5-5), compared with those with DN-ESRD (P = 0.02). Healthy controls were also more likely to be homozygous for the 5-5 genotype, compared with those with DN-ESRD (P = 0.008). No significant difference in 5-5 genotype frequency was observed between healthy controls and DM cases without nephropathy (P = 0.74). Conclusion European Americans homozygous for the 5-5 leucine repeat polymorphism in the CNDP1 gene are at significantly reduced risk for developing diabetic ESRD. This replicates the CNDP1 gene association with DN that initially detected in European Caucasians and in Arabs, and further demonstrates that CNDP1 gene and carnosine pathway appear to play a role in susceptibility to DN.

3. Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy.

Ma J, Mollsten A, Falhammar H et al.

J Diabetes Complications. 2007 21 (1): 28-33.

Objective Adiponectin [adipocyte C1q and collagen domain containing (ACDC)] is the most abundant adipose-specific protein. It is beneficial in that it improves insulin sensitivity and mitigates vascular damage, in additon to the possibility of it having anti-inflammatory properties. Clinical evidence demonstrate that serum adiponectin concentration are increased in patients with type 1 diabetes (T1D) as well as in patients with microvascular complications. However, the genetic influence of the ACDC gene in T1D and diabetic microvascular complications is still unclear. The present study ro evaluate the association of the ACDC genetic variation in T1D and diabetic nephropathy (DN). Material and Methods Ten single nucleotide polymorphisms (SNPs) of the ACDC gene were genotyped in 432 T1D patients (of which, 196 had DN) and 187 nondiabetic control subjects, who were all Swedish Caucasians, by using dynamic allele specific hybridization. Results Single-marker association analysis demonstrated that SNPs +45G15G (T/G) were strongly associated with T1D [P = 0.002, OR = 1.855 (1.266-2.717) and P = 0.001, OR = 1.694 (1.337-2.147) ]. Further analysis for haplotypes of these two SNPs indicated that one of the common haplotype (T_G) was strongly associated with T1D [P < 0.001, OR = 1.769 (1.430-2.188)]. However, there was no significant difference in the allele frequencies of these two SNPs between the groups of T1D patients with nephropathy and the patients without nephropathy. Conclusions The present study thus suggest that SNPs +45G15G (T/G) in the ACDC gene are associated with T1D but not with DN among Swedish Caucasians.

4. Association of adiponectin and resistin with cardiovascular events in Korean patients with type 2 diabetes: The Korean atherosclerosis study (KAS). A 42-month prospective study.

Lim S, Koo BK, Cho SW et al.

Atherosclerosis. 2006 Dec 16; [Epub ahead of print].

Adiponectin and resistin are proteins that effect insulin resistance and atherosclerosis significantly. We investigated adiponectin and resistin concentrations as predictors of cardiovascular events in Korean patients with type 2 diabetes. The study in 2001 comprised 343 unrelated patients with type 2 diabetes (65 +/- 9.2 years old). They followed up for 42 months. The baseline duration of diabetes, smoking status and history of cardiovascular diseases (CVD) were recorded. BMI, blood pressures, HbA1c, lipid profiles, ECG, creatinine and urine microalbuminuria were measured. Adiponectin and resistin were measured using enzyme-linked immunosorbent assays. The primary endpoint was defined as one of cardiovascular death, myocardial infarct, CABG, stroke, unstable angina or overt nephropathy. Thirty-eight patients (11.1%) experienced primary endpoint during the folow-up. After adjustment for age, sex, BMI, blood pressure and lipid status, participants in the lowest quartile of adiponectin levels compared with the highest had significantly increased risk of primary endpoint (relative risk = 3.03; 95% CI 1.09-8.41; P = 0.034). In contrast, resistin level had no influence on the risk of primary endpoint. A low level of adiponectin, not resistin, was a significant risk factor for the development of cardiovascular events in these Korean patients with type 2 diabetes.

5. Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy.

Li GS, Zhang H, Lv JC et al.

Kidney Int. 2007 Jan 17; [Epub ahead of print].

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galatosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1, 3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subject were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of –292C/- in IgAN patients were significantly lower than in the controls (P < 0.01). The frequency of haplotype YATIG (Y = C or T) was significantly lower in patients than controls (0.0719 vs 0.1168, P = 2.775 × 10 (-4), odds ratio (OR) = 0.70. The haplotype YAGDA (0.1236 vs 0.0791, P = 3.815 × 10 (-3), OR = 1.77) and YATDG (0.0840 vs 0.0298, P = 1.258 × 10 (-5), OR = 3.03) were significantly higher in patients than controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with genetic susceptibility to IgAN in Chinese population.

6. Characterization of a large Lebanese family segregating IgA nephropathy.

Karnib HH, Sanna-Cherchi S, Zalloua PA et al.

Nephrol Dial Transplant. 2007 Jan 4; [Epub ahead of print].

Background Familial aggregation of IgA nephropathy (IgAN) suggest the genetic factors contribute to the development of this trait. Beacuse clinical manifestations in IgAN families are often limited to episodic hematuria, large kindreds tractable to linkage analysis heve been difficult to identify. Methods We identified a large Lebanese-Druze kindred ascertained via an index case with biopsy-documented IgAN. We performed systematic screening of 38 family members and tested linkage to reported IgAN loci. Results Screening of this family identified 16 affected individuals, including 2 individuals with biopsy-documented IgAN and 14 with chronic renal failure or abnormal urinalyses on at least three separate occasions. This kindred spanned five generations and contained five consanguineous unions. Multigenerational inheritance suggested that autosomal dominant inheritance was most likely. Phenotypic manifestations among affected individuals varied from isolated haematuria to advanced renal failure necessitating transplantation; one instance of IgAN recurence after transplantation was also documented. Older age was associated with greater severity of disease and higher incidence of renal failure. Parametric and non-parametric analyses with 33 microsatellite markers did not reveal any evidence of linkage to reported IgAN loci on chromosomes 6q22-23, 2q36 and 4q22-31. Conclusions We describe on of the largest multigenerational IgAN kindreds reported to date. The high incidence of renal failure among older generations suggest a significant risk of progression to renal failure. We found no evidence of linkage to known loci, suggesting that familial IgAN encompasses multiple subtypes that will require distinction based on genetic or biomarker data.

7. Seroprevalence of hepatitis B and C viruses in patients with chronic kidney disease in the predialysis stage at a University Hospital in Turkey.

Sit D, Kadiroglu AK, Kayabasi H et al.

Intervirology. 2006 50 (2): 133-7.

Background Hepatitis B (HBV) and C (HCV) viruses are the most common viruses that cause viral infections among hemodialysis patients. Objectives To assess the prevalence of HBV and HCV in predialytic chronic kidney disease (CKD) patients. Design A cross-sectional study. Subjects 171 consecutive predialytic patients. Measurements Third-generation micro-ELISA assay was used for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core (anti-HBc) and surface antibody (ant-HBs), secretory form of hepatitis B envelop antigen (HBeAg), antibody to secretory form of hepatitis B envelop antigen (anti-HBe), and ELISA for antibody to hepatitis C virus (anti-HCV). Results The main causes of CKD were 29.8% diabetic nephropathy, 19.9% chronic glomerulonephritis, 16.3% hypertensive nephrosclerosis, 14.0% unknown, 5.3% amyloidosis, 4.7% autosomal-dominat polycystic kidney disease, 4.1% chronic tubulointerstitial nephritis, 3.5% malignancies, 1.7% benign prostatic hypertrophy, 0.6% Alport syndrome. The seroprevalence of hepatitis was: HBsAg 10.5%, anti HBc 36.8%, anti-HBs 28.7%, HBeAg 5.3%, anti-HBe 32.7%, anti-HCV 7% and HBsAg+anti-HCV 0.6%. Conclusions The seroprevalence of HBsAg and Anti-HCV among predialytic CKD patients was similar to our patients in hemodialysis program.

8. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis.

Roccatello D, Fornasieri A, Giachino O et al.

Am J Kidney Dis. 2007 49 (1): 69-82.

Background Mixed cryoglobulinemia is a multisystem disorder associated strongly with hepatitis C virus (HCV) infection. The kidney frequently is involved, and glomerulonephritis represents the key factor affecting prognosis. Methods Clinical, serological, immunogenetic, and morphological data were collected retrospectively from medical records of 146 patients with cryoglobulinemic glomerulonephritis who underwent biopsies in 25 Italian centers and 34 cryoglobulinemic controls without renal involvement. Results Eighty-seven percent of patients were infected with HCV; genotype 1b was more frequent than genotype 2 (55% versus 43%). Diffuse membranoproliferative glomerulonephritis was the most prevalent histological pattern (83%). Type II cryoglobulin (immunoglobulin Mkappa [IgMkappa] / IgG) was detected in 74.4% of cases. The remainder had type III (polyclonal IgM/IgG) cryoglobulins. A multivariate Cox proportional hazard model showed that age, serum creatinine level, and proteinuria at the onset of renal disease were associated independently with risk for developing severe renal failure at follow-up. Overall survival at 10 years was about 80%. Kaplan-Meier survival curves were worsened by a basal creatinine value greater than 1.5 mg/dL (> 133 mumol/L), but were unaffected by sex and HCV infection. Cardiovascular disease was the cause of death in more than 60% of patients. Conclusion Data confirm the close association between mixed cryoglobulinemia and HCV infection and between glomerulonephritis and type II cryoglobulin. Survival profiles are better than previously reported in the literature, probably because of improvement in therapeutic regimens. Causes of death reflect this improvement in survival, with an increased prevalence of cardiovascular events compared with infectious complications and hepatic failure, which were predominant in the past.

9. Malaria-induced renal damage: Facts and myths.

Ehrich JH, Eke FU.

Pediatr Nephrol. 2007 Jan 5; [Epub ahead of print].

Malaria infections repeatedly have been reported to induce nephrotic syndrome and acute renal failure. Question have been raised whether the association of a nephrotic syndrome with quartan malaria was only coincidental, and whether the acute renal failure was a specific or unspecific consequence of Plasmodium falciparum infection. This review attempts to answer question about ’’chronic quartan malaria nephropathy’’ and ’’acute falciparum malaria nephropathy’’. The literature review was performed on all publications on kidney involvement in human and experimental malarial infections accessible in PubMed or available at the library of the London School of Hygiene and Tropical Medicine. The association of a nephrotic syndrome with quartan malaria was mostly descibed before 1975 in children and rarely in adult patients living in areas endemic for Plasmodium malariae. The pooled data on malaria-induced acute renal failure included children and adults acquiring falciparium malaria in endemic areas either as natives or as travellers from non-tropical countries. Non-immunes (not living in endemic areas) had a higher risk of developing acute renal failure than semi-immune (living in endemic areas). Children with cerebral malaria had a higher rate and more severe course of acute renal failure than children with mild malaria. Today, there is no evidence of a dominat role of steroid-resistant and chronic ’’malarial glomerulopathies’’ in children with a nephrotic syndrome in Africa. Acute renal failure was a frequent and serious complication of falciparum malaria in non-immune adults. However, recently it has been reported more often in semi-immune African children with associated morbidity and mortality.

10. Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: A standardized mortality ratio analysis.

Meliker J, Wahl RL, Cameron LL et al.

Environ Health. 2007 Feb 2; [Epub ahead of print].

Abstarct. Background Exposure to arsenic concentrations in drinking water in excess of 300 mug/L is associated with disease of the circulatory and respiratory system, several types of cancer, and diabetes; however, little is known about the health consequences of exposure to low-to-moderate levels of arsenic (10-100 mug/L). Methods A standardized mortality ratio (SMR) analysis was conducted in a contiguous six county study area of southeastern Michigan to investigate the relationship between moderate arsenic levels and twenty-three selected disease outcomes. Disease outcomes included several types of cancer, disease of the circulatory and respiratory system, diabetes mellitus, and kidney and liver disease. Arsenic data were compiled from 9251 well water samples tested by the Michigan Department of Environmental Quality from 1983 through 2002. Michigan Resident Death files data were amassed for 1979 through 1997 and sex-specific SMR analyses were conducted with indirect adjustment for age race; 99% confidence intervals (CI) were reported. Results The six county study area had a population-weighted mean arsenic concentration of 11.00 mug/L and a population-weighted median of 7.58 mug/L. SMR analyses were conducted for the entire six county study area, for only Genesee County (the most populous and urban county), and for the five counties besides Genesee. Concordance of results across analyses is used to interpret the findings. Elevated mortality rates were observed for both males (M) and females (F) for all diseases of the circulatory system (M SMR, 1.11; CI, 1.09-1.13; F SMR, 1.15; CI , 1.13-1.17), cerebrovascular diseases (M SMR, 1.19, CI, 1.14-1.25; F SMR, 1.19; CI, 1.15-1.23), diabetes mellitus (M SMR, 1.28; CI, 1.18-1.37; F SMR, 1.27; CI, 1.19-1.35), and kidney diseases (M SMR, 1.28; CI, 1.15-1.42; F SMR, 1.38; CI, 1.25-1.52). Conclusions This is some of the first evidence to suggest that exposure to low-to-moderate levels of arsenic in drinking water may be associated with several of the leading causes of mortality, although further epidemiologic studies are required to confirm the results suggested by this ecologic SMR analysis.

11. Chronic kidney disease in children: The global perspective.

Warady BA, Chadha V.

Pediatr Nephrol. 2007 Feb 20; [Epub ahead of print].

In contrast to the increasing availability of information pertaining to the care of children with chronic kidney disease (CKD) from large-scale observational and interventional studies, epidemiological information on the incidence and prevalence of pediatric CKD is currently limited, imprecise, and flawed by methodological differences between the various data sources. There are distinct geographic differences in the reported causes of CKD in children, in part due to environmental, racial, genetic, and cultural (consanguinity) differences. However, a substantial percentage of children develop CKD early life, with congenital renal disorders such as obstructive uropathy and aplasia/hypoplasia/dysplasia being responsible for almost one half of all cases. The most favored end-stage renal disease (ESRD) treatment modality in children is renal transplantation, but a lack of health care resources and high patient mortality in the developing world limits the global provision of renal replacement therapy (RRT) and influences patients prevalence. Additional efforts to define the epidemiology of pediatric CKD worlwide are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired.

12. Epidemiological features of CKD in Taiwan.

Kuo HW, Tsai SS, Tiao MM et al.

Am J Kidney Dis. 2007 49 (1): 46-55.

Background The incidence of end-stage renal disease (ESRD) in Taiwan is the highest in the world. However, epidemiological features of earlier chronic kidney disease (CKD) have not been investigated. Methods Since implementation of the National Health Insurance Program in 1995, more than 96% of the population in Taiwan has been enrolled. A nationally representative cohort of 200 000 individuals randomly sampled from the National Health Insurance enrolles was followed up from 1996- to 2003. Clinical conditions were defined by using diagnostic codes. The prevalence and incidence of clinically recognized CKD were assessed. We also identified risk factors associated with the development of CKD. Results The prevalence of clinically recognized CKD increased from 1.99% in 1996 to 9.83% in 2003. The overall incidence rate during 1997 to 2003 was 1.35/100 person-years. The multivariate model indicates that age is a key predictor of CKD, with an odds ratio of 13.95 for the group aged 75-plus years compared with the group younger than 20 years. Other factors associated with increased risk for the development of CKD include diabetes, hypertension, hyperlipidemia, and female sex. Conclusion The prevalence and incidence of CKD in Taiwan are relatively high compared with other countries. Our finding provides a reasonable explanation for the subsequent epidemic of ESRD in Taiwan. Further study is need to identify the entire burden of CKD and the effectiveness of risk-factor modification.

13. Octogenarians and nonagenarians starting dialysis in the United States.

Kurella M, Covinsky KE, Collins AJ et al.

Ann Intern Med. 2007 146 (3): 177-83.

Background The elderly constitute the fastest-growing segment of the end-stage renal disease (ESRD) population, but the epidemiology and outcomes of dialysis among the very elderly, that is, those 80 years of age and older, have not been previously examined at a national level. Objective To describe recent trends in the incidence and outcomes of octogenarians and nonagenarians starting dialysis. Design Observational study. Setting U.S. Renal Data System, a comprehensive, national registry of patients with ESRD. Participants Octogenarians and nonagenarians initiating dialysis between 1996 and 2003. Measurements Rates of dialysis initiation and survival. Results The number of octogenarians and nonagenarians starting dialysis increased from 7054 persons in 1996 to 13 577 persons in 2003, corresponding to an average annual increase in dialysis initiation of 9.8%. After we accounted for population growth, the rate of dialysis initiation increased by 57% (rate ratio, 1.57 [95% CI, 1.53 to 1.62]) between 1996 and 2003. One-year mortality for octogenarians and nonagenarians after dialysis initiation was 46%. Compared with octogenarians and nonagenarians initiating dialysis in 1996, those starting dialysis in 2003 had a higher glomerular filtration rate and less morbidity related to chronic kidney disease but no difference in 1-year survival. Clinical characteristics strongly associated with death were older age, nonambulatory status, and more comorbid conditions. Limitations Survival of patients with incident ESRD who did not begin dialysis could not be assessed. Conclusions The number of octogenarians and nonagenarians initiating dialysis has increased considerably over the past decade, while overall survival for patients on dialysis remains modest. Estimates of prognosis based on patients characteristics, when considered in conjunction with individual values and preferences, may aid in dialysis decision making for the very elderly.

14. Risk factors for chronic kidney disease in a community-based population: A 10-year follow-up study.

Yamagata K, Ishida K, Sairenchi T et al.

Kidney Int. 2006 Nov 22; [Epub ahead of print].

The purpose of this study was to explore risk factors affecting the incidence of chronic kidney disease (CKD) in general population. We conducted a 10-year follow-up study with 123 764 (male: 41 012, female: 82 752) adults aged 40 years and over who received community-based annual examinations. The primary outcome for the analysis was the development of CKD during the follow-up period. Predictors for the development of CKD were obtained by the significant hazard ratios (HR) in Cox regression model by sex. During the follow-up period, 4 307 subjects (male: 2 048, female: 2 259) developed CKD stage II, and 19 411 subjects (male: 4 257, female: 15 154) developed CKD stage III or higher. The baseline-adjusted predictor of developing CKD included age, glomerular filtration rate, hematuria, hypertension, diabetes, serum lipids, obesity, smoking status, and conpsumption of alcohol. Treated diabetes in male subjects, and treated hypertension, systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg, diabetes and treated diabetes in female subjects were associated with more than a doubling of the HR. For the development of CKD stage III or higher, proteinuria of >/= ++, and proteinuria and hematuria were associated with more than a doubling of the HR in male subjects. The prevalence of newly developed CKD over 10 years was 23 718 subjects (19.2%) in adults. This study suggested that not only hypertension and diabetes but also, several metabolic abnormalities were independent risk factors for developing CKD.

15. Kidney disease in life-course socioeconomic context: The Atherosclerosis Risk in Communities (ARIC) Study.

Shoham DA, Vupputuri S, Diez Roux AV et al.

Am J Kidney Dis. 2007 49 (2): 217-26.

Background Persons belonging to the working class or living in an adverse social environment at particular periods of their life course may have an increased risk of chronic kidney disease (CKD). Methods This hypothesis was examined among participants of the Life Course Socioeconomic Status Study, and ancillary study of the Atherosclerosis Risk in Communities Study, conducted in 2001 (mean age, 67.4 years; N = 12 631). CKD was defined by hospital discharge diagnosis and/or estimated glomerular filtration rate less than 45 mL/min/1.73 m (2) (< 0.75 mL/s/1.73 m (2)). Social class was categorized as working class or non-working class at ages 30, 40, or 50 years. Area-level socioeconomic status was based on a composite of census scores during the same period. Adjusted odds ratios were obtained within strata of white and African-American race. Results The adjusted odds ratio of CKD for persons belonging to the working class versus non-working class at age 30 was 1.4 (95% confidence interval, 1.0 to 2.0) in whites and 1.9 (95% confidence interval, 1.1 to 3.0) in African Americans. Working class membership was associated with CKD, even at earlier stages of adult life, and class was associated more strongly with CKD than was education. Working class membership also suggested a stronger association with CKD among African Americans than whites, independent of diabetes and hypertension status. At later periods in the life course, area socioeconomic status was associated with CKD. Conclusion Socioeconomic factors, including area socioeconomic status and social class, are associated with CKD and may account for some of the racial disparity in kidney disease.

16. Confounding effect of comorbidity in survival studies in patients on renal replacement therapy.

van Manen JG, van Dijk PC, Stel VS et al.

Nephrol Dial Transplant. 2007 22 (1): 187-95.

Background After taking other confounding factors into account, the impact of comorbidity on mortality was investigated when comparing mortality between five European countries, dialysis modalities and renal disease groups. Methods The study included 15 571 incident patients on renal replacement therapy (RRT) from five national or regional registries participating in the European Renal Association-European Dialysis and Transplant Association Registry that collect comorbidity data. The presence of diabetes mellitus, ischaemic heart disease, peripheral vascular disease, cerbrovascular disease and malignancy was recorded at start of RRT. Results The comorbidities were each independently associated with mortality, with hazard ratios (HRs) ranging from 1.40 (95% CI: 1.30-1.51) for peripheral vascular disease to 1.65 (95% CI: 1.48-1.83) for diabetes. Age, gender, primary renal disease, modality and country together explained 14.4% of the variance in mortality; the comorbidities explained an additional 1.9%. In the comparison of renal vascular disease with glomerulonephritis, the crude HR of 2.40 (95% CI: 2.12-2.72) changed to 1.24 (95% CI: 1.09-1.41) after adjusment for age, gender, primary renal disease, treatment modality and country and to 1.06 (95% CI: 0.93-1.22) after further adjusment for the comorbidities. For the comparison between countries and other patients group, the change in the survival estimate after adjusment for comorbidity was less. Conclusion Comorbidity is an important predictor for mortality. However, after adjusment for age, gender, primary renal disease, treatment modality and country, when comparing outcomes between patient groups the influence of comorbidity may be less important than expected.

17. Obesity-hypertension: An ongoing pandemic.

Francischetti EA, Genelhu VA.

Int J Clin Pract. 2007 61 (2): 269-80.

Considerable evidence has suggested that excessive weight gain is the most common cause of arterial hypertension. This association has been observed in several populations, in different regions of the world. Obesity-hypertension, a term that underscores the link between these two deleterious conditions, is an important public health challenge, because of its high frequency and concomitant risk of cardiovascular and kidney disease. The obesity-hypertension pandemic imposes a considerable economic burden on societies, directly reflecting on healthcare system costs. Increased renal sodium reabsorption and blood volume expansion are central features in the development of obesity-hypertension. Overweight is also associated with increased sympathetic activity. Leptin, a protein expressed in and secreted by adipocytes, is the main factor linking obesity, increased sympathetic nervous system activity and hypertension. The renin-angiotensin-aldosteron system has also been causally implicated in obesity-hypertension, because angiotensinogen is expressed in and secreted by adipose tissue. Hypoadiponectinemia, high circulating levels of free fatty acids and increased vascular production of endothelin-1 (ET-1) have been reported as potential mechanisms for obesity-hypertension. Lifestyle changes are effective in obesity-hypertension control, though pharmacological treatment is frequently necessary. Despite the consistency of the mechanistic approach in explaining the causal relation between hypertension and obesity, there is yet no evidence that one class of drug is superior to the others in controlling obesity-hypertension. In this review, we present the current knowledge and research in obesity-hypertension, exploring the epidemiologic evidence of the association, its probable pathophysiological mechanisms and treatment issues.

18. Diabetes, kidney disease and anaemia: Time to tackle a troublesome triad?

Al-Khoury S, Afzali B, Shah N et al.

Int J Clin Pract. 2007 61 (2): 281-9.

Both chronic kidney disease (CKD) and type II diabetes mellitus (DM) are increasing in frequency among estern populations and both are potent risk factors for the development of anaemia. The presence of CKD and diabetes together represent the most important aetiopathogenic combination for the development of anaemia. New evidence has highlighted some of the underlying mechanisms which make diabetic patients more susceptible to dyserythropoiesis, particularly once they have developed concomitant CKD. In additon, recent publications from large-scale epidemiological studies have highlighted the impact of anaemia on diabetic patients. The purpose of this review was to focus on the pathophysiology and impact of anaemia in DM.

19. Prevalence and implications of isolated microscopic hematuria in asymptomatic Chinese pregnant women.

Szeto CC, To KF, Lai FM et al.

Nephron Clin Pract. 2007 105 (4): c147-52.

Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. However, the actual prevalence of microscopic hematuria and IgAN is unknown in the Chinese population. Methods We screened 7 828 consecutive pregnant women for microscopic hematuria in the antenatal clinic of a tertiary referral center. Persistent microscopic hematuria was defined as urine Hemastix (R) (Bayer Diagnostics, Hong Kong) of 1+ for red cells in two clinic visits. Subjects were referred to the renal clinic for specialist evaluation, including measurement of blood pressure, serum creatinine, urine bacterial culture, and quantification of proteinuria. Result There were 207 women (2.64%) with microscopic hematuria. Mean age was 31.8 +/- 5.0 years. In 101 patients (48.8%), there was proteinuria > 0.1 g/day by quantitative assay. Hematuria was found resolve before or shortly after delivery in 126 (60.9%) women (32.9%), respectively. Five patients (2.4%9 had urinary tract infection proved by repeated urine culture, 1 had paipllary necrosis, and 1 had duplex collecting system. Three patients were confirmed to have IgAN by renal biopsy; all had normal blood pressure and serum creatinine, but dysmorphic red cells in urine microscopy, and proteinuria of over 0.5 g/day that persisted after delivery. Renal biopsy on another woman showed no specific pathology. Two women were lost to follow-up, both with normal renal function and no detectable proteinuria. The overall prevalence of IgAN was 38 cases per 100 000 population (95% confidence interval: 8-112 cases). Conclusion Microscopic hematuria is not uncommon in pregnant women, and IgAN is present a small proportion of these patients. Further study is needed to determine whether screening for microscopic hematuria would allow early diagnosis and improve the prognosis of these patients.

20. Assessing the prevalence, monitoring and management of chronic kidney disease in patients with diabetes compared with those without diabetes in general practice.

New JP, Middleton RJ, Klebe B et al.

Diabet Med. 2007 Feb 28; [Epub ahead or print].

Abstract/Aims To compare rates of chronic kidney disease (CKD) in patients with diabetes and management of risk factors compared with people without diabetes using general practice computer records, and to assess the utility of serum creatinine and albuminuria as markers of impaired renal function. Methods The simplified Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (eGFR) and stage of CKD. Further data were extracted to assess how effectively impaired renal function was being indentified and how well potentially modifibale risk factors were being managed. The setting was 17 practices in Surrey, Kent and Greater Manchester (2003-2004). Participants were all patients with serum creatinine (SCr) recorded. Results Of the total population of 162 113, 5072 were recorded as having a diagnosis of diabetes, giving a prevalence of 3.1%. Of patients with diabetes, 31% had clinically significant CKD (defined as eGFR < 60 ml/min per 1.73 m (2); CKD stages 3-5) compared with 6.9% of those without diabetes. Only 33% of patients with diabetes at CKD stage 3 had serum creatinine > 120 micromol/l. Of patients with diabetes with eGFR < 60 ml/min per 1.73 m (2), 63% had normoalbuminuria. Considering those with eGFR 30-60 ml/min per 1.73 m (2), 42% of people with diabetes were on an ACE inhibitor compared with 25% of those without diabetes; 32% of patients with diabetes who had any record of micro- or macroalbuminuria at CKD stage 3 were taking an ACE inhibitor. Of people with diabetes and hypertension (BP > 140/80 mmHg), 26% were not prescribed any hypertensive mediaction, regradless of level of CKD. Conclusions CKD is common in people with diabetes living in the community in the UK. The study found a similar rate of stage 3-5 CKD to that found previously in the USA. Currently used measures of renal function fail to identify CKD as effectively as eGRF. Risk factors for CKD and its progression are suboptimally managed.

21. Relationship between inflammatory markers, metabolic and anthropometric variables in the Caribbean type 2 diabetic patients with and without microvascular complications.

Nayak BS, Roberts L.

J Inflamm (Lond). 2006 Dec 22; [Epub ahead of print].

Abstract. Background Serum sialic acid and C reactive protein are the markers for inflammation. The main objective of this study was to determine the sialic acid level in Caribbean type 2 diabetic patients with and without microvascular complications and its relationship with metabolic and anthropometric variables. Design and Methods The Caribbean subjects aged 15-60 years with type 2 diabetes were recruited for the study. Fasting venous blood samples were collected from 162 subjects of which 44 were healthy individuals, 44 were of type 2 diabetes, 44 were of type 2 diabetes with nephropathy and 30 were of diabetes with retinopathy. Simultaneously urine samples were also collected from each of the subjects. All the blood samples were processed for lipid profile, glucose, HbA1c, C-reactive protein and sialic acid. The urine samples were analysed for sialic acid and microalbumin. Results Serum sialic acid concentration were significantly higher among diabetic subjects (66.0 +/- 11.7 mg%) as compared to controls (55.2 +/- 8.3 mg%). There was a significantly increasing trend of serum sialic acid with severity of nephropathy (71.6 +/- 23.6 mg%) and degree of urinary albumin excretion (794.3 +/- 805.9). The diabetic retinopathy patients also demonstrated significantly higher values of serum sialic acid (77.9 +/- 29.0) and urine microalbumin (351.1 +/- 559.9). Elevated serum sialic acid and microalbumin concentration were associated with cardiovascular risk factors such as hypertension, increased waist to hip ratios (P < 0.05). Sialic acid had no correlation with CRP or any component of the lipid profile. Conclusion The increased serum sialic acid and microalbumin were strongly related to the presence of microvascular complications like diabetic nephropathy and diabetic retinopathy and cardiovascular risk factors like hypertension and waist to hip ratios in Caribbean type-2 diabetic patients. The serum sialic acid may be used as an inflammatory marker and possible indicator of microvascular complications in type-2 diabetic patients.

22. Association between the metabolic syndrome and chronic kidney disease in Chinese adults.

Chen J, Gu D, Chen CS et al.

Nephrol Dial Transplant. 2007 Feb 1; [Epub ahead of print].

Background The metabolic syndrome is a common risk for cardiovascular and chronic kidney disease (CKD) in estern populations. We examined the relationship between the metabolic syndrome and risk of CKD in Chinese adults. Methods A cross-sectional survey was conducted in a nationally representative sample of 15 160 Chinese adults aged 35-74 years. The metabolic syndrome was defined as the presence of three or more of the following risk factors: elevated blood pressure, low high density lipoprotein (HDL)-cholesterol, high triglycerides, elevated plasma glucose and abdominal obesity. CKD was defined as an estimation glomerular filtration rate < 60 ml/min/1.73 m (2) and elevated serum creatinine was defined as >/= 0.97 mg/dl in women (>/= 95th percentile of serum creatinine in Chinese men and women aged 35-44 years without hypertension or diabetes, respectively). Results The multivariate-adjusted odds ratios [95% confidence interval (CI)] of CKD and elevated serum creatinine in participants with compared to those without the metabolic syndrome were 1.64 (1.16, 2.32) and 1.36 (1.07, 1.73), respectively. Compared participants without any components of the metabolic syndrome, the multivariate-adjusted odds ratios (95% CI) of CKD were 1.51 (1.02, 2.23), 1.50 (0.97, 2.32), 2.13 (1.3, 3.50) and 2.72 (1.50, 4.93) for those with 1, 2, 3, and 4 or 5 componenets, respectively. The corresponding multivariate-adjusted odds ratios (95% CI) of elevated serum creatinine were 1.11 (0.88, 1.40), 1.39 (1.07, 2.04), 1.47 (1.06, 2.04) and 2.00 (1.31, 3.03), respectively. Conclusions These findings suggest that the metabolic syndrome might be an important risk factor for CKD in Chinese adults.

23. Prevalence of chronic kidney disease and associated risk factors - - United States, 1999-2004.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2007 56 (8): 161-5.

Chronic kidney disease (CKD) is a serious condition associated with premature mortality, decreased quality of life, and increased health-care expenditures. Untreated CKD can result in end-stage renal disease and necessitate dialysis or kidney transplantation. Risk factors for CKD include cardiovascular disease, diabetes, hypertension, and obesity. To estimate the prevalence of CKD in the United States (overall and by risk factors and other characteristics), CDC analyzed the most recent data from the National Health and Nutrition Examination Survey (NHANES). This report summarizes the results of that analysis, which determined that 16.8% of the U.S. population aged >/= 20 years had CKD, according to 1999-2004 NHANES data, compared with 14.5% from the 1988-1994 NHANES (i.e., NHANES III), an increase of 15.9% based on crude estimates prevalence. Persons with diabetes or cardiovascular had a greater prevalence of CKD than persons without those conditions. The results underscore the need to continue surveillance for CKD and its risk factors in the United States and to implement new strategies to reduce the number of persons with this condition.

24. Epidemiology of renal recovery after acute renal failure.

Bagshaw SM.

Curr Opin Crit Care. 2006 12 (6): 544-50.

Purpose of review Recovery of renal function after acute renal failure is an important clinical determinant of patient morbidity. Herein, the epidemiology of renal recovery after acute renal failure will be described, along with potential predictive factors and interventions. Recent findings Renal recovery has been variably defined, most often as recovery to independence from renal replacement therapy. A recent consensus definition for acute renal failure has been published and included provisions for defining renal recovery. Renal recovery to renal replacement therapy independence occurs in the majority by hospital discharge and peaks by 90 days. All of older age, female sex, co-morbid illnesses, especially chronic kidney disease, and late initiation of renal replacement therapy or conventional intermittent renal replacement therapy have been coupled with non-recovery. Analysis of the literature suggest several interventions may influence recovery. Summary The prognosis is generally good for recovery after acute renal failure. Most patients will be independent of renal replacement therapy by 90 days. Additonal research is necessary, however, to understand recovery rates not only to independence from renal replacement therapy, but also to complete and partial recovery. Future studies need to consider the health economic implications for survival and non-recovery. Finally, questions on the role of various interventions require characterization in randomized controlled trials to determine how they may influence renal prognosis.

II. ETIOPATHOGENESIS

1. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease.

Mittal RD, Manchanda PK.

Immunogenetics. 2007 59 (2): 159-65.

Earlier studies suggest that end-stage renal disease (ESRD) is associated with inflammation state and have bacome a major cause of morbidity and mortality worldwide. This study speculated the role of interleukins (IL)-2, -4, and -6 cytokines gene polymorphism with risk of susceptibility to ESRD. Polymorphism in IL-2 (-330 T/G, plymerase chain reaction [PCR]-restriction fragment lenght polymorphism), IL-4 (intron-3, variable number of tandem repeat, variable number tandem repeats analysis), and IL-6 (-174 G/C, amplification refractory mutation system, i.e. ARMS-PCR) were genotyped in 193 ESRD patients and 180 controls. Significant difference was observed in genotype frequencies of IL-4 and IL-6 between ESRD patients and control group (p < 0.001 and p = 0.032, respectively). Patients had higher frequency of homozygous B2B2 genotype (IL-4) than controls (62.7% vs 46.7%) and GG genotype of IL-6 (73.1% vs 60.6%). The genotypic frequencies of IL-2 were comparable in patients and controls (p = 0.102). Significant association of IL-4 was also observed in patients with glomerulonephritis (p = 0.001). Combination of low IL-4 and high IL-6 genotypes were significantly associated with ESRD showing the highest risk, i.e. > threefolds risk (odds ratio = 3.48, 95% CI = 1.88-6.42; p < 0.001) among the four possible combinations taking high IL-4 and low IL-6 as reference. Our study suggest that polymorphism in IL-4 and IL-6 may be associated with susceptibility to ESRD. Further, combined analysis implicated a higher risk in ESRD patients with low IL-4 and high IL-6 producing genotypes. This study provided the basis for defined anti-inflammatory approaches to limit renal disease progression.

2. Interleukin-1 receptor antagonist gene polymorphism affects the progression of chronic renal failure.

Buraczynska M, Ksiazek P, Kubit P et al.

Cytokine. 2007 Jan 13; [Epub ahead of print].

End-stage renal disease (ESRD) involves an inflammatory process. Interleukin-1 receptor antagonist (IL-1Ra) and interleukin-1beta gene polymorphisms affect susceptibility to the disease in several inflammatory diseases. We investigated whether these polymorphisms are involved in ESRD by genotyping DNA from 602 dialyzed patients and 433 controls with polymerase chain reaction and digestion with restriction endonuclease. Allele 2 of the IL-1Ra VNTR polymorphism was associated with ESRD (OR = 1.46, 95% CI 1.19-1.78). We also found a strong association between this allele and recurrent peritonitis in peritoneal dialysis patients. Odds ratio for the risk allele was higher compared to entire ESRD group (OR = 3.6, 95% CI 1.70-7.44). The homozygosity for the allele 2 was associated with disease progression, especially in patients with diabetic nephropathy and glomerulonephritis. For the patients from these two subgroups having 2.2 genotype, the mean time from disease onset to ESRD was 1.5 and 2.2 years, respectively, compared to 6.4 and 9.8 years for those with 1.1 genotype. The IL-1Ra allele 2 is associated with ESRD in our dialyzed patients. Our results demonstrate for the first time the association of the IL-1Ra allele 2 with faster progression to ESRD. If confirmed in other populations, it might be a predictor of faster disease progression.

3. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease.

Moller C, Wei C, Altintas MM et al.

J Am Soc Nephrol. 2007 18 (1): 29-36.

Injury to podocytes and their slit diaphragms typically leads to marked proteinuria. Mutations in the TRPC6 gene codes for a slit diaphragm-associated, cation-permeable ion channel have been shown recently to co-segregate with hereditary forms of progressive kidney failure. Herein is shown that induced expression of wild-type TRPC6 is a common feature of human proteinuric kidney diseases, with highest induction observed in membranous nephropathy. Cultured podocytes that are exposed to complement upregulate TRPC6 protein. Stimulation of receptor-operated channels in puromycin aminonucleoside-treated podocytes leads to increased calcium influx in a time-and dose-dependent manner. Mechanistically, it is shown that TRPC6 is functionally connected to the podocyte actin cytoskeleton, which is rearranged upon overexpression of TRPC6. Transient in vivo gene delivery of TRPC6 into mice leads to expression of TRPC6 protein at the slit diaphragm and causes proteinuria. These studies suggest the involvement of TRPC6 in the pathology of nongenetic forms of proteinuric disease.

4. DEC-205-mediated internalization of HIV-1 results in the establishment of silent infection in renal tubular cells.

Hatsukari I, Singh P, Hitosugi N et al.

J Am Soc Nephrol. 2007 18 (3): 780-7.

HIV-1 infection of renal cells has been proposed to play a role in HIV-1-associated nephropathy. Renal biopsy data further suggest that renal tubular cells may serve as reservoir for HIV-1. The mechanism by which HIV-1 enters these cells has not been identified. Renal tubular cells do not express any of the known HIV-1 receptors, and our results confirmed lack of the expression of CD4, CCR5, CXCR4, DC-SIGN, or mannose receptors in tubular cells. The aim of this study, therefore, was to determine the mechanism that enables viral entry into renal tubular cells. An in vitro model was used to study the HIV-1 infection of human kidney tubular (HK2) cells and to identify the receptor that enables the virus to enter these cells. Results of these studies demonstrate the C-type lectin DEC-205 acts as an HIV-receptor in HK2 cells. Interaction of HIV-1 with DEC-205 results in the internalization of the virus and establishment of a nonproductive infection. HIV-1-specific strong-stop DNA is detected in the infected HK2 cells for at least 7 d, and the virus can be transmitted in trans to sensitive target cells. HIV-1 entry is blocked by pretreatment with specific anti-DEC-205 antibody. Moreover, expression of DEC-205 in cells that lack the DEC-receptors renders them susceptible to HIV-1 infection. These findings suggest that DEC-205 acts as an HIV-1 receptor that mediates internalization of the virus into renal tubular cells, from which the virus can be rescued and disseminated by encountering immune cells.

5. Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway.

He JC, Lu TC, Fleet M et al.

J Am Soc Nephrol. 2007 18 (1): 93-102.

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is intersting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferntiation effects on podocytes, suggesting that RARalpha is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

6. HIV-1 Tat reduces nephrin in human podocytes: A potential mechanism for enhanced glomerular permeability in HIV-associated nephropathy.

Doublier S, Zennaro C, Spatola T et al.

AIDS. 2007 21 (4): 423-32.

Objective To determine whether HIV-1 Tat may directly alter glomerular permeability in HIV-associated nephropathy (HIVAN). Design Heavy proteinuria is a hallmark of HIVAN. The slit diaphragm is the ultimate glomerular filtration barrier critical for maintaining the efficiency of the ultrafiltration unit of the kidney. In this study, we evaluated the direct effect of Tat protein on the permeability of isolated glomeruli on the expression of nephrin, the main slit diaphragm component, by human cultured podocytes. Methods Permeability was studied by measuring the permeability to albumin in isolated rat glomeruli. We also evaluated the expression of nephrin in human cultured podocytes by using immunofluorescence and Western blot. Results We found that Tat increased albumin permeability in isolated glomeruli, and rapidly induced the redistribution and loss of nephrin in cultured podocytes. Pretreatment of glomeruli and podocytes with blocking antibodies showed that Tat reduced nephrin expression by engaging vascular endothelial growth factor receptors type 2 and 3 and the integrin alpha/beta3. Pre-incubation of podocytes with two platelet-activating factor (PAF) receptor antagonists prevented the loss and redistribution of nephrin induced by Tat, suggesting that PAF is an intracellular mediator of Tat action. Tat induced a rapid PAF synthesis by podocytes. When podocytes transfected to overexpress PAF-acetylhydrolase, the main catabolic enzyme of PAF, were stimulated with Tat, the redistribution and loss of nephrin was abrogated. Conclusion The present results define a mechanism by which Tat may reduce nephrin expression in podocytes, thus increasing glomerular pemeability. This provides new insight in the understanding of HIVAN pathogenesis.

7. Eosinophilic glomerulonephritis in children in Southwestern Uganda.

Walker A, Ellis J, Irama M et al.

Kidney Int. 2007 Jan 17; [Epub ahead of print].

Acute renal disease is common in sub-Saharan Africa, with high mortality. Its etiology is poorly understood; quartan malaria owing to Plasmodium malariae was implicated in previous series. Few studies have included histological data; furthermore, much of the literature pre-dates the human immunodeficiency virus (HIV) epidemic. We report prospective analysis of acute proteinuric renal disease in children in rural Uganda. Clinical and laboratory data are presented on 65 patients (aged 2-14 years, mean 8.4; 35 male, 30 female) in 41 of whom histological diagnosis was obtained by renal biopsy. The most frequent histological findings was endocapillary prolifearive glomerulonephritis (GN) in 24/41 cases, in 20 of which eosinophils were very prominent. No cases showed features of HIV nephropathy. Malarial films were positive in 11 cases: all owing to Plasmodium falciparum. Patients were treated with diuretics, antihypertensives, and supportive measures. Corticosteroids were rarely used, being reserved for patients with minimal changes on renal biopsy. Clinical outcomes were fair: 91% of patients survived to discharge. We conclude that acute GN is common in children in Uganda, that an unusual eosinophilic proliferative GN is the most frequent histological finding, that is not HIV implicated as an important factor in this age group, and that good outcomes can be achieved using simple clinical and laboratory diagnostic methods. Renal biopsy in selected cases is feasible and helpful, especially in allowing rational use of corticosteroids and other potentially toxic treatment. Symptomatic treatment and careful supportive care will allow the majority of children to recover.

8. The simple design of complement factor H: Looks can be deceiving.

Alexander JJ, Quigg RJ.

Mol Immunol. 2007 44 (1-3): 123-32.

The complement system is a powerful component of innate immunity which recognizes and facilitates the elimination of pathogens and unwanted host material. Since complement can also lead to host tissue injury and inflammation, strict regulation of its activation is important. One of the key regulators is complement factor H (CFH), a protein with an ever-expanding list of relevant functions. Inherited mutations in CHF can account for membranoproliferative glomerulonephritis (MPGN) type II, atypical hemolytic uremic syndrome, and age-related macular degeneration. The former can be associated with excessive systemic complement activation from dysfunctional CFH, while the latter two are associated with mutations affecting the ability of CHF to bind to anionic surfaces as on endothelial cells and glomerular and retinal capillary walls. Mice with targeted deletion of CHF can spontaneously develop MPGN and have increased susceptibility to models of GN. In the rodent, CHF on platelets functions as the immune adherence receptor, analogous to CR1 on primate erythrocytes. In mice, platelets lacking CFH are unable to effectively clear immune complexes which results in their accumulation in glomeruli. The same switch also appears to be true in the rodent podocyte where CFH is present in place of CR1 in human podocytes. Thus, CFH has a variety of functions which can affect the diverse roles the complement system plays in health and disease.

9. The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect.

Wolf MT, Beck BB, Zaucke F et al.

Kidney Int. 2007 Jan 24; [Epub ahead of print].

Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-interstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20-30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Ćlincal data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicouretral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.

10. Involvement of hypoxia-inducible transcription factors in polycystic kidney disease.

Bernhardt WM, Wiesener MS, Weidemann A et al.

Am J Pathol. 2007 170 (3): 830-42.

In polycystic kidney disease (PKD), erythropoietin (EPO) production and interstitial vascularization are increased compared with other kidney diseases. EPO and several angiogenic factors are controlled by hypoxia-inducible transcription factors (HIFs), which are composed of a constitutive beta-subunit and two alternative alpha-subunits (HIF-1alpha, HIF-2alpha). We hypothesized that cyst expansion may result in pericystic hypoxia and consecutive up-regulation of HIF and thus examined the expression of HIF-alpha and HIF target genes in human PKD and a rodent PKD model. HIF-1alpha and HIF-2alpha were found to be up-regulated in cyst epithelium of cyst walls, respectively. The distinct expression pattern of the HIF-alpha isoforms closely resembles the respective pattern in normal kidneys under systemic hypoxia. Pimonidazole staining, a marker for tissue hypoxia, confirmed the existence of regional hypoxia in polycystic kidneys. Immunohistochemistry for selected target genes implicated a role for HIF-1alpha in vascular endothelial growth factor and Glut-1 activation and HIF-2alpha in endoglin and EPO stimulation. Polycystin-deficient cells showed physiological, oxygen-dependent HIF-alpha modulation, excluding a direct influence of polycystin deficiency on HIF-alpha regulation. In conclusion, HIF accumulation in human and rat PKD seems to be responsible for increased EPO production and pericystic hypervascularity and may have an impact on progression of PKD.

11. A novel Cys1638Tyr NC1 domain substitution in {alpha} 5 (IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities.

Wilson JC, Yoon HS, Walker RJ et al.

Nephron Dial Transplant. 2007 Feb 3; [Epub ahead of print].

Background Mutations in the type IV collagen gene, COL4A5, are associated with Alport syndrome, characterized by ultrastructural abnormalities of the glomerular basement membrane (GBM), with or without progressive loss of renal function, characteristic ophtalmic signs and/or high tone sensorineural deafness. More than 300 sequence variants in type IV collagen have been identified, including alterations in the non-collagenous NC1 domain. Methods We performed linkage analysis and sequencing to identify the mutation in a New Zealand family with Alport glomerulonephritis and late onset renal failure without hearing loss or eye abnormalities. Results We report a novel c.4913G>A (p.Cys1638Tyr) alteration in the NC1 domain of COL4A5, identified in a moderately large family, eight of whom were confirmed by renal biopsy to have renal abnormalities. Only of eight mutant male members of the pedigree progressed to end-stage renal failure. The remaining five mutant males exhibit either chronic renal disease at age 36, 46 and 72, or as yet show no renal disease at ages 39 and 39. Extra-renal manifestations such as sensorineural deafness or ocular changes were absent from all family members carrying the mutation. Conclusion This variant is the first reported to affect the tenth of 12 cysteine residues in the NC1 domain. We conclude that the cystein to tyrosine substitution in the NC1 domain of the alpha 5 (IV) collagen chain in this family leads to a mild form of Alport syndrome, including absence of extra-renal features.

12. Role of matrix metalloproteinases in renal pathophysiologies.

Catania JM, Chen G, Parrish AR.

Am J Physiol Renal Physiol. 2006 Dec 26; [Epub ahed of print].

Matrix metalloproteinases (MMPs) are large family of proteinases which remodel extracellular matrix (ECM) components and cleave a number of cell surface proteins. MMP activity is regulated via a number of mechanisms, including inhibtion by tissue inhibitors of metalloproteinases (TIMPs). Originally thought to cleave only ECM proteins, MMP substrates are now known to include signaling molecules (growth factor receptors) and cell adhesion molecules. Recent data suggest a role for MMPs in a number of renal pathophysiologies, both acute and chronic. This review will focus on the expression and localization of MMPs and TIMPs in the kidney, as well as summarizing the current information linking these proteins to acute kidney injury, glomerulosclerosis/tubulointerstitial fibrosis, chronic allograft nephropathy, diabetic nephropathy, polycystic kidney disease and renal cell carcinoma.

Key words: kidney, matrix metalloproteinases, tissue inhibitor of metalloproteinase.

13. The expression of matrix metalloproteinase-11 protein in various types of glomerulonephritis.

Nakopoulou L, Lazaris AC, Boletis I et al.

Nephrol Dial Transplant. 2007 22 (1): 109-17.

Background Matrix metalloproteinases (MMPs) have been implicated to play important roles in a number of pathological processes such as inflammation. In human glomeruli, the mesangial matrix turnover is controlled by a dynamic equilibrium between synthesis and degradation to which metalloproteinases are known to contribute. Metalloproteinase-11 (MMP-11) was originally discovered as a gene whose expression was associated with tissue remodelling. The aim of this study was to investigate whether MMP-11 protein is expressed in various types of glomerulonephritis and to elucidate the role of this expression. Methods Using standard immunohistochemistry, we analysed MMP-11 expression in renal biopsies from 95 patients with primary glomerulonephritis (n = 44) and secondary, either lupus-associated glomerulonephritis (n = 22) or pauci-immune, ANCA-associated glomerulonephritis due to small vessel vasculitis (n = 23) or Wegener’s granulomatosis (n = 6). The examined cases were divided into two groups (proliferative and non-proliferative). Anti-Ki67 and -CD68 immunostaining was also performed in order to estimate cell proliferation and number of macrophages, respectively. Results MMP-11 immunopositivity was detected in the glomeruli of the majority of pathological samples. The highest incidence of MMP-11 immunopositivity (26.3%) was noticed in glomerulonephritides associated with microscopic polyangiitis and Wegener’s granulomatosis. Generally, MMP-11 was often expressed in segmental areas of sclerosis, microadhesions, cellular and fibrocellular crescents. Fibrotic crescents and fibrotic glomeruli were constantly MMP-11-immunonegative. In MMP-11 immunoreactive glomeruli, increased numbers of macrophages were often detected in the mesangium (P = 0.001), while no such observation could be made with regard to proliferating cells (P = 0.170). Conclusions MMP-11, like an inflammatory mediator, may exert a chemotactic influence on macrophages which aggregate in the mesangium: MMP-11 is not likely to have a parallel mitogenic or antifibrotic effect in diseased glomeruli.

14. Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-{beta}1 in patients with distinct types of primary glomerulonephritis.

Bauvois B, Mothu N, Nguyen J et al.

Nephrol Dial Transplant. 2007 Jan 5; [Epub ahead of print].

Background Dysregulated renal expression of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMP) and TGF-beta1 contribute to the development of tubulo-interstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). There is little information on the circulating levels of these proteins in human GNs. Here, we assessed whether different histopathological GN types could be associated with distinct plasma patterns of MMPs and regulatory proteins. Method Protein levels of MMP-2, MMP-9, TGF-beta1 and TIMP-1 were measured by ELISA in plasma from venous blood of 108 untreated patients with various types of primary GN defined by kidney biopsy, namely IgAN (n = 63), membranous GN (MN, n = 26), minimal change nephrotic syndrome (MCNS, n = 12) and focal and segmental glomerular sclerosis (FSGS, n = 7), and were compared with levels in 50 healthy subjects. Plasma samples were assayed for gelatinolytic activity (zymography). Results Zymography detected the proforms of MMP-2 and MMP-9. Compared with controls, IgAN patients exhibited a significant, parallel decrease in plasma levels of MMP-2, MMP-9 and TGFbeta1. In MN patients, decreased MMP-9 level contrasted with a high MMP-2 level and a normal TGF-beta1 level. In the MCNS/FSGS group, increased MMP-2 level contrasted with unchanged MMP-9 and decreased TGF-beta1 levels. Plasma concentration of TMPI-1 was elevated in all GN groups. There was no correlation between baseline MMP-2/MMP-9/TGFbeta1 levels and the degree of renal dysfunction or with progression toward ESRD. Conclusions Plasma concentration of MMP-2, MMP-9 and TGF-beta1 significantly differed between the various histopathological types of primary GNs, thus suggesting the involvement of different undelying mechanisms in the regulation of glomerular and tubulointerstitial fibrosis in these renal disease.

15. Chemokines and chemokine receptors in glomerulonephritis and renal allograft rejection.

Stasikowska O, Wagrowska-Danilewicz M.

Med Sci Monit. 2007 13 (2): RA31-6.

Infiltration by mononuclear cells is found within the renal tissue in various types of kidney diseases. The migration of leukocytes through vessels and beyond the vascular compartment is dependent in part on small chemoattractant proteins called chemokines. All types of renal cells can produce chemokines in a cell- and stimulus-specific manner. Some chemokines appear to be constitutively expressed, while proinflammatory chemokines are expressed only in responses to specific stimuli. MCP-1 expression in renal tubuli is enhanced in proteinuric states, irrespective of the types of renal disease, and this increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states. Expression of individual chemokines correlate with intrarenal T cells and monocyte/macrophage infiltrates as well as with interstitial kidney damage and renal function. Experimental data and studies on human renal tissue in patients with glomerulonephritis and renal allograft rejection indicate that MCP-1, MIP-1 alpha, beta, RANTES, and IL-8 play a main role in the resolution and progression of inflammatory processes in these cases. Renal cells and inflammatory cells also express chemokine receptors, especially CCR-5, CCR-1, CCR-2, and CXCR3. Anaylsis of the immunoexpression of chemokines and chemokine receptors in renal tissue of patients with glomerulonephritis and renal allograft rejection may be helpful in evaluating the progression of kidney disease, whereas monitoring chemokines in the urine may provide a dynamic pictures of the inflammatory state. The pharmacological regulation of chemokine and chemokine receptor expression may be a useful tool in the therapy of kidney diseases.

16. Expression and targeting of CX3CL1 (fractalkine) in renal tubular epithelial cells.

Durkan AM, Alexander RT, Liu GY et al.

J Am Soc Nephrol. 2007 18 (1): 74-83.

The chemokine CX (3) CL1 plays a key role in glomerulonephritis and can act as both chemoattractant and adhesion molecule. CX (3) CL1 also is upregulated in tubulonterstitial injury, but little is known about the subcellular distribution and function of CX (3) CL1 in renal tubular epithelial cells (RTEC). Unexpectedly, it was found that CX (3) CL1 is expressed predominatly on the apical surface of tubular epithelium in human renal transplant biopsy specimens with acute rejection or acute tubular necrosis. For studying the targeting of CX (3) CL1 in polarized RTEC, MDCK cells that expressed untagged or green fluorescent protein-tagged CX (3) CL1 were generated. The chemokine was present on the apical membrane and in subapical vesicles. Apical targeting of CX (3) CL1 was not due to signals that were confered by its intracellular domain, to association with lipid rafts, or to O-glycosylation but, rather, depended on N-linked glycosylation of the protein. With the use of fluorescence recovery after photobleaching, it was found that CX (3) CL1 is immobile in the apical membrane. However, CX (3) CL1 partioned with the triton-soluble rather than -insoluble cellular fraction, indicating that it is not associated directly with the actin cytoskeleton or with lipid rafts. Accordingly, dysruption of rafts through cholesterol depletion did not render CX (3) CL1 mobile. For exploration of potential functions of apical CX (3) CL1, binding of CX (3) CR1-expressing leukocytes to polarized RTEC was examined. Leukocyte adhesion to be the luminal surface was enhanced significantly when CX (3) CL1 was present. These data demonstrate that CX (3) CL1 is expressed preferentially on the apical membrane of RTEC and suggest a novel function for the chemokine in recruitment and retention of leukocytes in tubulointerstitial inflammation.

17. Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state.

Lai KN, Leung JC, Chan LY et al.

Kidney Int. 2007 Jan 24; [Epub ahead of print].

We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We estabilished in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PETC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can diffentially modulate the expression of chemokne receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.

18. The role played by endocytosis in albumin induced secretion of TGF {beta}-1 by proximal tubular epithelial cells.

Diwakar R, Pearson AD, Colville-Nash P et al.

Am J Physiol Renal Physiol. 2007 Jan 16; [Epub ahead of print].

Proteinuria predicts the decline of renal function in chronic kidney disease. Reducing albuminuria has been shown to be associated with a reduction in this rate of decline. PTECs, when exposed to albumin produce matrix proteins, pro-inflammatory and pro-fibrotic cytokines like TGFbeta-1. Some of these effects are dependent on endocytosis of albumin by PTECs. However, conditions like diabetic nephropathy, believed to be associated with reduced albumin endocytosis are associated with interstitial fibrosis. Moreover, megalin the putative albumin binding receptor in PTECs has potential signaling motifs in its cytoplasmic domain suggesting its ability to signal in response to ligand binding from the apical surface of PTECs. Hence we looked to see whether albumin induced secretio of TGF-beta-1 by PTECs is dependent on albumin endocytosis or if it could occur in the absence of albumin endocytosis. We studied the production of TGFbeta-1 in two accepted models of PTECs, Opossum kidney (OK) cells and HKC-8 cells, with widely varying degrees of endocytosis. We then studied the effect of inhibiting albumin endocytosis with various inhibitors on albumin induced TGFbeta-1 secretion. Our results indicate that albumin induced TGFbeta-1 secretion by PTECs does not require albumin endocytosis and therefore the mechanism for the induction of some pro-fibrotic responses by albumin may differ from those required for some of the inflammatory responses. Moreover, we found that albumin induced TGFbeta-1 secretion by PTECs is not dependent on its interaction with megalin.

Key words: megalin, albuminuria, simvastatin, receptor associated protein.

19. DNA fragmentation in chronic glomerulonephritis: An immunohistological analysis.

Ott U, Aschoff A, Pocock J et al.

Nephron Clin Pract. 2007 105 (1): 18-28.

Background Experimental data suggest that apoptosis plays an important pathophysiological role in glomerulonephritis by restoring tissue structure after proliferation of intrinsic renal cells and infiltration of leukocytes. Relatively little is known of apoptosis in human glomerulonephritis, particularly in predicting renal function during follow-up. Methods In order to colocalize different markers for cell damage in renal tissue from patients with different forms of glomerulonephritis (GN), a series of semithin sections from 34 kidney biopsies were studied retrospectively. Normal kidney from a nephrectomy specimen with a small renal adenocarcinoma served as a control. DNA fragmentation, expression of tissue transglutaminase II, BAX and BCL-2 were visualized immunohistochemically. In some renal biopsies, immunohistochemical staining for activated caspase 3 was performed. Proinflammatory markers (C-reactive protein, leukocytes), serum creatinine, creatinine clearence, total proteinuria, albuminuria, alpha (1)-microglobulin and IgG excretion were determined at the time of biopsy. Serum creatinine and total proteinuria were assessed 6 and 12 months after renal biopsy. Results Nuclei with different degrees of DNA fragmentation were mainly found in epithelial cells of tubules, but also in glomerular cells, regardless of the form of GN studied. Transglutaminase II expression was found only in cells with a strong staining for DNA fragmentation. DNA fragmentation localized to glomerular cells was more pronounced in proliferative than in non-proliferative forms of GN, being most abundant in patients with rapid progressive GN. Staining for activated caspase 3 in selected biopsies confirmed tha presence of apoptosis. BAX and BCL-2 staining was detected within the same cells, but exhibited a different intracellular distribution. In proliferative GN, the extent of DNA damage in tubular epithelial cells significantly corresponds with the concentration of serum creatinine (p < 0.04) and with urinary excretion of alpha (1)-microglobulin (p < 0.01) at the time of biopsy. A significant correlation (p < 0.01) was seen between glomerular DNA fragmentation and follow-up total proteinuria 12 months after biopsy for proliferative forms of GN. The damaged glomerular area (e.g. mesangial sclerosis) significantly correlated with DNA fragmentation in proliferative, but not in non-proliferative GN at the time of biopsy. Furthermore, glomerular damaged showed a significant correlation with tubular DNA damage in proliferative GN. Conclusion In glomerular cells, apoptosis may be important for the clearence of proliferating cells whereas in tubules, cell damage showed dependence on the degree of tubular injury mediated by inflammation and/or proteinuria. Although the degree of apoptosis in tubular cells correlates with serum creatinine in proliferative GN at the time of biopsy, it is of limited use to predict future renal function.

20. Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: Evidence for a role of P2X4.

Solini A, Santini E, Chimenti D et al.

Am J Physiol Renal Physiol. 2007 Jan 30; [Epub ahead of print].

Apoptosis, a normal event in renal tissue homeostasis, has been considered as a major mechanism for either resolution of glomerular hypercellularity in glomerulonephritis or loss of cellularity and progression to glomerulosclerosis in chronic renal disease. This study was aimed at investigating the role of extracellular ATP (eATP) in mediating apoptosis in human mesangial cells (HMC) and identifying the subtype (s) of purinergic receptors involved. eATP, but not uridin-5’-triphosphate (UTP), caused dose-dependent modifications of cellular morphology, as assessed by contrast.phase microscopy, and late apoptosis, as measured by Annexin V/propidium iodide based flow-cytometry and caspase-3 activation. Both phenomena were prevented by the P2X antagonist oxidized-ATP. 2’, 3’-O- (4-benzoylbenzoyl) adenosine 5’-triphophate (BzATP) was less effective than ATP, whereas 1 [N, O-bis (5-isoquinolinesulfonyl)-M-methyl-L-tyrosyl]-4-phenylpiperazine (KN62), a selective inhibitor of human P2X7, prevented morphological changes but potentiated apoptosis induced by BzATP. P2X7 was barely expressed in HMC, and showed a relatively scarce functional activity, as assessed by monitoring nucleotide-induced intracellular calcium surge and plasma membrane depolarization by Fura-2/AM and bis [1, 3-diethylthiobarbiturate] trimethineoxonal uptake, respectively. These data indicated a negligible role of P2X7 in eATP-mediated apoptosis and pointed to the involvement of other P2X receptor (s). Molecular and inhibitor studies suggested a main role for P2X4 receptor in nucleotide-induced apoptosis in HMC, indicating a relevant role for purinergic signaling in regulating death rate in these cells.

Key words: extracellular ATP, purinergic receptors, apoptosis, mesangium.

21. Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis.

Turner CM, Tam FW, Lai PC et al.

Nephrol Dial Transplant. 2007 22 (2): 386-95.

Background The involvement of IL-1beta and other pro-inflammatory cytokines in most forms of glomerulonephritis is now well estabilished. The P2X (7) receptor, an ATP-sensitive P2X receptor, functions not only as a non-selective cation channel, but it is also involved in the rapid processing and release of IL-1beta, apoptosis and necrotic cell death. Therefore, we wanted to investigate if expression of this receptor is altered in the glomeruli of rodent models of glomerulonephritis. Methods P2X (7) receptor protein expression was investigated using immunohistochemistry, and apoptosis was assessed using the TUNEL assay and caspase-3 immunostaining. Real-time PCR with gene-specific primers was used to detect P2X (7), IL-1beta, p53, bax an bcl-2 mRNA expression. Results Although the levels of the P2X (7) receptor protein in mouse kidney are normally very low, or undetectable, we detected an increase in glomerular expression of this receptor and an increase in glomerular apoptotic cells in a mouse model of accelerated nephrotoxic nephritis. We also observed increased glomerular and tubular expression of the P2X (7) receptor protein in renal biopsy tissue of patients with autoimmune-related glomerulonephritis. Furthermore, P2X (7) receptor mRNA increased in the kidney of a rat model of proliferative glomerulonephritis and this coincided with onset of proteinuria. We also observed increase mRNA expression of IL-1beta and the pro-apototic markers p53and bax, but not of anti-apoptotic bcl-2. Conclusion Although there is an association between expression of the pro-inflammatory and pro-apoptotic P2X (7) receptor and glomerulonephritis in these rodent models, and in at least one form of human glomerulonephritis, the underlying relationship and its functional significanmce remain to be explored.

22. The contribution of B cells to renal interstitial inflammation.

Heller F, Lindenmeyer MT, Cohen CD et al.

Am J Pathol. 2007 170 (2): 457-68.

Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed large nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of interstitial lymphoid follicle-like structures. These might represent an intrarenal immune system.

23. Mast cell, a promising therapeutic target in tubulointerstitial fibrosis.

Li Y, Liu FY, Peng YM et al.

Med Hypotheses. 2007 Jan 24; [Epub ahead of print].

Tubulointerstitial fibrosis is a final common pathway to the eventual structural desolation of kidneys. However, the mechanism involved in this phenomenon is still poorly understood, and current therapies are ineffective or only marginally effective. Mast cell has a variety of physiological and pathological functions through the production of heparin, histamine, neutrophil chemoattractants, immunoregulatory cytokines, and mast cell-specific serine proteases tryptase and chymase. The survival and proliferation of mast cell are dependent upon stem cell factor. Presently, mast cells are known to participate in the pathogenesis of tubulointerstitial fibrosis in many kidney diseases. Several therapeutic approaches to inhibit mast cell activation have already demonstrated some clinical utility in tissue fibrosis or inflammatory diseases such as the use of mast cell stabilizers, inhibitors of tryptase or chymase, blockade of stem cell factor and anti-IgE therapy. We hypothesize that mast cell has a significant role in the progression of tubulointerstitial fibrosis, thus the treatment strategies based on mast cell appear to promising in these conditions. Development of these novel therapeutic approaches will enable us to target any types of renal disease.

24. Smooth muscle alpha-actin deficiency in myofibroblasts leads to enhanced renal tissue fibrosis.

Takeji M, Moriyama T, Oseto S et al.

J Biol Chem. 2006 281 (52): 40193-200.

Myofibroblasts are a major source of proinflammatory cytokines and extracellular matrix in progressive tissue fibrosis leading to chronic organ failure. Myofibroblasts are characterized by de novo expression of smooth muscle alpha-actin (SMalphaA), which correlates with the extent of disease progression, although their exact role is unknown. In vitro cultured myofibroblasts from kidney SMalphaA knock-out mice demonstrate significantly more prominent cell motility, proliferation, and type-I procollagen expression than those of wild-type myofibroblasts. These pro-fibrotic properties are suppressed by adenovirus-mediated SMalphaA re-expression, accompained by down-regulation of focal adhesion proteins. In interstitial fibrosis model, tissue fibrosis area, proliferating interstitial cell number, and type-I procollagen expression are enhanced under SMalphaA deficiency. In mesangioproliferative glomerulonephritis model, cell proliferation in the mesangial area is also enhanced in SMalphaA knock-out mice. Adenoviral SMalphaA introduction into renal interstitium obviously ameliorates tissue fibrosis in interstitial fibrosis model. These results indicate that SMalphaA suppress the pro-fibrotic properties of myofibroblasts, highlighting the significance of smooth muscle-related proteins in moderating chronic organ fibrosis under pathological conditions.

25. Comparison of pathomolecular markers of fibrosis and morphology in kidney from autopsies of African Americans and whites.

Pat B, Hughson MD, Nicol JL et al.

Virchows Arch. 2006 Nov 23; [Epub ahead of print].

African Americans have an increased incidence of chronic kidney disease (CKD) due to hypertension and arteriosclerosis and increased death due to coronary artery disease, compared with whites. The pathogenesis of CKD involves the increased presence and activation of myofibroblasts and macrophages, promotion of tubulointerstitial fibrosis, and effects of tubulointerstitial cell mitosis and apoptosis. We hypothesized that increased risk of hypertensive vascular disease may be identified by renal pathomolecular markers that are associated with progressive CKD. Renal sections were available from 50 autopsies of 33 African Americans (55% males) and 17 whites (76% males) undergoing forensic autopsy for unexpected death. Sclerotic glomeruli, severity of cortical fibrosis, and renal arteriosclerosis, total glomerular number (N (glom)), average glomerular volume (V (glom)), birth weights, and blood pressure were known. Presence and locality of markers for myofibroblasts (alpha-SMA), macrophages (CD68), collagen, pro-fibrotic transforming growth factor-beta1 were scored in renal autopsies, and tubulointerstitial apoptosis was recorded. The results demonstrated a strong positive correlation between age, cortical fibrosis and alpha-SMA (p < 0.05), and between CD68 and hypertension and coronary artery disease (p < 0.05). The findings confirm the role of myofibroblasts and macrophages in pathogenesis of human CKD. However, the markers showed no significant relationships to V (glom), N (glom), birth weight, or race.

26. Oxidants in chronic kidney disease.

Shah SV, Baliga R, Rajapurkar M et al.

J Am Soc Nephrol. 2007 18 (1): 16-28.

Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once estabilished, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM) or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.

27. Red blood cell and plasma glutathione peroxidase actvities and selenium concentration in patients with chronic kidney disease: A review.

Zachara BA, Gromadzinska J, Wasowitz W et al.

Acta Biochim Pol. 2006 Dec 11; [Epub ahead of print].

The metabolism of oxigen in aerobic organisms leads to generation of reactive oxygen species (ROS). These entities are able to oxidize almost all classes of macromolecules, including proteins, lipids and nucleic acids. The physiological level of ROS is usually regulated by antioxidant defense mechanisms. There are at least three groups of antioxidant enzymes: superoxide dismutases, catalases and glutathione peroxidases (GSH-Pxs) which neutralize ROS. The trace elements (copper, zinc and selenium) bound to the active sites of the above listed enzymes play an important role in the antioxidant defense system. In mamals, a major function of selenium (Se) and Se-dependent GSH-Pxs is to protect cells from oxidative stress. Selenium concentrations and GSH-Px activities are altered in blood components of chronic kidney disease (CKD) patients. The Se level is frequently lower than in healthy subjects and the concentration very often decreases gradually with advancing stage of the disease. Studies on red cell GSH-Px activity in CKD patients reported its values significantly lower, significantly higher and lower or higher, but not significantly as compared with helathy subjects. On the other hand, all authors who studied plasma GSh-Px activity have shown significantly lower values than in healthy subjects. The degree of the reduction decreases gradually with the progression of the disease. High inverse correlation were seen between plasma GSH-Px activity and creatinine (cr.) level. A gradual decrease in plasma GSH-Px activity in CKD patients is due to the fact this enzyme is synthesized predomintly in the kidney and thus the impairment of this organ is the cause of the enzyme’s lower activity. Se supplementation to CKD patients has a slightly positive effect in the incipient stage of the disease, but usually no effect was observed in end-stage CKD. Presently, kidney transplantation is the only treatment that may restore plasma Se level and GSH-Px activity in patients suffering from end-stage CKD. A few studies have shown that in kidney recipients, plasma Se concentration and GSH-Px activity are restored to normal values within a period of 2 weeks to 3 months following surgery and thus it can be acknowledged that Se supplementation to those patients has a positive effect on plasma GSH-Px activity.

28. Angiotensin II-induced genomic damage in renal cells can be prevented by angiotensin II type 1 receptor blockade or radical scavenging.

Schupp N, Schmid U, Rutkowski P et al.

Am J Physiol Renal Physiol. 2007 Jan 16; [Epub ahead of print].

Hypertensive patients exhibit elevated cancer incidence, especially of cancers of the kidney. Elevated levels of angiotensin II (AngII), the active peptide of the renin-angiotensin system, regulating blood pressure and cardiovascular homeostasis, are known to cause hypertension and kidney disease. There is evidence that AngII is an activator of NAD (P) H oxidase, leading to the formation of free radical, which is known to participate in the induction of DNA damage. This study was undertaken to characterise AngII-induced DNA damage. DNA damage was measured by comet assay and micronucleus frequency test. Incubation of pig kidney cells (LLC-PK1) in vitro with AngII concentrations between 85 and 340 nM led to a 6- to 15-fold increase of DNA damage compared to the control as revealed by comet assay analysis. Micronuclei were induced approximately 4-fold compared to the control in pig and rat kidney cells (LLC-PK1, NRK) and in human promyelocytic cells (HL-60). AngII-induced DNA damage could be prevented by co-incubation with the AngII type 1 receptor blocker candesartan and the antioxidants N-acetylcysteine and alpha-tocopherol. The AngII type 2 receptor antagonist PD123319 could not reduce AngII-induced DNA damage. Measurement of reactive oxygen species (ROS) by flow cytometry showed an enhanced formation after exposure to AngII and a reduction of ROS after candesartan, N-acetylcysteine and alpha-tocopherol. The present findings support our hypothesis that AngII causes DNA damage via AngII type 1 receptor binding and subsequent formation of oxidative stress.

Key words: kidney cells, DNA damage, oxidative stress, candesartan, antioxidants.

29. Associations between the CYBA 242C/T and the MPO -463G/A polymorphisms, oxidative stress and cardiovascular disease in chronic kidney disease patients.

Grahl DA, Axelsson J, Nordfors L et al.

Blood Purif. 2007 25 (2): 210-8.

Genetic variations in the NADPH/MPO system in chronic kidney disease (CKD) patients might lead to altered activity of these enzymes, and thus to altered risk for oxidative stress (OS) and cardiovascular disease (CVD). We evaluated the impact of 242C/T CYBA and -463G/A MPO polymorphism on OS and CVD mortality in stage 5 CKD patients starting dialysis. Two hundred and fifty-seven patients were genotyped using Pyrosequencing. Plasmalogen [dimethylacetal (DMA) 16/C16 : 0] was used as OS marker. CVD was assessed from patient history and clinical symptoms. Prevalence of CVD was higher (35%) in GG patients (MPO) compared to AG (26%) and AA (0%) patients (p < 0.01). Patients with CC genotype (CYBA) had lower levels of DMA 16/C16 : 0 (ratio 0.071 +/- 0.003) compared to TT patients (0.089 +/- 0.006; p < 0.05). These patients also had increased CVD mortality compared to CT and TT patients (chi (2) 2.19; p < 0.05). We conclude that genetic variations in the NADPH/MPO system are associated with OS, presence of CVD and CVD-related mortality in CKD patients.

30. Is inflammation the link between atherosclerosis and vascular calcification in chronic kidney disease?

Tsirpanlis G.

Blood Purif. 2007 25 (2): 179-82.

Atherosclerosis and vascular calcification often co-exist in chronic kidney disease (CKD) patients. Although the former has been recently recognized as an active inflammatory process, atherosclerosis-related calcification of the intima is still viewed as a passive epiphenomenon. Recent experimental data showed that ossification of the internal vascular wall might also be an active inflammatory process interrelated to atherosclerosis. Factors like RANKL (receptor activator of nuclear factor kappaB ligand), RANK and osteoprotegerin modulate vascular calcification and the same time are involved in the process of atherosclerosis. Moreover, basic calcium phosphate crystals could interact with and activate monocytes-macrophages that produce proinflammatory cytokines capable of initiating - via endothelial activation and leukocyte adhesion - the atherosclerotic process. Thus, vascular calcification mihgt be an active player and not simply an epiphenomenon in atherosclerosis. Should be above-mentioned data be confirmed in future studies, calcification of the internal vascular wall and atherosclerosis might be viewed and treated as tightly interconnected and linked by inflammation processes in CKD patients.

31. Vascular calcifications: Pathogenesis, management, and impact on clinical outcomes.

Cannata-Andia JB, Rodriguez-Garcia M, Carrillo-Lopez N et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S267-73.

The predisposition to vascular calcifications in patients with chronic kidney disease (CKD) has gained great interest in recent years as many studies have described its likely impact on morbidity and mortality. The mechanism by which the process of vascular calcification is produced is complex, and it does not consist in a simple precipitation of calcium and phosphate but is instead an active and modifiable process. Several ’’modifiable and nonmodifiable’’ factors that are able to promote vascular calcification are extremely frequent in patients with CKD. Most of the present strategies to decrease vascular calcifications are based in the control of the more prevalent modifiable risk factors. Unfortunately, the extremely important nonmodifiable risk factors, which are highly prevalent, such as older age, time of dialysis, and diabetes, are not under one’s control. Recent studies also have shown that vascular calcifications in some localizations were associated with increased osteoporotic fractures not only in dialysis patients but also in the general population, and interestingly, mortality also was associated significantly and positively with vascular calcifications and nontraumatic bone fractures. Despite that new strategies may improve the management of vascular disease and specifically have a positive impact on the high prevalence of vascular calcifications, still the best possible control of the bone metabolic and inflammatory parameters are in the primary line. The horizont of the coming decade looks promising, but solid clinical and epidemiologic data are needed to manage better the bone- and cardiovascular-related disorders in patients with CKD.

32. Vitamin D and vascular calcification.

Zittermann A, Schleithoff SS, Koerfer R.

Curr Opin Lipidol. 2007 18 (1): 41-6.

Purpose of review Vascular calcification is frequently found in patients with osteoporosis, atherosclerosis and chronic kidney disease, leading to high morbidity and mortality rates. The effects of vitamin D excesss and deficiency on vascular calcification are reviewed in this article. Recent findings There is evidence from experimental studies that mediacalcinosis induced by vitamin D excess is an active and reversible process. Vitamin D excess, however, is rarely seen in the general human population. Experimental data also demonstrate that physiologic vitamin D actions include the inhibition of processes that are important for intimal and medial artery calcification such as pro-inflammatory cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells. In uremic rats, low levels of the vitamin D hormone calcitriol are associated with massive vascular and soft tissue calcifiactions. Whereas retrospective studies already indicate a beneficial effect of active vitamin D on mortality rates in chronic kidney disease, little is yet known about the effect of vitamin D deficiency on cardiovascular morbidity and mortality in the general population. Summary Available data indicate that vitamin D exerts a biphasic ’dose response’ curve on vascular calcifiaction with deleterious consequences not only of vitamin D excess but also of vitamin D deficiency.

33. Expression of nestin in the podocytes of normal and diseased human kidneys.

Su W, Chen J, Yang H et al.

Am J Physiol Regul Integr Comp Physiol. 2007 Jan 25; [Epub ahead of print].

The complex cyto-architecture of the podocyte is critical for glomerular permeselectivity. The present study characterizes the expression of nestin, an intermediate filament protein, in human kidneys. In normal kidneys, nestin was detected at the periphery of glomerular capillary loops. Co-labeling showed nestin was expressed in WT1 positive cells. Within the podocyte, nestin immunoreactivity was present in the cell body and primary process. This was supported by immunoelectron microscopy (immuno-EM). Nestin also co-localized with vimentin in the periphery of capillary loops, but not in the mesangium. Nestin was not detected in other structures of the adult human kidney. To determine the potential role of nestin in proteinuria, nestin was examined in kidney biopsies from patients with or without proteinuria. These patients were diagnosed with IgA nephropathy (IgAN) with mild mesangial expansion but without proteinuria, IgA nephropathy with proteinuria, membranous nephropathy (MN) and focal segmental glomerular sclerosis (FSGS). The distribution of nestin in these biopsies was similar to that in the normal kidney. Semi-quantitative analysis of immunostaining showed that glomerular nestin expression in IgA nephropathy without proteinuria was not different from normal kidney, however, nestin expression in kidneys of patients with IgA nephropathy and proteinuria, MN and FSGS with proteinuria was significantly reduced compared to normal kidney (p < 0.01). Reduced nestin mRNA expression in the patients with IgA nephropathy with proteinuria and FSGN was also observed by quantitative real time PCR. These studies suggest that nestin may play an important role in maintaining normal podocyte function in the human kidney.

Key words: cytoskeleton, proteinuria, intermediate filament.

34. Mechanisms of renal damage in plasma cell dyscrasias: An overview.

Merlin G, Pozzi C.

Contrib Nephrol. 2007 (153): 66-86.

The kidney is a target organ in plasma cell dyscrasisas. Usually the offending molecules are the monoclonal light chains (LCs), but the complete immunoglobulins can participate in the pathogenesis of organ damage. The primary structure of the monoclonal proteins is at the basis of the ultrastructural organization of their aggregates which translates into characteristic kidney injuries. The kidney targeting is due to the concurrence of several factors such as the local catabolism of monoclonal LCs, specific interactions of the monoclonal proteins with tissue and cellular components, and local environmental conditions. Glomerulopathic LCs interact wit mesangial cells producing, through two distinct pathways, LC amyloidosis or monoclonal immunoglobulin deposition disease. Tubulopathic LCs damage the proximal tubule causing Fanconi’s syndrome or precipitate in the distal tubule determining the cast nephropathy. The use of electronmicroscopy combined with immuno-labeling has allowed the identification of other rare patterns of kidney damage. In patients with known plasma cell dyscrasia, the recognition of these patterns of renal injury should lead to appropriate therapeutic intervention.

35. Paraproteinemic renal diseases that involve the tubulo-interstitium.

Herrera GA, Sanders PW.

Contrib Nephrol. 2007 (153): 105-15.

The renal response to deposition of monoclonal light chains represents a spectrum of pathologic changes that can be divided into glomerular or tubulo-interstitial processes. Involvement of the tubulo-interstitium can include activation of the proximal tubule, proximal tubule injury/cell death, and cast nephropathy. In these diseases, the culprit is not the intactv immunoglobulin protein but instead the immunoglobulin light chain. Recent noninvasive tests, including immunofixation electrophoresis or quantification of serum free light chains, have increased the sensitivity for detection of an abnormality in circulating free light chains and are invaluable ancillary tools, but short of renal biopsy, the diagnosis of these diseases can prove challenging. A description of the pathobiology and overview of the approach to management of these light chain-mediated renal lesions is provided.

36. The not so ’mighty chondrion’: Emergence of renal diseases due to mitochondrial dysfunction.

Hall AM, Unwin RJ.

Nephron Physiol. 2007 105 (1): p1-10.

Mitochondria are intracellular organelles with a variety of vital functions, including the provision of energy in the form of adenosine 5’-triphosphate. Increasingly, we are becoming more aware of the importance of mitochondrial dysfunction in a number of common medical conditions. In this review and overview, we focus on the growing evidence that mitochondrial dysfunction is involved in either the etiology or underlying pathophysiology of a broad spectrum of renal diseases, including acute renal injury due to ischemia-reperfusion injury, renal Fanconi syndrome, and glomerular diorders such as focal segmental glomerulosclerosis. In addition, mitochondrial dysfunction may also contribute to the growing burden of chronic kidney disease seen in our aging population, which is still largely unexplained. Unfortunately, at present, our ability to diagnose and treat renal disorder related to mitochondrial dysfunction is limited, and further work in this field is needed.

37. Cachexia in chronic kidney disease: Role of inflammation and neuropeptide signaling.

Mak RH, Cheung W.

Curr Opin Nephrol Hypertens. 2007 16 (1): 27-31.

Purpose of review This review will update clinicians and basic scientists who are interested in the clinical relevance and molecular mechanism of uremic cachexia. Recent studies that examine the role of cytokines and hypothalamic neuropeptides are emphasized. Recent findings A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate. Proinflammatory cytokines also activate the transcription factor nuclear factor-kappaB, resulting in decreased protein synthesis, and activate the ubiquitin-mediated proteolytic system, which is the major system involved in increased protein degradation. Summary This review highlights the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and the potential of peripheral administration of melanocortin-4 receptor antagonists as a novel therapeutic approaches.

38. Pathology and immunology of lupus glomerulonephritis: Can we bridge the two?

Liapis H, Tsokos GC.

Int Urol Nephrol. 2007 Jan 12; [Epub ahead of print].

Aberrant immune response underwrite lupus glomerulonephritis and may contribute to glomerular cell proliferation and inflammation. Recent studies provide evidence that apoptotic immune cells may initiate immune events leading to tissue damage. Nucleosomes within apoptotic particles are recognized by B cells and other antigen presenting cells and represent the most likely inciting antigen for autoantibody production. Some of these antibodies are nephritogenic depending on fine structural composition and antigen recognition in the circulation or on renal cells. Deficient complement components contribute to reduced clearence of circulating and native kidney apoptotic cells. This review summarizes current concepts in lupus immune pathogenesis and attempts to bridge immunology to pathology of lupus glomerulonephritis.

39. Pathogenic role of antiC1q autoantibodies in the development of lupus nephritis--a hypothesis.

Flierman R, Daha MR.

Mol Immunol. 2007 44 (1-3): 133-8.

A substantial proportion of patients with systemic lupus erythematosus (SLE) develop renal inflammatory disease, so-called lupus nephritis. LN is a severe complication of SLE which is strongly associated with the presence of autoantibodies against C1q, the first component of the complement system, and other self-antigens (i.e. against DNA and nucleosomes) as well. In this review, the authors focus on anti-C1q autoantibodies and interpret the available data in order to explain how LN may develop and how anti-C1q autoantibodies contribute to its pathogenesis.

40. Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis.

Matsuura K, Uesugi N, Hijiya N et al.

Hum Pathol. 2007 Jan 18; [Epub ahead of print].

Cardiac ankyrin-repeated protein (CARP) was originally identified as a protein specifically expressed in cardiomyocytes, but has recently been found to be upregulated in some muscle disease including muscular dystrophy and myopathy, suggesting that CARP may be induced in some pathologic conditions. In this study, we immunhistochemically analyzed 69 renal biopsy from patients with glomerular disease and 2 individuals with normal kidney. We found that CARP was expressed in renal podocytes at a high level in 10 to 13 cases of crescentic glomerulonephritis, 7 of 19 cases of diabetic nephropathy, and 12 of 20 cases of lupus nephritis, although it was not expressed in endocapillary glomerulonephritis, minimal change disease, thin basement membrane disease, membranous glomerulonephritis, and normal kidney. Interestingly, in lupus nephritis, CARP expression tended to be induced in cases exhibiting nephrotic syndrome, but less so in cases without nephrotic syndrome, suggesting that CARP expression is correlated with the severity of proteinuria. Furthermore, we found that CARP was not expressed in membranous glomerulonephritis but evidently expressed in most cases of membranous lupus nephritis. Although membranous glomerulonephritis and membranous lupus nephritis are sometimes morphologically indistinguishable, it is suggested that their pathologic mechanisms differ. Therefore, we propose that examination of CARP expression is useful for precise differential diagnosis of membranous glomerulonephritis and membranous lupus nephritis.

41. Does renal function influence plasma levels of advanced glycation and oxidation protein products in patients with chronic rheumatic diseases complicated by secondary amyloidosis?

Rysava R, Kalousova M, Zima T et al.

Kidney Blood Press Res. 2006 30 (1): 1-7.

Background The aim of the study was to assess the contribution of carbonyl and oxidative stresses to the development of amyloidosis in patients suffering from chronic rheumatic diseases, and the potential influence of renal function to their concentrations was considered. Methods We investigated 17 patients with chronic rheumatological diseases and histologically proven diagnosis of AA amyloidosis (group AA-RA), 26 patients suffering from rheumatoid arthritis wihout any signs of AA amyloidosis (gropu nonAA-RA) and 20 healthy volunteers (Co). In all patients, advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), pregnancy-associated plasma protein A (PAPP-A) and other selected proinflammatory markers were measured. Results An increase in serum levels of AOPP and AGEs was found in the AA-RA group in comparison with nonAA-RA patients and also with Co (p < 0.001 for all comparisons). AGEs positively correlated with serum creatinine (r = 0.67, p = 0.004) and negatively with glomerular filtration rate (r = -0.54, p = 0.027). We did not find a correlation between AOPP and any other assessed parameters including proteins and renal parameters. PAPP-A levels were not significantly increased in any group of patients (AA-RA, nonAA-RA) in comparison with Co. Conclusions Increased plasma levels of AGEs and AOPP in the group of patients with AA-RA may have been partly explained by the diminished renal clearence. However, the increase in AOPP levels was higher than what is expected in this degree of renal failure (glomerular filtration rate in the AA-RA group corresponding to chronic kidney disease stage III).

42. Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.

Kallenberg CG.

Curr Opin Rheumatol. 2007 19 (1): 17-24.

Purpose of review This review focuses on recent advances in the diagnosis, pathogenesis and treatment of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Recent findings Antineutrophil cytoplasmic autoantibodies are closely associated with Wegener’s granulomatosis and microscopic polynagiitis. Within the Churg-Strauss syndrome, antineutrophil cytoplasmic autoantibodies, mostly directed towards myeloperoxidase, characterize patients with glomerulonephritis and small-vessel vasculitis. There is increasing evidence that myeloperoxidase-antineutrophil cytoplasmic autoantibodies are directly involved in the pathogenesis of necrotizing vasculitis. This is less clear for proteinase 3-antineutrophil cytoplasmic autoantibodies, markers for Wegener’s granulomatosis. With respect to proteinase 3-antineutrophil cytoplasmic autoantibodies, complementary proteinase 3, a peptide translated from the antisense DNA strand of proteinase 3 and homologous to several microbal peptides, may be involved in induction of proteinase 3-antineutrophil cytoplasmic autoantibodies. Currently, various controlled trials hav been initiated. Methotrexate has been shown to be effective for induction of remission in locoregional Wegener’s granulomatosis. Other trials are underway. Summary Apart from its diagnostic potential, antineutrophil cytoplasmic autoantibodies, particularly myeloperoxidase-antineutrophil cytoplasmic autoantibodies, are directly involved in the pathogenesis of the associated vasculitidies. New treatment modalities, supposedly more efficacious and less toxic than daily oral cyclophophamide, are being tested in randomized controlled trials.

43. Antineutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis.

Chen M, Yu F, Wang SX et al.

J Am Soc Nephrol. 2007 18 (2): 599-605.

Pauci-immune crescentic glomerulonephritis (CrGN) is one of most common causes of rapidly progressive glomerulonephritis. The majority of patients with pauci-immune CrGN had circulating antineutrophil cytoplasmic autoantibody (ANCA). However, patients with ANCA-negative pauci-immune CrGN were not investigated fully. This study aimed to analyze the characteristics of this subgroup of patients. Patients whose pauci-immune CrGN was diagnosed from 1997 to 2006 in one were studied retrospectively. The criteria of pauci-immune was defined as ’’the intensity of glomerular immunoglobulins staining by direct immunoflurescence assay in renal section was negative to 1+ staining on a scale of 0 to 4+’’. Clincal and pathologic characteristics were compared between patients with and without ANCA. Among the 85 patients with pauci-immune CrGN, 28 (32.9%) were ANCA negative. Compared with 57 ANCA-positive patients, the ANCA-negative patients were much younger (39.7 +/- 17.0 versus 57.6 +/- 14.0 yr; P < 0.001). The level of urinary protein and prevalence of nephrotic syndrome were significantly higher in ANCA-negative patients than that in ANCA-positive patients (P < 0.01 and P < 0.001, respectively). However, the prevalence of extrarenal involvement was significantly lower in ANCA-negative patients than that in ANCA-positive patients. The renal survival was poorer in ANCA-negative patients than that in ANCA-positive ones (P < 0.05). ANCA-negative pauci-immune CrGN was not rare and might represent an independent disease entity from ANCA-positive vasculitis.

44. Churg-Strauss syndrome.

Pagnoux C, Guilpain P, Guillevin L.

Curr Opin Rheumatol. 2007 19 (1): 25-32.

Purpose of review Churg-Strauss syndrome is a small-vessel necrotizing vasculitis typically characterized by asthma, lung infiltrates, extravascular necrotizing granulomas and hypereosinophilia. The most recent clinical studies on its pathogenesis and treapeutic management are reviewed here. Recent findings French and Italian clinical studies found that the clinical characteristics of patients with Churg-Strauss syndrome differed according to their antineutrophil cytoplasmic autoantibody status: cardiomyopathy predominated in antineutrophil cytoplasmic autoantibody-negative patients while necrotizing glomerulonephritis was more often in antineutrophil cytoplasmic autoantibody-positive patients. These histologically documented findings suggest the existence of different Churg-Strauss syndrome subtypes, characterized by the predominance of distinct pathogenetic mechanisms, To date, following the therapeutic recommendations for Churg-Strauss syndrome (i.e. corticosteroids and, when required, immunosuppressants), patients outcomes are good, with 5-year survival exceeding 90%, but often with the need to continue low-dose corticosteroids to control residual asthma. Summary The precise pathogenetic mechanisms of Churg-Strauss syndrome are only partly elucidated. Recent results suggest that antineutrophil cytoplasmic autoantibodies are probably more involved in the vasculitic manifestations of Churg-Strauss syndrome (e.g. glomerulonephritis) whereas eosinophil tissue infiltration and associated cytotoxicity would be responsible for cardiomyopathy. If confirmed, these results could support individual therapeutic stratification according to the clinical pattern. Furthermore, some patients may benefit from new biologic therapies under development, for example antiinterleukin-5 or antiimmunoglobulin E monoclonal antibodies.

45. Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet.

Rodriguez-Iturbe B, Batsford S.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

Considerable insight has been gained into the etiopathogenesis of poststreptococcal glomerulonephritis since the landmark theoretical construct of Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever. Over the years, molecular mimicry between streptococcal products and renal components, autoimmune reactivity and several streptococcal antigens have been extensively studied. Recent investigations assign a critical role to both in situ formation and deposition of circulating immune complexes that would trigger a variety of effector mechanisms. Glomerular plasmin-binding activity of streptococcal glyceraldehyde-3-phosphate-dehydrogenase may play a role in nephritogenicity and streptococcal pyrogenic exotoxin B and its zymogen precusor may be the long-sought nephritogenic antigen.

46. Significance of glomerular cell apoptosis in the resolution of acute post-streptococcal glomerulonephritis.

Oda T, Yoshizawa N, Yamakami K et al.

Nephrol Dial Transplant. 2007 22 (3): 740-8.

Background Glomerular hypercellularity due to resident glomerular cell proliferation and leukocyte infiltration has been described in acute post-streptococcal glomerulonephritis (APSGN). APSGN usually resolves without progression. However, the mechanism of resolution remains to be determined. Methods Renal biopsy tissues from 15 patients with APSGN (obtained 1-31 days after disease onset) and five control patients with minor glomerular abnormality were evaluated with respect to glomerular resolution. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) as well as by immunostaining of single-stranded DNA (ssDNA). Results The number of glomerular cells was high in the early-phase of APSGN and decreased over time. No TUNEL+ glomerular cells were found in control subjects, whereas prominent glomerular TUNEL+ cells were observed in APSGN patients, particularly in the early phase of the disease. The number of glomerular TUNEL+ cells decreased exponentially but was still prominent in renal tissue biopsied at 31 days after disease onset. Double staining for ssDNA and glomerular cell markers showed that glomerular apoptotic cells were predominantly mesangium and endothelial cells, with some neutrophils and macrophages. Conclusions These results suggest that apoptosis exists in the glomerulus in patients with APSGN from early to the late stages of the disease and contributes to resolution of glomerular hypercellularity.

47. Is IgA nephropathy induced by abnormalities of CD4 (+) CD25 (+) Treg cells in the tonsils?

Huang H, Peng Y, Liu F et al.

Med Hypotheses. 2007 Feb 24, [Epub ahead of print].

IgA nephropathy (IgAN) is characterized by the accumulation of IgA deposits, predominatly in the glomerular mesangium, and represents the most common form of glomerulonephritis. Much evidence showed that tonsils were closely related to IgAN. Urinary findings were deteriorated after tonsil stimulation in patients with IgAN. Tonsillectomy can improve the urinary findings, keep stable renal function, improve mesangial proliferation, decrease IgA deposits and have a favorable effect on long-term renal survival in some IgAN patients. Recent studies that CD4 (+) CD25 (+) regulatory T cells (Treg) are of critical importance to the maintenance of tolerance by inhibiting the activation and proliferation of autoreactive T cells. Depletion of the minor CD4 (+) CD25 (+) Treg cells results in the development of organ-specific autoimmunity. Autoimmune disease can be prevented by reconstitution of the animals with CD4 (+) CD25 (+) Treg cells. CD4 (+) CD25 (+) Treg cells are regulators in almost all of the animal models of human organ-specific diseases, transplant rejection and allergic diseases. Some patients with recurrent chronic tonsillitis have not suffered from renal disease, implying that is possible to find a balance between immunity and tolerance. Some patients, however, suffered from IgAN along with recurrent chronic tonsillitis. It could be hypothesized that a numerical and/or functional deficit of CD4 (+) CD25 (+) Treg cells in the tonsils of IgAN patients might trigger the development of the diseases. If the hypothesis is correct, altering CD4 (+) CD25 (+) Treg numbers and/or enhancing CD4 (+) CD25 (+) Treg responses might be useful in the prevention and treatment of IgAN.

48. Involvement of transglutaminase-2 in pathological changes in renal disease.

Ikee R, Kobayashi S, Hemmi N et al.

Nephron Clin Pract. 2007 105 (3): c139-46.

Background Transglutaminase (Tg)-2 is shown to be related to renal fibrosis. However, its role in human kidney disease have not been fully studied. Methods Using immunohistochemistry, we examined Tg-2 expression in renal biopsy specimens from 22 patients with IgA nephropathy (IgAN) and correlated the intensity of Tg-2 staining with clinical and histopathological parameters. We compared the distribution and intensity of Tg-2 staining with those of transforming growth factor (TGF)-beta staining. Results In normal human kidneys, Tg-2 staining was not significant. In IgAN kidneys, glomerular Tg-2 staining correlated with serum creatinine (S-Cr), creatinine clearence (Ccr), urinary protein excretion, glomerular sclerosis, and mesangial cell proliferation. Tubulointerstitial Tg-2 correlated with S-Cr, Ccr, N-acetyl-beta-glucosaminidase, urinary beta (2)-microglobulin, and tubulointerstitial injuries. Tg-2 staining in the vicinity of vascular poles of glomeruli preceded the development of mesangial lesions, and was more remarkable in cases with renal impairment. The distribution and intensity of Tg-2 staining were not consistent with those of TGF-beta staining. In glomerular crescents, Tg-2 staining was remarkable. Conclusion The present study showed a correlation between Tg-2 expression and renal function and pathological changes. Tg-2 expression in the vicinity of vascular poles was notable because that may be an initial marker of glomeruar injury.

49. Is hypertension a tissue perfusion disorder? Implications for renal and myocardial perfusion.

Mourad JJ, Laville M.

J Hypertens. 2006 (Suppl 5): S10-6.

Structural alteration in the microcirculation form a major link between hypertension and target organ damage. More than 60% of the overall peripheral resistance of the circulatory system arises at the level of the microcirculation. The primary function of the microcirculation is to supply oxygen and nutriens to tissues. In hypertension, remodelling of the microvascular vessels occurs, leading to an early, functional then anatomical reduction in the number of arterioles or capillaries in a given vascular bed. Such changes have been seen in the structure and density of the microvasculature of different target organs such as the myocardium and the kidneys. In hypertension, capillary rarefaction induces in blood pressure, a relative decrease in tissue perfusion and an increased cardiovascular risk. Recent in-vivo non-invasive techniques for exploring the human microcirculation have allowed the detection of myocardial and renal microvascular impairment in hypertensive patients. In comparative therapeutic studies, antihypertensive drugs have been shown to have different capacities for preventing or reversing changes to the microvasculature of affected organs.

50. Disorders in high-density metabolism with insulin resistance and chronic kidney disease.

Kaysen GA.

J Ren Nutr. 2007 17 (1): 4-8.

Cardiovascular risk increases with each decrement in renal function. Low-density lipoprotein (LDL) cholesterol levels are not associated with increased mortality, but high-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Lipoprotein composition with increased abundance of small dense LDL and HDL and reduced levels of more buoyant isoforms is similar to what is found in states of insulin resistance and in the metabolic syndrome (MS). In both cases, high triglyceride levels are associated with reduced HDL levels. Chronic kidney disease (CKD) is itself with increasing insulin resistance as renal function fails. In both instances, decreased levels of apo A-I and apo A-II are a consequence of increased fractional catabolic rate (FCR), resulting from a predominance of small HDL particles. HDL maturation is impaired in CKD through decreased activity of lecithin : cholesterol acyltransferase (LCAT), and increased cholesterol ester transfer protein (CETP) activity in MS shuttles triglycerides back into HDL, thereby destabilizing it. Whether insulin resistance is entirely responsible for disorder of HDL metabolism in CKD, or whether the process is a result of unrelated pathophysiology, is currently unknown.

51. Adiponectin and chronic kidney disease.

Guebre-Egziabher F, Drai J, Fouque D.

J Ren Nutr. 2007 17 (1): 9-12.

Enhanced chronic inflammation and reduced insulin sensitivity are often present in chronic kidney disease (CKD). Cardiovascular disease remains a major cause of morbidity and mortality in end-stage renal patients. Adiponectin (ADP) is a hormone exclusively by adypocytes and possesses anti-inflammatory and cardioprotective properties. Despite the high prevalence of insulin resistance and cardiovascular disease, levels of ADP are increased among end-stage renal disease patients on hemo- or peritoneal dialysis but also among patients with moderate renal failure or with the nephrotic syndrome. Furthermore, lower ADP levels are associated with poor cardiovascular outcome. In this review, we examine ADP modifications in CKD and discuss the different factors that may have an impact on this adipokine metabolism in renal failure.

52. Expression pattern of genes in periheral blood mononuclear cells in diabetic nephropathy.

Moczulski DK, Fojcik H, Wielgorecki A et al.

Diabet Med. 2007 Jan 29; [Epub ahead of print].

Aims Only one-third of type 1 diabetes patients develop diabetic nephropathy, and a genetic predisposition is postulated. To obtain more insight into processes that lead to diabetic nephropathy, messenger RNA expression profiles of peripheral blood mononuclear cells from patients with and without diabetic nephropathy were compared. Methods We studied seven male patients with type 1 diabetes and proteinuria and 12 male patients with type 1 diabetes and normoalbuminuria after at least 20 years of diabetes duration. The expression of genes was examined using the microarray method with Human Genome U133A Arrays (Affymetrix, Santa Clara, CA, USA). We analysed the expression of all candidate genes suggested to be involved in the pathogenesis of diabetic nephropathy in previously published articles. Altogether, expression of 198 genes were ananlysed. Results We found that thrombospondin 1 (THBS1) and cyclooxygenase 1 (COX1) genes were overexpressed in patients with diabetic nephropathy, and matrix metalloproteinase 9 (MMP9) and cyclooxygenase 2 (COX2) genes had lower expression in diabetic nephropathy. For other genes, we did not observe different expression between patients with and without diabetic nephropathy, or the expression was too low for analysis. Conclusions The different gene expression pattern in peripheral blood mononuclear cells in patients with diabetic nephropathy might indicate an important pathway in the pathogenesis this complication.

53. Common polymorphisms of the PAI1 gene do not play a major role in the development of diabetic nephropathy in type 1 diabetes.

Martin RJ, Savage DA, Patterson CC et al.

Diabet Med. 2007 Jan 29; [Epub ahead of print].

Aim Plasminogen activator inhibitor 1 (PAI1) plays a key role in the regulation of extracellular matrix (ECM) degradation. The PAI1 gene is therefore an excellent candidate gene for diabetic nephropathy. The aim of this study was to employ gene resequencing to identify common DNA polymorphisms in the PAI1 gene, and subsequently assess haplotype tagged single nucleotid polymorphisms (htSNPs) using a case control design. Methods All nine exons, exon-intron boundaries, introns 1, 4 and 7 and approximately 3 kb upstream and 5 kb downstream of the PAI1 gene were screened for DNA polymorphisms in 15 case and 15 control subjects using WAVE (R) denaturing high-performance liquid chromatography technology and confirmed by DNA sequencing. Polymorphisms were genotyped in 86 healthy individuals using direct sequencing and haplotype tagged single nucleotide polymorphisms (htSNPs) identified. Genotyping of the htSNPs was performed in 583 type 1 diabetic patients (222 with nephropathy, 361 without nephropathy) using Pyrosequencing. Results Twenty-one polymorphisms with a minor allele frequency (MAF) > 1% were identified; 14 had a MAF >/= 10%. Five htSNPs [c.-1968_69insG, c.43 -- > A (Ala15Thr), c.1092-105 A -- >G, c.*1737 G-- >A, c.*3711 C-->T were identified. Haplotype frequencies were similar in case and control groups (likelihood ratio chi (2) test, P = 0.66). Conclusion It is unlikely that common polymorphisms of the PAI1 gene strongly influence susceptibility to diabetic nephropathy in the white type 1 diabetic population.

54. Altered chaperone and protein turnover regulators expression in cultured skin fibroblasts from type 1 diabetes mellitus with nephropathy.

Tessari P, Puricelli L, Iori E et al.

J Proteome Res. 2007 6 (3): 976-86.

In type-1 diabetes mellitus (T1DM) with diabetic nephropathy (DN), accumulation of abnormal proteins in the kidney and other tissues may derive from constitutive alterations of intracellular protein recognition, assembly, and turnover. We characterized the proteins involved in these functions in cultured skin fibroblasts from long-term T1DM patients with [DN+] or without [DN-] nephropathy but was similar metabolic control, and from matched healthy subjects. 2-D gel electrophoresis and MS-MALDI analysis were employed. The [DN+] T1DM patients, compared with two other groups, exhibited increased abundance of a high-molecular weight isoform of protein disulphide-isomerase A3 and a decrease of two low-molecular weight isoforms. They also had increased levels of heat shock protein (HSP) 60 kDa isoform #A4, of HSP71 kDa isoform #A30, and of HSP27 kDa isoform #A90 and #A71 were decreased. Cathepsin beta-2 (#40), the cation-independent mannose 6-phosphate receptor binding protein 1 (CIMPR) (#A27), and annexin 2 (#A9) were also decreased in the [DN+] T1DM patients, whereas the RNA-binding protein regulatory subunity (#38) and the translationally-controlled tumor protein (TCTP) (#A45) were increased. These changes of chaperone-like proteins in fibroblasts may highlight those of the kidney and be patho-physiologically related to the development of nephropathy in T1DM.

Keywords: proteomics * fibroblasts * diabetic nephropathy * protein folding * chaperones.

55. Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy.

Osawa N, Koya D, Araki SI et al.

J Hum Genet. 2006 Dec 2; [Epub ahead of print].

To elucidate the role of the renin-angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the gene that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P < 0.05), five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P = 0.01), odds ratio = 1.34, 95% CI 1.07-1.69). Three SNPs the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P = 0.01, odss ratio = 0.74, 95% CI 0.59-0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allale in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value = 0.00005). We concluded that RAS gene polymorphisms may contrbute to the susceptibility to diabetic nephropathy in type 2 diabetes.

56. Phenotypic transitions and fibrosis in diabetic nephropathy.

Simons MS.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

The cause of renal fibrosis in diabetic nephropathy is widely believed to be phenotypic switching of fibroblasts to an activated state. However, emerging evidence suggest that diabetes also alters the phenotype of normal, non-fibroblast kidney cells, such as mesangial cells, tubular epithelial cells, and bone marrow-derived progenitors. Experiments have shown that cytokines, high glucose, and advanced glycation end products induce profibrotic changes in kidney cell phenotype by the processes of myofibroblast transdifferentiation and and epithelial-mesenchymal transition. As a results, differentiated kidney cells become reprogrammed to secrete and accumulate extracellular matrix. This revised view implies that inhibiting phenotypic transition in nonfibroblasts might limit fibrosis in diabetic nephropathy.

57. Dysregulated intracellular signaling impairs CTGF stimulated responses in human mesangial cells exposed to high extracellular glucose.

Furlong FM, Crean J, Thornton L et al.

Am J Physiol Renal Physiol. 2007 Feb 27; [Epub ahead of print].

High ambient glucose activates intracellular signaling pathways to induce the expression of extracellular matrix and cytokines such as connective tissue growth factor (CTGF). Cell responses to CTGF in already glucose stressed cells may act to transform the mesangial cell phenotype leading to the development of glomerulosclerosis. We have analyzed cell signaling downstream of CTGF in high glucose stressed mesangial cells to model signaling in the diabetic milieu. The addition of CTGF to primary human mesangial cells activates cell migration which is associated with PKC-zeta-GSK3beta signaling axis. In high ambient glucose basal PKC-zeta and GSK3beta phosphorylation levels are selectively increased and CTGF stimulated PKC-zeta and GSK3beta phosphorylation was impaired. These effects were not induced by osmotic changes. CTGF driven profibrotic cell signaling as determined by p42/44 MAPK and Akt phosphorylation wetre unaffected by high glucose. Non responsiveness of the PKC-zeta-GSK3beta signaling axis suppressed effective re-modeling of the microtuble network necessary to support cell migration. However, interstingly the cell remain plastic: Modulation of glucose induced PKC-beta activity in human mesangial cells reversed some of the pathological effects of glucose damage in these cells. We show that inhibition of PKC-beta with LY379196 and PKC-beta siRNA, reduced basal PKC-zeta and GSK3beta phosphorylation in human mesangial cells exposed to high glucose. CTGF stimulation under these conditions again resulted in PKC-zeta phosphorylation and human mesangial cell migration. Regulation of PKC-zeta by PKC-beta in this instance may estabilish PKC-zeta as a target for constraining the progression of mesangial cell dysfunction in the pathogenesis of diabetic nephropathy.

Key words: CTGF * glucose * mesangial cells * diabetic nephropathy

58. Investigation of the estrogen receptor-{alpha} gene with type 2 diabetes and/or nephropathy in African-American and European-American populations.

Gallagher CJ, Keene KL, Mychaleckyj JC et al.

Diabetes. 2007 56 (3): 675-84.

The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-ajusted P(a) = 0.021). genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 Europen-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.

59. Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss.

Baelde HJ, Eikmans M, Lappin DW et al.

Kidney Int. 2007 Jan 31; [Epub ahead of print].

Micro-vascular and renal complications in diabetic patients are a considerable clinical challenge. In a previous study, we found a significant decrease in vascular endothelial growth factor A (VEGF-A) mRNA levels in glomeruli from patients with diabetic nephropathy (DN). We now set out to investigate the relationship between reduced VEGF-A and connective tissue growth factor (CTGF) expression levels, the number of podocytes, and the extent of interstitial fibrosis. Laser capture microdissection was applied to obtain glomerular RNA from patients with DN and 22 controls. MRNA levels of VEGF-A, CTGF, nephrin, podocin, and Wilms tumor1 (WT1) were measured using real-time polymerase chain reaction. Protein expression was evaluated using immuno-stainings for VEGF-A and CTGF, as well as markers for podocytes (WT1) and endothelial cells (CD31). We found a significant decrease in glomerular mRNA levels for VEGF-A (2.5 times), CTGF (1.6), nephrin (2.8), podocin (3.3), and WT1 (1.7) in patients with DN. There was a significant correletion between expression of podocyte markers and VEGF-A mRNA levels, and an inverse correlation between podocin message ant the extent of interstitial fibrosis. CD31-positive area was significantly decreased (3.2 times) in patients with DN. Reduction of angiogenic factors correlated with the extent of interstitial fibrosis. This downregulation was related to a reduction of podocytes in DN. The results may suggest that downregulation of VEGF-A and CTGF in DN is a result of podocyte loss.

60. Norepinephrine transporter gene (NET) polymorphism in patients with type 2 diabetes.

Ksiazek P, Buraczynska K , Buraczynska M.

Kidney Blood Pres Res. 2006 29 (6): 338-43.

Background Norepenephrine transporter (NET) is involved in the regulation of norepinephrine (NE) turnover and metabolism. Neuronal NE reuptake may be impaired in individuals with renal disease and/or hypertension due to dysfunction of the NE transporter. A silent G1287A nucleotide substitution in exon 9 of the NET gene was studied in human condition involving hypertension. We investigated its effect in patients with type 2 diabetes. Methods The study involved 215 type 2 diabetes patients with nephropathy, 95 patients with diabetes duration >/= 10 years, free of nephropathy, and 360 healthy subjects. All individuals were genotyped for NET-8 gene polymorphism with the PCR-RFLP method. Genotype and allele frequencies were compared between the groups. NE was measured by high-performance liquid chromatography and electrochemical detection. Results We genotyped 310 patients and 360 controls for the NET gene polymorphism. Genotype distribution in both groups was in accordance with the Hardy-Weinberg equilibrium. There were no significant differences in the frequency of genotypes and alleles between patients and controls (p = 0.43). The frequencies were also similar with nephropathy and those without. Aftter dividing the patients into hypertensive (n = 208) and normotensive (n = 102) subjects, there was a significant increase in the frequency of the AA genotype in patients with hypertension compared to normotensives (19 vs. 10%, p < 0.05). Conclusion No association was found between G1287A polymorphism in the NET gene and diabetes. Our results suggest that this polymorphism has a possible role in increased susceptibility to hypertension with type 2 diabetes.

61. A genome-wide search for linkage to renal function phenotypes in west africans with type 2 diabetes.

Chen G, Adeyemo AA, Zhou J et al.

Am J Kidney Dis. 2007 49 (3): 394-400.

Background Reduced renal funcrion often is a major consequence of diabetes and hypertension. Although several indices of renal function (eg, creatinine clearence) are clearly heritable and show linkage to several genomic regions, the specific underlying genetic determinants are still being sought. The purpose of this study is to conduct a genome-wide search for regions linked to 3 renal function phenotypes, serum creatinine, creatinine clearence, and glomerular filtration rate (GFR), in persons with type 2 diabetes. Methods A genome-wide panel of 372 autosomal short tandem repeat markers at an average spacing of 9 centimorgan were typed in 691 patients with type 2 diabetes (321 sib pairs and 36 half-sib pairs) in an affected sib pair study in West Africa. Linkage analysis was conducted with the 3 phenotypes by using a multipoint variance components linkage method. Result Creatinine clearence showed higher logarithm of odds (LOD) score than the other 2 phenotypes. Linkage to creatinine clearence was observed on chromosomes 16 (marker D16S539, LOD score of 3.56, empirical P = 0.0001), 17 (D17S1298, LOD score of 2.08, empirical P = 0.0018), and 7 (D7S1818, LOD score of 1.84, nominal P = 0.00181, empirical P = 0.0022). maximun LOD scores for serum creatinine were observed on chromosomes 10 (D10S1432, LOD score of 2.53, empirical P = 0.0001) and 3 (D3S2418, LOD score of. 2.21, empirical P = 0.0003) and for GFR on chromosomes 6 (D6S1040, LOD score of 2.08, empirical P = 0.0001) and 8 (D8S256, LOD score of 1.80, empirical P = 0.0001). Several of these results are replications of significant findings from other genome scans. Conclusion A genome-wide scan for serum creatinine, creatinine clearence, and GFR, in a West African sample showed linkage regions that may harbor genes influencing variation in these phenotypes. Potential candidate genes in these regions that have been implicated in diabetic nephropathy and/or renal damage in models of hypertension CYBA (or P22PHOX) (16q24), NOX1 (10q22), and NOX3 (6q25.1-q26).

62. Inflammation and diabetic nephropathy.

Mora C, Navarro JF.

Curr Diab Rep. 2006 6 (6): 463-8.

Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic consideration, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatment for diabetic nephropathy.

63. The role of TNF-alpha in diabetic nephropathy: Pathogenic and therapeutic implications.

Navarro JF, Mora-Fernandez C.

Cytokine Growth Factor Rev. 2006 17 (6): 441-50.

Diabetes mellitus and its complications are a public health problem. Diabetic nephropathy has become the main cause of renal failure, and furthermore is associated with a dramatic increase in cardiovascular risk. Unfortunately, the mechanisms leading to the development and progression of renal injury in diabetes are not yet fully known. There is now evidence that activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Furthermore, different inflammatory molecules, including pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), play a critical role in the development of microvascular diabetic complications, including nephropathy. This review discusses the role of TNF-alpha as a pathogenic factor in renal injury, focusing on diabetic nephropathy, and describes potential treatment strategies based on modulation of TNF-alpha activity.

64. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications.

Nishikawa T, Araki E.

Antioxid Redox Signal. 2007 Jan 1; [Epub ahead of print].

In this review, the importance of mitochondrial reactive oxygen species (ROS) on diabetes and its complications are described. In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all which are belived to be the main molecular mechanisms of diabetic complications. Glomerular hyperfiltration, one of the characteristics of early diabetic nephropathy, may be caused by mitochondrial ROS through activation of COX-2 gene transcription, followed by PGE (2) overproduction. In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppress the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH (2)-terminal kinases (JNK), increase serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. These results suggest the importance of mitochondrial ROS in the pathogenesis of diabetes mellitus and its complications through modification of various cellular events in many tissues, including vessels, kidney, pancreatic beta cells, and liver.

65. Renal microvascular injury in diabetes: RAGE and redox signaling.

Coughlan MT, Cooper ME, Forbes JM.

Antioxid Redox Signal. 2007 Jan 1; [Epub ahead of print].

Diabetic nephropathy remains a major cause of morbidity and mortality in the diabetic population and is the leading cause of end-satge renal failure in the Western World. Despite current therapeutics including intensified glycemic control and blood pressure lowering agents, renal disease continues to progress relentlessly in diabetic patients, albeit at a lower rate. It is well recognized that metabolic and hemodynamic factors play a central role in accelerating renal disease in diabetes. However, recent experimental studies have suggested that increased generation of reactive oxygen species (ROS) as a results of the diabetic milieu may play a central role in the progression of diabetic microvascular complications. These ROS appear to be generated primarily from mitochondrial sources and via the enzyme, NADPH oxidase. This review focuses on how ROS play a deleterious role in the diabetic kidney and how they are involved in crosstalk among various signaling pathways, ulimately leading to renal dysfunction and structural injury.

66. Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes.

Mostafa AA, Randell EW, Vasdev SC et al.

Mol Cell Biochem. 2007 Feb 21; [Epub ahead of print].

In diabetes mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator or nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18-36 years) and eighteen individuals without diabetes (17-35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (mug/l) and CEC (mug/l) were significantly higher in DM (55.73 +/- 29.43, 521.47 +/- 239.13, respectively) compared to controls (24.25 +/- 10.26, 262.85 +/- 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.

67. Lipids and diabetic nephropathy.

Rosario RF, Prabhakar S.

Curr Diab Rep. 2006 6(6): 455-62.

Although several factors may mediate the development and progression of diabetic nephropathy, hyperlipidemia is now considered an independent and major determinant of progression of renal disease in diabetes. The following discussion focuses on the experimental evidence that incriminates hyperlipidemia as a pathogenic factor for diabetic nephropathy and the potential mechanisms that may mediate renal injury from hyperlipidemia, as well as the clinical studies involving therapeutic interventions for hyperlipidemia and their impact on progression of diabetic renal disease.

68. Identification of the glomerular podocyte as a target for growth hormone action.

Reddy GR, Pushpanathan MJ, Ransom RF et al.

Endocrinology. 2007 Feb 1; [Epub ahead of print].

Growth hormone (GH) excess in both the human and in transgenic animal models is characterized by significant changes in blood pressure and renal function. The GH/GH receptor (GHR) axis is also implicated in the development of diabetic nephropathy. However, it is not clear if GH’s actions on renal funtion are due to indirect actions mediated via changes in blood pressure and vascular tone or due to direct action of GH on the kidney. We hypothesized that functional GHRs are expressed on the glomerular podocyte enabling direct actions of GH on glomerular function. Real-time PCR, immunihistochemistry, and Western blot analysis of murine podocyte (MCP-5) and kidney glomeruli demonstrated expression of GHR mRNA and protein. Exposure of both murine and human podocytes to GH (50-500 ng/ml) resulted in an increase in abundance of phosphorylated STAT5, JAK2 and ERK1/2 proteins. Exposure of podocytes to GH also caused changes inthe intracellular distribution of the JAK2 adapter protein SH2-Bbeta, stimulation of focal adhesion kinase, increase in reactive oxygen species (ROS), and GH-dependent changes in the actin cytoskeleton. We concluded that glomerular podocytes express funtional GHRs and that GH increases levels of ROS and induces reorganization of the actin cytoskeleton in these cells. These results provide a novel mechanistic link between GH’s actions and glomerular dysfunction in disorders such as acromegaly and diabetic glomerulosclerosis.

69. Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase.

Shastry S, Ingram AJ, Scholey JW et al.

Kidney Int. 2006 Dec 6; [Epubahead of print].

Hyperhomocysteinemia is prevalent among patients with chronic kidney disease (CKD) and has been linked to progressive kidney and vascular disease. Increased glomerular mesangial cell (MC) turnover, including proliferation and apoptosis, is a hallmark of CKD. Activation of p38-mitogen-activated protein kinase (p38-MAPK) has been linked to apoptosis in many cell lines. Accordingly, we studied the effect of homocysteine (Hcy) on MV p38-MAPK signalling and apoptosis. Hcy (50 muM/24 h) increased MC apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) and single-stranded DNA (ssDNA) analysis. In addition to increases in pro-caspase-3 protein and caspase-3 activity, cells exposed to Hcy manifested enhanced reactive oxygen species content. Hcy increased p38-MAPK activity (fivefold), with maximal effect at 5 muM and 20 min; p38-MAPK activation was attenuated by N-acetylcysteine (Nac) and catalase (Cat), further indicating that the effect was via oxidative stress. Confocal microscopy revealed activation and nuclear translocation of p38-MAPK that was attenuated by Cat. In addition, Hcy-induced apotosis as determined by TUNEL and ssDNA assay was abrogated by Nac, Cat, and SB203580 (p38-MAPK inhibitor). We conclude that in MC, Hcy (i) activates p38-MAPK and increases p38MAPK nuclear translocation via an oxidative stress dependent mechanism and (ii) induces DNA damage and apoptosis that is dependent on oxidative stress and p38-MAPK activation.

70. Membrane targeting and secretion of mutant uromodulin in familial juvenile hyperuricemic nephropathy.

Jennings P, Aydin S, Kotanko P et al.

J Am Soc Nephrol. 2007 18 (1): 264-73.

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant genetic disorder that is characterized by hyperuricemia, gout, and tubulointerstitial nephritis. FJHN is caused by mutations in the UMOD gene, which encodes for uromodulin, the most abundant urinary protein. Herein is demonstrated that patients with FJHN and renal insufficiency exhibit a profound reduction in urinary uromodulin together with either elevated or decreased plasma uromodulin. One young patient with FJHN, however, had normal serum creatinine and normal urinary uromodulin with elevated plasma uromodulin. These observation suggest that there are different urinary and plasma uromodulin profiles in early and late disease and that there may be an altered direction of uromodulin secretion in the course of FJHN as a result of improper intracellular sorting of the mutated protein in the thick ascending limb. With the use of immunohistochemistry and a quantitative immunoassy, targeting and secretion of wild-type and mutant (C77Y and N128S) uromodulin were investigated in the polarized renal epithelial cell line LLC-PK1. In transfected cells, uromodulin mutants were targeted properly to the apical membrane but were secreted less efficiently to the apical compartment than wild-type protein. The expression of mutant uromodulin had no effect on caspase 3 activity. These results indicate that the mutations studied do not impair glycosyl-phosphatidylinositol-mediated apical targeting of the protein but do affect apical secretion. Because the mutant proteins are secreted as efficiently as wild type to the basolateral compartment, the possibility arises that interactions with the immune system at the site of secretion are contributing factor to the development of tubulointerstitial nephritis in FJHN.

71. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome.

Richards A, Kathryn Liszewski M, Kavanagh D et al.

Mol Immunol. 2007 44 (1-3): 111-22.

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic uremic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in CMP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanism leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homzygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduce ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst > 50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.

72. Thin basement membrane nephropathy cannot be diagnosed reliably in deparaffinized, formalin-fixed tissue.

Nasr SH, Markowitz GS, Valeri AM et al.

Nephrol Dial Transplant. 2007 Feb 3; [Epub ahead of print].

In diagnostic renal pathology, electron microscopy is ideally performed on glutaraldehyde-fixed, plastic resin-embedded tissue (EM-G). When no glomeruli are present in the portion of the biopsy fixed in glutaraldehyde, formalin-fixed, paraffin-embedded tissue can be reprocessed for electron microscopy (EM-F). The usefulness of this slavage technique for the diagnosis of thin basement membrane nephropathy (TBMN) has not been studied systematically. Here we compare the glomerular basement membrane (GBM) thickness by EM-G vs EM-F in 21 renal biopsies, including TBMN (eight patients), normals (two patients), minimal change disease (MCD) (six patients) and diabetic nephropathy (DN) (five patients). There was significant reduction of the GBM thickness by EM-F compared with EM-G all diagnostic categories in all 21 cases. The mean percentage reduction in GBM thickness was 23% for the TBMN cases, 40% for the normal/MCD cases and 34% for the DN cases. Four patients with MCD had a mean GBM thickness by EM-F that fell below the defining threshold for diagnosis of TBMN. For the TBMN cases, the 99th perecentile for GBM thickness by EM-F was 194 nm, suggesting that the diagnosis of TBMN by EM-F can be excluded with confidence if the GBM thickness is above 200 nm. No clear criteria could be estabilished to diagnose TBMN by EM-F. Renal pathologists should be aware that reprocessing of paraffin tissue for EM causes artifactual GBM thinning that precludes accurate diagnosis of TBMN.

III. CLINICAL PRESENTATION

1. Advances in urinary proteome analysis and biomarker discovery.

Fliser D, Novak J, Thongboonkerd V et al.

J Am Soc Nephrol. 2007 Feb 28, [Epub ahead of print].

Noninvasive diagnosis of kidney disease and assessment of the prognosis are still challenges in clinical nephrology. Definition of biomarkers on the basis of proteome analysis, especially of the urine, has advanced recently and may provide new tools to solve those challenges. This article highlights the most promising technological approaches toward deciphering the human proteome and applications of the knowledge in clinical nephrology, with emphasis on the urinary proteome. The data in the current literature indicate that although a thorough investigation of the entire urinary proteome is still a distant goal, clinical applications are already available. Progress in the analysis of human proteome in health and disease will depend more on the standardization of data ana availability of suitable bioinformatics and software solutions than on new technological advances. It is predicted that proteomics will play an important role in clinical nephrology in the very near future and that this progress will require interactive dialogue and collaboration between clinicians and analytical specialists.

2. Diagnostic potential for urinary proteomics.

Hortin GL, Sviridov D.

Pharmacogenomics. 2007 8 (3): 237-55.

Urine represents a modified ultrafiltrate of plasma, with protein concentrations typically approximately 1000-fold lower than plasma. Urine’s low protein concentration might suggest it to be a less promising diagnostic specimen than plasma. However, urine can be obtained noninvasively and tests of many urinary proteins are well-estabilished in clinical practice. Proteomic technologies expand opportunities to analyze urinary proteins, identifying more than 1000 proteins and peptides in urine. Urine offers a sampling of most plasma proteins, with increased proportions of low-molecular-weight protein and peptide components. Urine also offers enriched sampling of proteins released along the urinary tract. Although urine presents some challenges as a diagnostic specimen, its diverse range of potential markers offers great potential for diagnosis of both systemic and kidney diseases. Examples of clinical situations where this may be of value are for more sensitive detection of kidney transplant rejection or of renal toxicity of medications.

3. Circulating levels of visfatin/pre-B-cell colony enhancing factor 1 in relation to genotype, GFR, body composition, and survival in patients with CKD.

Axelsson J, Witasp A, Carrero JJ et al.

Am J Kidney Dis. 2007 49 (2): 237-44.

Background Visfatin, also known as pre-B-cell colony-enhancing factor 1 (PBEF-1), recently was shown to be secreted from adipocytes and have insulin-mimetic properties in mice. Because renal failure per se is associated with both increased levels of circulating peptides and marked insulin resistance, even in the absence of diabetes mellitus, we hypothesized that visfatin could be a factor linking inflammation, kidney disease, and insulin resistance in this patient group. Methods Altogether, we studied 189 patients with chronic kidney disease (CKD), comprising with CKD stage 5 (glomerular filtration rate [GFR] < 15 mL/min; 7 +/- 2 mL/min [< 0.25 mL/s; mean, 0.12 +/- 0.03 mL/s]; 61% men; mean age, 54 +/- 12 years) and 40 patients with CKD stages 3 to 4 (GFR, 15 to 60 mL/min; mean 33 +/- 21 mL/min [0.25 to 1.00 mL/s; mean, 0.55 +/- 0.35 mL/s]; age, 59 +/- 15 years). We compared these with 30 randomly selected population controls (mean GFR, 85 +/- 16 mL/min [1.42 +/- 0.27 mL/s]; age, 64 +/- 11 years). Serum visfatin was measured by using commercially available enzyme-linked immunosorbent assay, and we also performed genotyping of 3 verified polymorphims in the visfatin gene (-423A/G, -1001T/G, and –1535C/T). Body fat was estimated by using dual-energy x-ray absorptiometry. Results Serum visfatin levels were greater in patients with CKD stage 5 (41.3 +/- 18.0 ng/mL) than in those with CKD stages 3 to 4 (34.0 +/- 9.8 ng/mL; P < 0.01 varsus CKD stage 5) or healthy controls (29.3 +/- 8.1 ng/mL; P < 0.0001). However, there was no significant differences between patients with and without diabetes, and the significant differences in circulating visfatin levels between genotypes disappeared after adjusment for differences in age, sex, GFR, and serum albumin level. In univariate analysis, visfatin level correlated with levels of GFR (rho = -0.22; P = 0.001), interleukin 6 (IL-6; rho = 0.17; P = 0.01), high-sensitivity C-reactive protein (rho = 0.14; P < 0.05), and soluble vascular cell adhesion molecule 1 (sVCAM-1), but not total or truncal fat mass, insulin resistance, or hemoglobin A (1c) level, High plasma visfatin level predicted mortality in patients with CKD, also after adjusment for age and sex (likelihood ratio, 18.2; P < 0.0001), but not after additional correction for GFR, sVCAM-1, serum albumin, and serum IL-6 levels. Conclusion Circulating levels of the visfatin/PBEF-1are influenced by renal function, but are not associated with fat mass or surrogate of insulin resistance in patients with CKD. Visfatin was associated independently with level of sVCAM-1, a marker of endothelial damage.

4. Kidney function and risk of peripheral arterial disease: Results from the Atherosclerosis Risk in Communities (ARIC) Study.

Wattanakit K, Folsom AR, Selvin E et al.

J Am Soc Nephrol. 2007 18 (2): 629-36.

Chronic kidney disease (CKD) is associated with an increased risk for cardiovascular disease, but its association with peripheral arterial disease (PAD) is unclear. With the use of data from the Atherosclerosis Risk in Communities (ARIC) Study, 14 280 middle-aged adults were categorized on the basis od estimated GFR >/= 90, 60 to 89, and 16 to 59 ml/min per 1.73 m (2) for normal kidney function, mildly decreased kidney function, and stages 3 to 4 CKD, respectively. Incident PAD was defined as new onset of ankle-brachial index < 0.9 assessed at regular examinations, new intermittent claudication assessed by annual surveillance, or PAD-related hospital discharges. Incidence rates and relative risks (RR) for PAD were compared across these categories. During a mean follow-up time of 13.1 yr (186 616 person-years), 1016 participants developed PAD. The incidence per 1000 person-years were 4.7, 4.9, and 8.6 for the normal kidney function, mildly decreased kidney function, and CKD groups, respectively. Compared with participants with normal kidney function, the age-, gender-, race-, and ARIC field center-adjusted RR for PAD was 1.04 (95% confidence interval [CI] 0.91 to 1.18) for those with mildly decreased kidney function and 1.82 (95% CI 1.34 to 2.47) for those with CKD. After additional adjusment for cardiovascular disease risk factors, an increase in risk for incident PAD still was observed in participants with CKD, with a multivariable adjusted RR of 1.56 (95% CI 1.13 to 2.14). Patients with CKD are at increased risk for incident PAD. Development of strategies for screening and prevention of PAD in this high-risk population seems warranted.

5. Spectrum of renal failure in elderly patients.

Kohli HS, Bhat A, Sud K et al.

Int Urol Nephrol. 2007 Jan 23; [Epub ahead of print].

This prospective study was undertaken to study the spectrum of renal failure and the outcome in elderly patients. Patients included in the study group were elderly (age > 60 years) who either attended outpatients renal clinic and or were hospitalized. Renal failure was classified as acute renal failure (ARF), rapidly progressive renal failure (RPRF) and chronic renal failure (CRF). A total of 4255 elderly patients were seen, of these 236 (5.5%) had renal failure. Mean age was 65.1 +/- 4.2 years (60-86 years). CRF was the commonest, seen in 137 (58.1%) followed by ARF 69 (29.2%) and RPRF in 30 (12.7%) patients. Diabetic nephropathy was commonest cause of CRF, seen in 58.4% followed by chronic interstitial nephritis in 9.5% and chronic glomerulonephritis in 8.7% of patients. Of 137 patients 53 (38.7%) presented in end stage renal disease (ESRD). Of these 41 (77.3%) were initiated on maintenance hemodialysis and 12 (22.6%) on continous ambulatory peritoneal dialysis. Only 15 patients were on dialytic support at the end of 1 year. Sepsis contributed to ARF in 75.4% of cases. Forty of 69 patients (57.9%) needed dialytic support. Forty (57.9%) were critically ill, defined as presence of two or more organ system failure (excluding renal failure). Forty two patients (60.9%) died patients. Acute interstitial nephritis (AIN) was the commonest cause of RPRF seen in 10 (33.3%) patients followed by vasculitis in 7 (23.3%). Myeloma cast nephropathy contributed towards RPRF in 20% of patients. Of 30 patients, 10 (33.3%) reached ESRD at end of 3 months of follow-up, 4 (13.3%) died due to sepsis. Only 2 showed complete recovery while 14 (46.6%) had partial improvement. AIN patients had a relatively better otucome.

6. Derivation and validation of a clinical index for prediction of rapid progression of kidney dysfunction.

Hemmelgarn BR, Culleton BF, Ghali WA.

QJM. 2007 100 (2): 87-92.

Background Chronic kidney disease is common among the elderly, and these patients are at risk of progressive kidney dysfunction. Aim To develop and index to predict rapid progression of kidney dysfunction. Design Community-based cohort divided into derivation (n = 6789) and validation (n = 3395) subsets. Methods We identified 10 184 subjects aged >/= 66 years from computerized laboratory data. Prescription drug data was used to define disease categories and medication exposure, and an index for predicting rapid progression of kidney dysfunction (>/= 25% decline in glomerular filtration rate over a 2-year period) was obtained from a logistic regression model in the derivation cohort. The risk score for each subject was calculated by summaring the component variables together, which were subsequently categorized into five risk classes. Results Five predictors of rapid progression were identified: age > 75 years, cardiac disease, diabetes mellitus, gout, and use of anti-emetic medictaions. Rates of rapid progression for risk classes I through V were 8.6%, 10.9%, 13.9%, 15.6% and 24.1%, respectively, for the derivation cohort, and 8.4%, 11.6%, 15.5%, 17,3%, 21.9%, respectively, for the validation cohort. The risk index distinguished between low and high risk of rapid progression, with a 2.5-fold greater risk for the highest, compared to lowest, risk decile. Discussion Readily available clinical data can be used to identify most elderly at risk of rapid progression of kidney dysfunction. This simple index could help clinicians to identify patients at risk, and implement strategies to slow the progression of kidney dysfunction.

7. Effect of organic solvent exposure on chronic kidney disease progression: The GN-PROGRESS Cohort Study.

Jacob S, Hery M, Protois JC et al.

J Am Soc Nephrol. 2007 18 (1): 274-81.

It has been suggested that solvent exposure may have a role in the progression of glomerulonephritis (GN) to ESRD, but this has never been tested with an appropriate cohort study design. A total of 338 patients with a first biopsy for primary GN between 1994 and 2001 were included: 194 IgA nephropathies (IgAN), 75 membranous nephropathies (MN), and 69 FSGS. ESRD, defined as an estimated GFR < 15 ml/min per 1.73 m(2) or dialysis, was registered during a mean follow-up period of 5 yr. Patients’ lifelong solvent exposures before and after diagnosis were recorded by interview an assessed by industrial hygienist experts. Cox model were used to estimate adjusted hazard ratios (HR) of ESRD related to exposures. Overall, 15 and 14% of the patients had been exposed at a low and high level before diagnosis, respectively. Forty-two with IgAN, 12 with MN, and 22 with FSGS reached ESRD. A graded relationship was observed for MN (age- and gender-adjusted HR [95% confidence interval] for low exposure versus none was 3.1 [0.5 to 18.2] and for high exposure versus none was 8.2 [1.9 to 34.7]) and for IgAN (1.6 to 3.91] and 2.2 [1.0 to 4.8]) but not for FSGS. Solvent risk was meadiated by only partly by baseline proteinuria: Adjusted HR for high exposure versus none was 5.5 (1.3 to 23.9) for MN and 1.8 (0.8 to 3.9) for IgAN. In patients with IgAN, there was a trend in increasing HR with exposure duration before and its persistence after diagnosis. These findings support the hypothesized association of solvent exposure with the progression of GN to ESRD. They should prompt clinicians to give greater attention to patients’ occupational exposures and possibly to consider professional reclassification.

8. The association of anemia and hypoalbuminemia with accelerated decline in GFR among adolescents with chronic kidney disease.

Furth SL, Cole SR, Fadrowski JJ et al.; The Council of Pediatric Nephrology and Urology, New York/New Jersey; The Kidney and Urology Foundation of America.

Pediatr Nephrol. 2006 Nov 21; [Epub ahead of print].

We sought to describe rates of kidney function decline and to identify modifiable risk factors for CKD progression in a multicenter prospective cohort study of adolescents with CKD aged 11 to 18 years seen semiannually for up to three years. Of the 23 subjects meeting iclusion criteria, the average estimated GFR was 51 +/- 27 ml/min/1.73 m(2) (0.85 +/- 0.45 ml/min/1.73 m(2) ) at entry. The overall annualized decline in GFR was 5.6 ml/min/1.73 m(2) (0.093 ml/s/1.73 m(2)) per year (95% confidence interval [95% CI]: 1.9 to 9.3 [0.032 to 0.16]). The adjusted decline in GFR was found to be accelerated in males, as well as among those over 15 years of age. The adjusted annualized decline in GFR was greater among those with either anemia (hematocrit below 36%), or hypoalbuminemia (albumin below 4 g/dl [40 g/L]). After adjusment, anemia was associated with an accelerated decline of 7.8 ml/min/1.73 m(2) (0.13 ml/s/1.73 m(2)) (95% CI: 3.3 to 12 [0.055 to 0.21]) and hypoalbuminemia was associated with an accelerated decline of 17 ml/min/1.73 m(2) (0.28 ml/s/1.73 m(2)) (95% CI: 11 to 22 [0.18 to 0.37]). Further study is needed to evaluate whether treatment of anemia or hypoalbuminemia, as outlined in current clinical care guidelines for CKD, may slow the progression of CKD in adolescents.

9. Functional impairment of monocyte-derived dendritic cells in patients with severe chronic kidney disease.

Verkade MA, van Druningen CJ, Vaessen LM et al.

Nephrol Dial Transplant. 2007 22 (1): 128-38.

Background Dendritic cells (DCs) are antigen-presenting cells that are pivotal for the initiation of the primary immune response. Patients with chronic kidney disease (CKD) with or without chronic intermittent haemodialysis (CIHD) show an impaired immune response. Dysfunction of DCs may underlie this phenomenon. Methods In this study, several different functions of monocyte-derived DCs (moDC) of patients with CKD class IV-V (glomerular filtrationn rate < 30 ml/min) and patients on CIHD were studied in vitro and compared with age- and sex-matched healthy volunteers. Results We demonstrate that, independent of the maturation stimulus used, mature moDC from both groups of patients did not acquire the same level of terminal differentiation as moDC from controls, as shown by analysis of cell surface markers and the relative high macropinocytosis activity of moDC. The stimulation of allogenic T-cells by immature moDC and mature moDC did not differ between patients and controls. However, in the presence of immature moDC or antigen-loaded matured moDC from patients, less proliferation of autologous T-cells was observed in response to recall antigens. There was no difference between moDC from controls and patients in their ability to activate naive T-cell and to differentiate them into TH1 and TH2 cells. Conclusions These results show that the terminal differentiation of moCD in patients with severe CKD is impaired. This impairment is not restricted to one maturation stimulus and is independent of treatment with haemodialysis.

10. Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD.

Axelsson J, Moller HJ, Witasp A et al.

Am J Kidney Dis. 2006 48 (6): 916-25.

Background Recently, adipose tissue was shown to contain macrophages capable of contributing to systemic inflammation and cardiovascular disease (CVD). Here, we investigate this putative relationship in patients with chronic kidney disease (CKD) by using the novel macrophage marker soluble (s) CD163. Methods One hundred twenty patients with CKD stage 5 (mean glomerular filtration rate [GFR], 7 +/- 1 mL/min [0.12 +/- 0.02 mL/s; mean age 53 +/- 1 years; 65% men), 38 patients with CKD stages 3 to 4 (mean GFR, 33 +/- mL/min [0.55 +/- 0.05 mL/s]; mean age, 67 +/- 2 years; 68% men), and 28 healthy controls (mean GFR, 89 +/- 3 mL/min [1.48 +/- 0,05 mL/s]; mean age, 63 +/- 2 years; 69% men) were characterized post hoc with a follow-up to 5 years (mean, 47 +/- months). sCD163 levels, body composition (dual-energy x-ray absorptiometry), clinical parameters, and levels of circulating inflammatory markers (enzyme-linked immunosorbent assay) were assessed at baseline and, in a subset population, after 1 year of dialysis therapy (hemodialysis, n = 19; peitoneal dialysis, n = 30). Results sCD163 level increased in patients with both severe (median, 4.3 mg/L; range, 1.3 to 23.4 mg/L) and moderate (median, 3.6 mg/L, range, 1.6 to 9.8 mg/L) CKD compared with controls (median, 2.6 mg/L; range, 0.8 to 7.6 mg/L; P < 0.001). Furthermore, sCD163 levels correlated with both truncal (rho = 0.17, P < 0.05) and total (rho = 0.17, P < 0.05) fat mass, as well as with all measured markers of inflammation and endothelial adhesion molecules. After 1 year, patients who increased body fat mass (average, 11% +/- 5% versus –5% +/- 5%, P < 0.05) also showed a significant increase in sCD163 levels (median, 2.2 versus –0.97 mg/L, P < 0.01). Finally, patients with sCD163 levels greater than 4.0 mg/L had a statistically significantly worse outcome than patients with sCD163 levels less than this value, even after adjusment for age, sex, and diabetes mellitus(chi-square = 19.98; P < 0.001). However, this effect was lost after adjusment for either inflammation or CVD. Conlusion We show that increasing fat mass is associated with increasing levels of sCD163, a circulating marker of macrophages also associated with inflammatory biomarkers. We thus hypothesize that adipose tissue macrohages may have a role in the proinflammatory state observed in patients with renal disease. Finally, we propose the term ’’uremic-metabolic syndrome’’ to describe this state of increased adipose tissue signaling in patients with uremia, a phenomenon that may share some characteristics with the metabolic syndrome of obesity.

11. Adiponectin and renal function, and implication as a risk of cardiovascular disease.

Iwashima Y, Horio T, Kumada M et al.

Am J Cardiol. 2006 98 (12): 1603-8.

The relation among adiponectin, renal function, and incident cardiovascular disease (CVD) in patients with different degrees of renal dysfunction was investigated. In total, 150 subjects were included in this study and followed prospectively for a mean of 32 months. At baselin, adiponectin levels for chronic kidney disease (CKD) stages 1, 2, 3, 4 and 5, as estimated by creatinine clearence (> or = 90, 60 to 90, 30 to 60, < 30 ml/min), were 3.06, 4.04, 6.43, and 11.9 microg/ml (p for trend < 0.01), and a significant association between adiponectin and CKD stages was also confirmed in multivariate regression analysis (F = 6.2, p < 0.001). During follow-up, 31 subjects developed CVD, including myocardial infarction, angina pectoris, and stroke, and transient ischemic attack. Gender-specific median values of adiponectin were used to separate the higher group from the lower group, and the Kaplan-Meier curve showed a significantly lower event-free survival rate in the lower adiponectin group (< 4.39 microg/ml in men, < 6.84 microg/ml in women, chi-square 4.88, p < 0.03). The risk factor-adjusted Cox regression showed that an increase in idiponectin per 1 microg/ml was associated with a decrease in the risk of CVD to 0.86 (95% confidence interval 0.75 to 0.96, p = 0.004). In the subgroup with previous ischemic heart disease (IHD; n = 65), a significantly lower event-free survival rate of IHD was also observed in the lower adiponectin group (< 4.45 microg/ml in men, < 4.49 microg/ml in women, chi-square 3.96, p < 0.05). The relative distribution of adiponectin isoforms was examined in patients with severe CKD, and the percentage of the high-molecular-weight form in patients with IHD during follow-up (n = 3) was significantly smaller than that in those without IHD (n = 4, p < 0.02). In conclusion, renal function is a significant regulator of adiponectin when categorized by CKD stage, whereas hypoadiponectinemia is a predictor of CVD, including recurrent IHD.

12. Insulin resistance, inflammation, and blood pressure determine vascular dysfunction in CKD.

Dogra G, Irish A, Chan D et al.

Am J Kidney Dis. 2006 48 (6): 926-34.

Background Conventional cardiovascular risk equations underestimated the risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD), implying a role for novel risk factors. Our aim was to compare vascular function and arterial compliance, known markers of CVD, between patients with CKD and healthy controls and examine their association with traditional and novel CVD risk factors. Methods vascular function was determined by using high-resolution ultrasonography to measuer brachial artery endothelial-dependent flow-mediated dilatation (FMD) and endothelial-independent glyceril trinitrate (GTN)-mediated dilatation. Arterial compliance was measured by using pulse contour analysis to generate large-artery (C1) and small-artery (C2) compliance. We also examined the relationship between vascular function, arterial compliance and blood pressure, lipid and lipoprotein levels, insulin resistance, inflammation, oxidative stress, and calcium and phosphate levels in 105 patients with CKD and 40 healthy controls. Results Vascular function and arterial compliance were significantly impaired in patients with CKD compared with healthy controls: mean FMD, 3.8% +/- 0.3% (SE) versus 5.7% +/- 0.6%; GTN.mediated dilatation, 15.7% +/- 0.9% versus 19.6% +/- 1.0%; C1, geometric mean, 12.1 mL/mm Hg; 95% confidence interval (CI), 11.2 to 13.1 versus 15.1 ml/mm Hg; 95% CI, 13.7 to 16.5; and C2, 3.8 mL/mm Hg; 95% CI, 3.4 to 4.3 versus 5.0mL/mm Hg; 95% CI, 4.2 to 6.0; all P < 0.05. Patients with CKD had greater waist-hip ratios, systolic blood pressures (SBPs), pulse pressures, triglyceride levels, oxidized low-density lipoprotein levels, high-sensitivity interleukin 6 levels, and Homeostasis Model Assessment (HOMA) scores (all P < 0.05) and lower high-density lipoprotein levels (P < 0.001). In patients with CKD, HOMA score and SBP were associated negatively with FMD (model R (2) = 0.28; P < 0.001), and SBP and waist-hip ratio were associated negatively with GTN-mediated dilatation (model R (2) = 0.25, P < 0.001). Pulse pressure was associated negatively with C1 (R (2) = 0.37; P /= 50% of glomeruli +/- membranous glomerulonephritis (class III >/= 50% +/- V) were significantly more common (white 44%, black 76%, other 36%; P < 0.05) and diffuse proliferative glomerulonephritis +/- membranous glomerulonephritis (class IV +/- V) was less common (white 54%, black 24%, other 65%) among black patients. Attainment of a remission among white patients (white 52%, black 29%, other 27%; P = 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV +/- V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P = 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P = 0.015) were significantly poorer in black patients. Preditors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class III > / = 50% +/- V lesions, and failure to achive a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were assocated with more aggressive renal disease and resulted in worse outcomes than white patients.

31. Acute amphotericin B overdose.

Burke D, Lal R, Finkel KW et al.

Ann Pharrmacother. 2006 40 (12): 2254-9.

Objective To report the clinical course of a women with cryptococcal meningitis and no previous cardiac disease who developed a fatal cardiac arrhythmia after an acute overdose of amphotericin B and to review its toxicity. Case summary A 41-year-old woman with a history of proliferative glomerulonephritis from systemic lupus erythematosus was addmitted with a diagnosis of cryptococcal meningitis.Liposomal amphotericin B was prescribed at the standard dose of 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently administered (usual dose of deoxycholate formulation is 0.5-0.8 mg/kg/day). The patient developed cardiac arrhythmias, acute renal failure, and anemia. The medication error was noticed after she had received 2 doses of amphotericin B deoxycholate, and it was then discontinued. Despite treatment in the intensive care unit, the women died on the sixth day after admission. Discussion Amphotericin B deoxycholate has been reported to produce significant cardiac toxicity, with ventricular arrhythmias and bradycardia reported in overdose in children and in adults with preexisting cardiac disease, even when administered in conventional dosages and infusion rates. Use of the Naranjo probability scale indicated a highly probable relationship between the observed cardiac toxicity and amphotericin B deoxycholate therapy in this patients. Conclusions Given the fulminat course of amphotericin B deoycholate overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place.

32. Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid syndrome.

Mora CS, Segami MI, Hidalgo JA.

Semin Arthritis Rheum. 2006 36 (3): 135-43.

Objective The Strongyloides stercoralis hyperinfection syndrome (SHS) may develop in individuals with asymptomatic infection receiving immunosuppressive treatment. This report summarizes current knowledge regarding SHS in patients with systemic lupus erythematosus (SLE) and associated antiphospholipid syndrome (APS). Methods Two patents with active SLE and associated APS presenting with SHS are reported. Additonal cases of strongyloidiasis in SLE were identified and reviewed. Results Patient 1: A 34-year-old women with SLE and APS characterized by active glomerulonephritis, stroke, and several hospital-acquired infections presented with vomiting and diffuse abdominal pain. Intestinal vasculitis was suspected, and treatment with methylprednisolone and cyclophosphamide was given. Response was partial. A gastric biopsy revealed S. stercoralis larvae. She received ivermectin and eventually recovered. Patient 2: A 37-year-old man with active glomerulonephritis and APS with recurrent thrombosis presented with digital necrosis. Necrotizing vasculitis was suspected and treated with immunosuppressants. He suddenly developed respiartory failure secondary to alveolar hemorrhage and bronchoalveolar lavage was performed. The patients developed Gram-negative septic shock and died. The postmortem result of bronchoalveolar lavage yielded Stringyloides larvae. Nine cases of strongyloidiasis and the SHS in SLE patients reported in the literature were identified and reviewed. Five of these patients died; none had associated APS. Conclusions These cases suggest that the SHS can exacerbate SLE and APS, predisposing to Gram-negative sepsis and death. Immunocompromised patients need an early diagnosis ans specific treatment of parasitic diseases and their complications. The SHS should be considered in the differential diagnosis of lupus complications in patients from endemic areas.

33. Antigen and epitope specificity of anti-glomerular basement membrane antibodies in patients with Goodpasture disease with or without anti-neutrophil cytoplasmic antibodies.

Yang R, Hellmark T, Zhao J et al.

J Am Soc Nephrol. 2007 Feb 28; [Epub ahead of print].

Goodpasture disease (GP) is defined by the presence of anti-glomerular basement membrane (anti-GBM) antibodies and rapidly progressive glomerulonephritis. Besides anti-GBM, many patients with GP produces anti-neutrophil cytoplasmic antibodies (ANCA). For elucidation of the pathophysiologic significance of ANCA in this setting, epitope and antigen specificity of the anti-GBM antibodies and antigen specificity of ANCA were studied. Bovine testis alpha (IV) NC1 (tNC1); recombinant human alpha1, alpha3, alpha4, and alpha5 (IV)NC1 (ralpha1 through ralpha5); and three chimeric proteins that contain previously defined epitope regions designated EA, EB, and S2 were used to examine the anti-GBM antibodies by ELISA in 205 Chinese patients with or without ANCA. In the 205 anti-GBM antibody-positive sera, 63 (30.7%) were also ANCA positive (61 myeloperoxidase-ANCA and six proteinase 3-ANCA, four being triple positive). All 205 sera recognized tNC1 and ralpha3 (IV) NC1. In the double-positive group, 54.0, 66.7, 71.4% of the sera could recognize ralpha1, and ralpha5, respectively, compared with 49.3, 60.6, and 55.6% for patients with anti-GBM antibodies alone. The levels of the antibodies to ralpha3, tNC1, and the alpha3/alpha1 ratio lower in the double-positive group than in patients with anti-GBM antibody alone (P < 0.05). Most of the sera could recognize the epitope regions EA, EB, and S2, but the absorbance values to EA, EB, and S2 were lower in double-positive group (P < 0.05). Double-positive patients had a broader spectrum of anti-GBM antibodies and lower levels of antibodies against alpha3 (IV) NC1 compared with that of patients with anti-GBM antibodies alone.

34. Life-threatening cryoglobulinemia: Clinical and immunological characterization of 29 cases.

Ramos-Casals M, Robles A, Brito-Zeron P et al.

Semin Arthritis Rheum. 2006 36 (3): 189-96.

Objectives To analyze the etiology, clinical presentation, and outcomes of patients with life-threatening cryoglobulinemic vasculitis. Methods We studied 209 consecutive patients with cryoglobulinemic vasculitis. A potentially life-threatening cryoglobulinemia was considered as the development of renal failure, vasculitic abdominal involvement, pulmonary hemorrhage, or central nervous system involvement. Results Twenty-nine (14%) patients had life-threatening cryoglobulinemic vasculitis. There were 17 women and 12 men, with a mean age of 57 years. In 17 (59%) patients, life-threatening cryoglobulinemia was the initial clinical feature of the disease. The 29 patients had a total of 33 life-threatening episodes, which included renal failure due to cryoglobulinemic glomerulonephritis (n = 18), intestinal vasculitis (n = 8), pulmonary hemorrhage (n = 4), and central nervous system involvement (n = 3). In comparison with a control group of age-sex-matched patients with milder cryoglobulinemic vasculitis, those with severe cryoglobulinemic vasculitis had a higher frequency of fever (28% versus 7%, P = 0.017) type II cryoglobulins (100% versus 59%, P = 0.008), low C3 levels (55% versus 20%, P = 0.001), and a higher mean value of cryocrit (11.4% versus 3.3%, P = 0.004). Nineteen (66%) of the 29 patients with life-threatening involvement died, with the mortality rate reaching 100% in patients with intestinal ischemia and pulmonary hemorrhage. Conclusion Life-threatening cryoglobulinemic vasculitis was observed in 14% of our patients, with almost two-thirds of episodes occuring at the onset of the disease. Fever, high cryocrit levels, and low C3 levels were associated with this severe presentation. Two-thirds of the patients died, with mortality for pulmonary hemorrhage and intestinal ischemia reaching 100%.

35. Cytoplasmic antineutrophil cytoplasmic antibody positive pauci-immune glomerulonephritis associated with infectious endocarditis.

Kishimoto N, Mori Y, Yamahara H et al.

Clin Nephrol. 2006 66 (6): 447-54.

Abstract Renal deterioration often occurs in case of infectious endocarditis (IE), but, IE-associated nephritis with rapidly progressive glomerulonephritis (RPGN) is rare. Patients with severe infection (e.g., IE) sometimes show positivity for cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA). Therefore, diagnosis and treatment are very difficult in cases of RPGN with IE and positivity for C-ANCA. Such cases are rare, only 12 have been reported in the English literature. Herein, we describe the case of a 50-year-old man who presented with RPGN with IE and tested positively for C-ANCA. He was referred to our hospital because of leg edema, purpura and renal dysfunction. Laboratory tests revealed serum creatinine elevation and positivity for C-ANCA and proteinse 3-specific (PR3)-ANCA. RPGN and acute renal failure were diagnosed. Hemodialysis and steroid therapy were started. Streptococcus oralis was isolated by blood culture. Transthoracic echocardiopgraphy revealed grade III mitral valve insufficiency with two vegetations. Therefore, IE was diagnosed. The steroid therapy was stopped, and antibiotic therapy was begun. Because there was no improvement, surgical therapy was performed. The operation was successful, but the patients died of brain hemorrhage. Our experience in this case indicates C/PR3-ANCA positive RPGN must be ruled out in patients with infectious disease, particularly IE, together with renal symptoms, and renal biopsy should be performed.

36. Thrombopoietin and interleukin-6 levels in Henoch-Schonlein purpura.

Lin CY, Yang YH, Lee CC et al.

J Microbiol Immunol Infect. 2006 39 (6): 476-82.

Backgroun and purpose Depending on the severity of the illness, thrombocytosis is found in about 60% to 70% of patients with Henoch-Schonlein purpura (HSP). Whether thrombocytosis is the result of an inflammatory reaction mediated by thrombopoietin (TPO) or other cytokines such as interleukin (IL)-6 remains unknown. Methods Thirty two patients who met the diagnostic criteria for HSP were included. They were divided into two groups - HSP patients with thrombocytosis (n = 14) and those without thrombocytosis (n = 18) with a platelet count of 400 000/muL. Eight normal healthy controls were also included. TPO and IL-6 serum levels during acute phase were measured by enzyme-linked immunosorbent assay. Results Patients with platelet counts greater than 400 000/muL in the acute stage had significantly lower TPO levels than patients with platelet counts lower 400 000/muL (310 +/- 65.6 pg/L vs 608 +/- 97.8 pg/mL, p = 0.013). However, HSP patients with or without thrombocytosis had similar TPO levels as the healthy controls (441 +/- 176 pg/mL, p = 0.89 and 0.29, respectively. Il-6 serum levels were significantly elevated in HSP patients during the acute stage of HSP (28.6 +/- 61.7 pg/mL vs 3.16 +/- 1.35 pg/mL, p = 0.049). In patients with complications of glomerulonephritis or gastrointestinal hemorrhage (n = 12), IL-6 levels were significantly lower than in those without such complications (8.7 +/- 3.79 pg/mL vs 40.9 +/- 16.9 pg/mL, p = 0.007). Conclusions This study showed that thrombocytosis in HSP patients is a type of inflammatory reactve thrombocytosis, and that IL-6 may also play a role in the pathogenesis of HSP.

37. Henoch-Schonlein purpura nephritis complicated by reversible posterior leukoencephalopathy syndrome.

Sasayama D, Shimojima Y, Gono T et al.

Clin Rheumatol. 2007 Jan 5; [Epub ahead of print].

We report a young female patient with Henoch-Schonlein purpura (HSP) nephritis complicated by reversible posterior leukoencephalopathy syndrome (RPLS). The patient suddenly showed generalized seizures and cortical blindness with severe hypertension due to renal insufficiency apporximatelly 1 year after cessation of corticosteroid treatment for HSP nephritis. Magnetic resonance imaging (MRI) demonstrated bilateral signals mainly in the cerebellum and white matter of the occipital lobe. Clinical symptoms quickly improved in conjunction with disappearence of abnormal signals on brain MRI after starting control of hypertension and continous hemodiafiltration with steroid pulse therapy and plasmapheresis. RPLS may be caused by vasculitis and also by hemodynamic change due to severe hypertension in HSP, particularly in patients with nephropathy. In such cases intensive treatment should be performed as soon as possible to avoid neurologcal sequelae.

38. Minimal change nephrotic syndrome in association with strongyloidiasis.

Hsieh YP, Wen YK, Chen ML.

Clin Nephrol. 2006 66 (6): 459-63.

Abstract Although parasitic infections hav been known to be associated with immune complex-mediated glomerular lesions, strongyloidiasis-related glomerulopathy has not been well documented. We report a patient with delayed-recognized disseminated strongyloidiasis who developed nephrotic syndrome 3 months after the begining of the manifestations related to strongiloidiasis. A kidney biopsy showed minimal change disease. We treated strongyloidiasis and hesitated to give steroid therapy for the treatment of minimal change nephrotic syndrome (MCNS) because of the risk of aggravation of Strongyloides stercoralis infection. Surprisingly, resolution of heavy proteinuria occured after antihelmintic therapy with ivermectin. This case suggest a possible causal relationship between S. stercoralis infection and MCNS. In addition, a review of another 4 cases previously reported in the literature demonstrates the importance of detecting underlying S. stercoralis infection in patients with nephrotic syndrome since steroid therapy can cause hyperinfection or disseminated strongiloidiasis, and which may lead to fatal outcome.

39. Membraneous glomerulonephritis and non-Hodgkin’s lymphoma in a patient with primary Sjogren’s syndrome.

Iwanaga N, Kamachi M, Fujikawa K et al.

Intern Med. 2007 46 (4): 191-4.

The most common renal manifestation of Sjogren’s syndrome is tubulointerstitial nephritis, and glomerular disease is rare (3). A 62-year-old women with primary Sjogren’s syndrome developed nephrotic syndrome. Kidney biopsy was consistent with membraneous glomerulonephritis. Steroid pulse therapy was not effective. Three months later she was diagnosed with non-Hodgkin’s lymphoma of the tongue, and she was given CHOP therapy and radiation. Both the lymphoma and menbraneous glomerulonephritis were resolved.

40. Membranous nephropathy associated with fluconazole treatment.

Shin GT, Yim H, Park J et al.

Am J Kidney Dis. 2007 49 (2): 318-22.

About 6% to 9% cases of menbranous nephropathy develop secondary to exposure to drugs. Fluconazole is a widely used antifungal agent that was never implicated in the development of membranous nephropathy. We report the case of a patient found to have membranous nephropathy secondary to fluconazole treatment. This patient had recurrent episodes of nephrotic syndrome by readministration of fluconazole. This is the first reported case of membranous nephropathy caused by fluconazole treatment and the first case report of the clinical course of recurrent membranous nephropathy caused by reexposure to this medication.

41. Is paraoxonase 192 gene polymorphism a risk factor for membranoproliferative glomerulonephritis in children?

Bilge I, Sirin A, Agachan B et al.

Cell Biochem Funct. 2007 25 (2): 159-65.

We investigated the effects of paraoxonase (PON1) 192 polymorphism on serum PON1 activity and the impact of phenotypic expression on the risk and prognosis of Turkish children with membranoproliferative glomerulonephritis (MPGN). Eighteen children with biopsy-proven Type I MPGN (10 boys, 8 girls) and age-matched 53 healthy controls were included study. PCR (polymerase chain reaction), RFLP (restriction fragment lenght polymorphism) and agarose gel electrophoresis techniques were used to determine the PON1 192 genotype. PON1 activity was measured by spectrophotometric assay of p-nitrophenol production following addition of paraoxon. We found that PON1 192 genotype (AA, AB, BB) in MPGN patients were 61.1%, 22.3% and 15.1%, 35.8%, 49.1% in controls respectively. The frequency of AA genotypes was significantly higher in the MPGN group (0.611) compared with the healthy controls (0.151) (p < 0.001). Although the serum PON1 activity was lower in MPGN patients (103.3 +/- 55.2 U/l) than the healthy controls (130.9 +/- 71.2 U/mol), the difference was not statistically significant (p = 0.0563). In the genotypes of patients and controls classified according to PON1 A/B polymorphism; serum PON1 activities were significantly increased (p < 0.001, ANOVA) in the order of PON1 AA, AB, and BB in both MPGN patients (82.4, 91,7 and 173.6 U/l) and healthy controls (85.9, 119.9 and 193.1 U/l), respectively. There was a significant relationship between the poor prognosis and having AA genotype and low PON1 activity. Of the 8 patients with poor prognosis, 7 had genotype AA and the remaining one was AB heterozygote. Our resulsts suggest that homozygosity for the A allele might have an important role on the risk for developing MPGN and may also be associated with the poor prognosis of disease. In conclusion, we suggest that the PON1 activities are affected by PON1 genetic variability in Turkish patients with MPGN.

42. Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy.

Li GS, Zhang H, Lv JC et al.

Kidney Int. 2007 71 (5): 448-53.

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1,3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subjects were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs, -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of -292C/- in IgAN patients were significantly lower than in the controls (P < 0.01). The frequency of haplotype YATIG (Y=C or T) was significantly lower in patients than in controls (0.0719 vs 0.1168, P = 2.775 × 10 (-4), odds ratio (OR) = 0.70). The haplotype YAGDA (0.1236 vs 0.0791, P = 3.815 × 10 (-3), OR = 1.77) and YATDG (0.0840 vs 0.0298, P = 1.258 × 10 (-5), OR = 3.03) were significantly higher in patients than in controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with the genetic susceptibility to IgAN in Chinese population.

43. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels.

Moldoveanu Z, Wyatt RJ, Lee JY et al.

Kidney Int. 2007 Mar 7; [Epub ahead of print].

Immunoglobulin A (IgA) nephropathy is the most prevalent form of glomerulonephritis worldwide. A renal biopsy is required for an accurate diagnosis, as no convenient biomarker is currently available. We developed a serological test based upon the observation that this nephropathy is characterized by undergalactosylated IgA1 in the circulation and in mesangial immune deposits. In the absence of galactose, the terminal saccharide of O-linked chains in the hinge region of IgA1 is terminal or sialylated N-acetylgalactosamine. A lectin from Helix aspersa, recognizing N-acetylgalactosamine, was used to develop an enzyme-linked immunosorbent assay that measures galactose-deficient IgA1 in serum. The median serum lectin-binding IgA1 level was significantly higher for 153 Caucasian adult patients with IgA nephropathy without progression to end-stage renal disease as compared with that for 150 healthy Caucasian adult controls. As the lectin-binding IgA1 levels for the controls were not normally distributed, the 90th percentile was used for determination of significant elevation. Using a value of 1076 U/ml as the upper limit of normal, 117 of the 153 patients with IgA nephropathy had an elevated serum lectin-binding IgA1 level. The sensitivity as a diagnostic test was 76.5%, with specificity 94%; the positive predictive value was 88.6% and the negative predictive value was 78.9%. We conclude that this lectin-binding assay may have potential as noninvasive diagnostic test for IgA nephropathy.

44. Absence of increased a1-microglobulin in IgA nephropathy proteinuria.

Yokota H, Hiramoto M, Okada H et al.

Mol Cell Proteomics. 2007 Jan 21; [Epub ahead of print].

To search for biomarkers of IgA nephropathy, protein profiles of urine samples from patients with IgA nephropathy and normal vlunteers were compared using 2D-DIGE. Most of the 172 spots identified in the urine were serum proteins, and their amounts in IgA nephropathy urine were much higher than those in normal urine, which can be explained as proteinuria caused by glomerular dysfunction. However, only a1-microglobulin, also one of the major serum proteins, in IgA nephropathy urine was not higher in amount than that is normal urine. We confirmed using ELISA analysis that the amounts of transferrin and albumin in IgA nephropathy and diabetic nephropathy urine were much higher than those in normal urine, whereas the amount of a1-microglobulin in IgA nephropathy urine was not higher that in normal urine and serum was much lower than that in diabetic nephropathy urine. Approximately 50% of a1-microglobulin forms a complex with IgA in serum. These results suggest that a1-microglobulin in IgA nephropathy urine is a characteristics protein and might be a biomarker for IgA nephropathy, and that a1-microglobulin might have a relationship with IgA nephropathy pathology.

45. Insulin resistance and the progression of IgA glomerulonephritis.

Kaartinen K, Syrjanen J, Porsti I et al.

Nephrol Dial Transplant. 2007 22 (3): 778-83.

Background IgA glomerulonephritis (IgAN) has a highly variable prognosis with 15-40% of patients progressing to end-stage renal disease. Hypertension, proteinuria and renal insufficiency are risk factors associated with poor prognosis. The role of insulin resistance is unclear in IgAN. Methods From a retrospective cohort of IgAN patients, a total of 174 patients (104 males) were invited for two visits at the clinic, 11 and 16 years (median times) after IgAN was diagnosed in renal biopsy. Of all the patients, 63% had been diagnosed at least 10 years before the first visit. Progressive disease was defined as cystatin-C exceeding normal limits and showing over 20% elevation between the first and second visits, or kidney transplantation or start of dialysis. Plasma insulin, homeostasis model assessment of insulin reistance (HOMA-IR) index and cystatin-C were obtained for analysis from 118 patients. Results IgAN was progressive in 19.5% of the patients on the second visit. Insulin level and HOMA-IR of the first visit showed significant association with the progression of IgAN (P = 0.019 and 0.005, respectively). Conclusions Our results show that in addition to the known risk factors age, hypertension, proteinuria and hyperuricemia, plasma insulin level and calculated HOMA-IR are associated with the progression of IgAN.

46. Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy.

Myllymaki JM, Honkanen TT, Syrjanen JT et al.

Kidney Int. 2006 Dec 27; [Epub ahead of print].

Many risk factors for progression in immunoglobulin A nephropathy (IgAN) have been found. We

focused on renal leukocyte infiltration and cytokines in IgAN. The subjects were 204 IgAN patients.

Renal histopathological changes were semiquantitatively graded. Expression of tubulointerstitial leukocyte common antigen (LCA), CD3, CD68, interleukin (IL)-1beta, and IL-10 was evaluated by immunohistochemistry. These parameters were correlated with progression of IgAN. The significance of these correlations was tested by a multivariate analysis. Glomerulosclerosis, tubular atrophy, interstitial inflammation, and hyaline arteriosclerosis correlated with progression in all patients and also in patients with initially normal serum creatinine. Tubulointerstitial LCA, CD3, CD68, and IL-1beta expression correlated with progression. CD3 had the strongest correlation. In the multivariate analysis, tubulointerstitial CD3, hypertriglyceridemia, elevated serum creatinine concentration, and interstitial fibrosis were independently associated with progressive disease in all patients, and tubulointerstitial CD3 expression and hyaline arteriosclerosis in patients with initially normal serum creatinine. We found parameters reflecting tubulointerstitial inflammation to predict deterioration of renal function in IgAN. This was also seen in patients whose serum creatinine was normal at the time of renal biopsy. Our findings show that, an immunohistochemical evaluation of tubulointerstitial inflammation seems to be a useful tool in determining the prognosis in IgAN.

47. Long-term efficacy of tonsillectomy in Chinese patients with IgA nephropathy.

Chen Y, Tang Z, Wang Q et al.

Am J Soc Nephrol. 2007 27 (2): 170-5.

Background To investigate the clinical efficacy of tonsillectomy on long-term clinical remission and renal survival of immunoglobulin A nephropathy (IgAN) patients in China. Methods We performed a 130-month retrospective case-control study of 112 patients with idiopathic biopsy diagnosed IgAN from 1983 to 1999. Fifty-four patients underwent tonsillectomy and 58 patients did not. The clinical remission rate during follow-up and variables to predict clinical remission were estimated by chi (2) test and multivariate Cox regression analysis; renal survival was evaluated by Kaplan-Meier analysis. Results Up to 2006, the follow-up period lasted 130 +/- 50.3 months (60-276 months). The clinical remission rate was 46.3% in patients with tonsillectomy and 27.6% in those without tonsillectomy during follow-up. Multivariate analyisis demonstrated that tonsillectomy was not an independent impact factor for renal clinical remission (p = 0.386). By Kaplan-Meier analysis, there was no significant difference in renal survival rate between patients with tonsillectomy, and those without tonsillectomy (p = 0.059). Conclusion The clinical remission rate in IgAN patients with tonsillectomy was higher than that in patients without tonsillectomy during follow-up. But within 130 months, it was difficult to find statistically differences in renal survival between IgAN patients with and without tonsillectomy.

48. Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed

by immunosuppression for acute lymphocytic leukemia.

Iwata Y, Wada T, Uchiyama A et al.

Intern Med. 2006 45 (22): 1291-5.

We report a case with immunoglobulin A (IgA) nephropathy, showing IgA deposition which disappeared after peripheral blood stem cell transplantation (PBSCT) for acute lymphocytic leukemia (ALL). In 1996, a 28-year-old man was diagnosed with IgA nephropathy by renal biopsy. Steroid therapy improved proteinuria from 3 g/day to 1g/day. In 2003, he received PBSCT following the initial therapy for ALL. After complete remission, urinary protein and hematuria remained at between (-) and (+/-). In 2004, the second renal biopsy specimen revealed no deposit of IgA or C3. These findings suggested that immune reconstruction with PBSCT following immunosuppression therapy was of benefit to IgA nephropathy.

49. IgA nephropathy associated with Hodgkin’s disease in children: A case report, literature review and urinary proteome analyisis.

Khositseth S, Kanitsap N, Warnnissorn N et al.

Pediatr Nephrol. 2006 Dec 2; [Epub ahead of print].

We report herein a rare case of IgAN associated with Hodgkin’s disease in a 14-year-old boy. Clinical manifestations and laboratory parameters were improved after treatment with CHOP chemotherapy and enalapril. Urinary proteins were isolated and examined using state-of-the-art proteomic technology, before and during the treatment course. Two-dimensional gel electrophoresis showed obvious alterations in the urinary proteome profile in response to such therapy. Quantitative intensity analysis and gel mapping revealed 14 altered proteins with reduced excretion levels during the treatment course, including albumin, albumin complexed with decanoic acid, alpha-1 antitrypsin, cadherin-11 precursor, collagen alpha 1 (VI) chain precursor, complement C1q tumor necrosis factor-related protein, Ig heavy chain, Ig light chain, kininogen, inter-alpha-trypsin inhibitor (alpha-1 microglobulin), inter-alpha-trypsin inhibitor heavy chain, leucine-rich alpha-2 glycoprotein, beta-2 microglobulin, and transferrin precursor. Their potential roles in the pathogenesis and pathophysiology of IgAN are discussed.

50. Relationship between ankle-brachial index and chronic kidney disease in hypertensive patients with no known cardiovascular disease.

Mostaza JM, Suarez C, Manzano L et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S201-5.

Both decreased GFR and albuminuria are associated with an elevated prevalence of peripheral artery disease. However, the combined effects of these alterations previously were not evaluated. Patients with hypertension and with known vascular disease (n = 955; mean age 66 yr; 56% male) were selected from internal medicine outpatient clinics throughout Spain. Cardiovascular risk factors, urinary albumin excretion, and the ankle-brachial index (ABI) were assessed in all participants. GFR was estimated according to the Cockroft-Gault equation. Of the study population, 62% had diabetes, 23.8% had a GFR < 60 ml/min per 1.73 m (2), and 43.8% had albuminuria. The prevalence of ABI < 0.9 was greater in patients with a GFR < 60 ml/min per 1.73 m (2) (37.4 versus 24.3%; P < 0.0001) and in those who had albuminuria (32.2 versus 23.3%; P = 0.001). In patients with both alterations, the prevalence of ABI < 0.9 was 45.7%. Multivariate analysis indicated that the factors that were associated independently with low ABI were age (odds ratio [OR] 1.06; 95% confidence interval [CI] 1.03 to 1.08; P < 0.0001), triglyceride concentration (OR 1.003; 95% CI 1.001 to 1.005; P = 0.001), presence of albuminuria (OR 1.61; 95% CI 1.18 to 2.20; P = 0.003), smoking habit (OR 1.72; 95% CI 1.13 to 2.63; P = 0.012), and GFR < 60 ml/min per 1.73 m (2) (OR 1.47; 95% CI 1.01 to 2.17; P = 0.049). In patients with hypertension and without known vascular disease, reduced GFR and albuminuria are associated independently with an ABI < 0.9. Their combined presence characterizes a subgroup of the population who have an elevated prevalence of peripheral artery disease and could benefit early diagnosis and treatment.

51. Role of pulse pressure on cardiovascular risk in chronic kidney disease patients.

Fernandez-Fresnedo G, Rodrigo E, de Francisco AL et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S246-9.

Epidemiologic studies have emphasized the close relationship between high BP and cardiovascular disease (CVD). Recently published prospective studies have focus on systolic and pulse pressure (PP). Systolic BP seems to be a more important factor than diastolic BP on cardiovascular and all-cause mortality in older patients. PP reflects stiffness of the large arteries and increases with age. Increasingly, PP is recognized as an independent predictor of myocardial infarction, congestive heart failure, and cardiovascular death, even in hypertensive patients who undergo successful antihypertensive drug therapy, especially in older individuals. Chronic kidney disease (CKD) is a major public health problem. The progression of kidney disease and its associated cardiovascular complications are the major causes of morbidity and mortality. This holds true for all stages of kidney disease, including ESRD that requires renal replacement therapy. Most of the traditional CVD risk factors are highly prevalent in CKD, and several nontraditional factors also are associated with atherosclerosis in CKD. The burden of hypertension is present at all stages of CKD. Several studies have shown that PP is a reliable prognostic factor for mortality and CVD in patients who have CKD and are on hemodialysis and in renal transplant patients. The purpose of this review is to show the importance of PP on cardiovascular risk in patients with CKD, including kidney transplant recipients.

52. Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects.

Perlstein TS, Gerhard-Herman M, Hollenberg NK et al.

J Am Soc Nephrol. 2007 18 (3): 944-51.

Insulin stimulates the renin-angiotensin system and induces renal vasodilation. The relationship between these opposing influences of insulin on renal vascular tone has not been explored. A hyperinsulinemic euglycemic clamp and sham insulin clamp each of 270 min duration were performed in 15 healthy individuals during high sodium balance. An angiotensin receptor blocker was administered at time 180 min. Renal plasma flow and plasma renin activity were measured serially. The response to insulin or sham insulin was defined as the change from time 0 to 180 min; the response to angiotensin receptor blockade (ARB) was defined as the change from time 180 to 270 min. Insulin infusion increased plasma renin activity (P < 0.01) and renal plasma flow (P < 0.01); the latter effect plateaued by time 150 min. ARB caused a greater vasodilator response during insulin infusion compared with during sham insulin infusion (P = 0.02). Increasing renin response to insulin predicted blunting of the renal vasodilator response to insulin infusion (R (2) = 0.36, P = 0.02) and senzitizing of the renal vasodilator response to ARB during insulin infusion (R (2) = 0.59, P < 0.01). Insulin-induced activation of the renin-angiotensin system modulates insulin-induced renal vasodilation in healthy individuals. Further studies are warranted to address this balance in states of insulin resistance and the possible implications for the association of insulin resistance with risk for chronic kidney disease.

53. A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.

Mollsten A, Marklund SL, Wessman M et al.

Diabetes. 2007 56 (1): 265-9.

Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radicals. The demand for antioxidants is increased by smoking, which could disturb the balance between antioxidants and radicals. The present study aimed to determine whether a valine/alanine polymorphism in MnSOD (V16A, rs4880), alone or in combination with smoking, can contribute to development of diabetic nephropathy in 1 510 Finnish and Swedish patients with type 1 diabetes. Overt diabetic nephropathy (n = 619) was defined as having an albumin excretion rate (AER) > 200 mug/min or renal replacement therapy; incipient diabetic nephropathy was defined as having an AER of 20-200 mug/min (n = 336). The control subjects had diabetes duration of >/= 20 years, without albuminuria (AER < 20 mug/min) and without antihypertensive treatment (n = 555). In additon to male sex and elevated A1C, smoking was significantly associated with diabetic nephropathy (overt plus incipient), odds ratio (OR) 2.00 (95% CI 1.60-2.50). When controlling for age onset, diabetes duration, A1C, smoking, and sex, the Val/Val genotype was associated with an increase in risk of diabetic nephropathy (1.32 [1.00-1.74], P = 0.049). When evaluating the combined effect of genotype and smoking, we used logistic regression with stratification according to smoking status and genotype. The high-risk group (ever smoking plus Al/Val genotype) had 2.52 times increased risk of diabetic nephropathy (95% CI 1.73-3.69) compared with the low-risk group, but no departure from additivity was found. Our results indicate that smoking and homozygous for the MnSOD Val allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to development of diabetic nephropathy.

54. Association between haptoglobin gene variants and diabetic nephropathy: Haptoglobin polymorphism in nephropathy susceptibility.

Conway BR, Savage DA, Brady HR et al.

Nephron Exp Nephrol. 2007 105 (3): e75-9.

Background / Aims The Hp (1) / Hp (2) DNA polymorphism has previously been implicated in susceptibility to diabetic nephropathy in some but not all studies. In an attempt to clarify these conflicting findings, we conducted a case-control association study in a Caucasian population. Methods We recruited 224 and 285 type 1 diabetic patients with (cases) and vithout (controls) nephropathy, respectively, from 2 centres based Northern Ireland and the Republic of Ireland. Hp (1) / Hp (2) genotyping was performed using a combination of long-range and multiplex PCR. Allele and genotype frequencies in cases and controls were compared using the chi (2) test. Results There was a statistically significant increase in the frequency of the Hp (29 allele in cases compared to controls (65.6 vs 58.6%, OR = 1.35, 95% CI 1.07-1.76, P = 0.03). The distribution of genotypes were in Hardy-Weinberg equilibrium for both cases and controls, and the overall frequency of the Hp (1) allele was 38.3%, which is similar to that found in other Western European populations. Conclusions The results suggest that the Hp (2) allele may confer susceptibility to nephropathy in patients with type 1 diabetes.

55. Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy -- a nationwide 5-year-study in Japan.

Murase Y, Imagawa A, Hanafusa T et al.

Diabetologia. 2007 50 (3): 531-7.

Aims / Hypothesis The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes. Materials and Methods In a nationwide survey, we followe 41 patients with fulminant type 1 diabetes and 76 age- and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA (1c) level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosage of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination. Results The 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the Kaplan-Meier method, the cumulative incidence of each form of microangiopathy was signficantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p = 0.014), nephropathy 12.2% vs 2.6% (p = 0.015) and neuropathy 12.2% vs 1.3% (p = 0.010), respectively. Mean HbA (1c) levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group. Conclusion / Interpretation These data suggest that patients with fulminant type 1 diabetes are a high-risk subgroup for diabetic microangiopathy associated with the lack of endogenous insulin secretion from the onset of diabetes.

56. Maternal history of type 2 diabetes is associated with diabetic nephropathy in type 1 diabetic patients.

Hadjadj S, Duengler F, Torremocha F et al.

Diabetes Metab. 2007 Jan 25; [Epub ahead of print].

Aims Insulin resistance is a key feature of type 2 diabetes. It is also involved in the development and progression of microvascular complications. We analysed the relationship between parental history of diabetes, insulin resistance and diabetic nephropathy (DN) and assessed the specific maternal and paternal influences of history of type 2 diabetes on DN in type 1 diabetic offspring. Methods We recorded information regarding family history of type 2 diabetes and of cardiovascular disease in 160 consecutive, unrelated type 1 diabetic patients. Insulin resistance was assessed using a validated estimation of the glucose disposal rate (eGDR). Results Type 1 diabetic patients with a maternal history of type 2 diabetes were more likely to be insulin-resistant (P = 0.043) and to have renal complications (P = 0.0041) than those from the reference group (without parental history of diabetes), while patients with a paternal history were not different from those from the reference group, regarding eGDR and DN. Time of development of abnormal albuminuria was significantly affected by maternal history of type 2 diabetes (log-rank = 12.66; P = 0.0004) and by familial history of premature cardiovascular disease (log-rank = 5.48; P = 0.0234). In multivariate analysis, a maternal history of type 2 diabetes was independently associated with nephropathy after adjusment for sex, diabetes duration and familial history of premature cardiovascular disease. Conclusion Maternal history of type 2 diabetes is independently associated with DN in type 1 diabetic patients. This might suggest the transmission of a maternal trait related to microvascular complications, raising the hypothesis of imprinted genes predisposing to diabetic renal disease.

57. Renal and retinal microangiopathy after 15 years of follow-up study in a sample of type 1 diabetes mellitus patients.

Romero P, Salvat M, Fernandez J et al.

J Diabetes Complications. 2007 21 (2): 93-100.

Purpose In the present study, the objective is to determine the epidemiological risk factors in the appearence of diabetic retinopathy and nephropathy in 112 type 1 diabetic patients after 15 years. Methods A 15-year follow-up study was done in a cohort of 112 consecutive type 1 (IDDM) diabetes mellitus patients without diabetic retinopathy or nephropathy at enrolment in 1990. We studied the incidence of diabetic retionopathy and/or microalbuminuria. The epidemiological risk factors included in the study were gender, diabetes duration, HbA(1c) levels, arterial hypertension, levels of triglycerides and fractions of cholesterol (HDL-cholesterol and lDL-cholesterol). Results The incidence of diabetic retinopathy was 55.40% at the end of study; the risk factors associated were duration of diabetes mellitus (P < .001), high levels of HbA(1c) (P = .009), presence of arterial hypertension (P = .007) and high of LDL-cholesterol (P = .002). The incidence of microalbuminuria was 41.07% and that of overt nephropathy, 19.60%; the risk factors associated were high levels of HbA(1c) (P < .001) and presence of arterial hypertension (P = .023). At the end of study, four groups of patients were formed: patients without microalbuminuria or retinopathy, patients with microalbuminuria only, patients with retinopathy only and patients with retionopathy and microalbuminuria. From the results of the discriminate analysis, wa may assume that for the development of retinal lesions only, in the diabetes mellitus, the duration of the disease, the high levels of HbA81c) and the arterial hypertension are most important, and for the develoment of renal and retinal lesion simultaneously, the important factor is poor control of glycemia measured by levels of HbA(1c) and arterial hypertension. Conclusions In conclusion, microalbuminuria correlated well with severe forms of diabetic retinopathy, and at the end of the study, two groups of patients had been configured: the first group had developed only diabetic retinopathy, and the second, their patients with diabetic retinopathy together with renal lesion (microalbuminuria). For the first group, the duration of diabetes mellitus was the most important risk factor, and for the second group, the levels of HbA(1c) and blood pressure were the most important.

58. Kidney function after islet transplant alone in type 1 diabetes: Impact of immunosuppressive therapy on progression of diabetic nephropathy.

Maffi P, Bertuzzi F, De Taddeo F et al.

Diabetes Care. 2007 Jan 26; [Epub ahead of print].

Objective Islet transplantation alone (ITA) is an alternative for the replacement of pancreatic endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmondton Immunosuppressive protocol (tacrolimus-sirolimus association) in kidney function. Research Design and Methods 19 patients with type 1 diabetes and metabolic instability received islet transplantation alone and immunosuppressive therapy according to the Edmonton protocol. Serum creatinine (sCR), creatinine clearence (ClCr) and 24 hour urinary protein excretion (24h UPE) was assessed at baseline and during a follow-up of 339 patient month. Results After islet transplantation we observed: 1) sCR within the normal range in all but two patients where sCr increased immediately after islet transplantation, despite immunosuppression withdrawal patients progressed toward end-stage renal disease (ESRD); 2) ClCr remained within the normal range for those patients who normal baseline and decreased progressing toward ESRD in two patients with a decreased baseline CrCl; and 3) 24hUPE worsened (> 300mg/24 hours) in four patients. In the two patients who progressed to ESRD the worsening of 24hUPE occured immediately after islet transplantation. In one patient 24hUPE worsening occured at 18 months: after withdrawal of immunosuppression it returned within the normal range. In another patients 24hUPE increased at 24 months stable while continuing immunosuppression. Conclusions In type 1 diabetic patients receiving ITA, the association of tacrolimus-sirolimus should be used only in patients with normal kidney function. Alternative options for immunosuppressive treatment should be considered for patients with even a mild decrease of kidney function.

59. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: ’’ Double diabetes’’ in the Diabetes Control and Complications Trial.

Kilpatrick ES, Rigby AS, Atkin SL.

Diabetes Care. 2007 30 (3): 707-12.

Objective The presence of insulin resistance and the metabolic syndrome are known risk markers for macrovascular disease in patients with and without type 2 diabetes. This study examined whether these also were predictors of micro- and macrovascular complications in type 1 diabetic patients participating in the Diabetes Control and Complications Trial (DCCT). Research Design and Methods International Diabetes Federation (IDF) criteria were used to identify the resistance was calculated using their estimated glucose disposal rate (eGDR). Insulin dose (units/kg) was also used as a separate marker of insulin resistance. Results The eGDR (but not insulin dose or metabolic syndrome) at baseline strongly predicted the development of retinopathy, nephropathy, and cardiovascular disease (hazard ratios 0.75. 0.88, and 0.70, respectively, per mg × kg (-1) change; P < 0.001, and P = 0.002, respectively). Through mainly weight gain, the prevalence of the metabolic syndrome increased steadily from baseline to year 9 in conventionally treated (from 15.5 to 27,2%) and especially in the intensively treated (from 13.7 to 45.5%) patients. Conclusions Higher insulin resistance at baseline in the DCCT (as estimated by eGDR) was associated with increased subsequent risk of both micro- and macrovascular complications. Insulin dose and the presence of IDF-defined metabolic syndrome were poor predictors by comparison. Although intensive treatment was associated with a higher subsequent prevalence of metabolic syndrome, the benefits of improved glycemia appear to outweight the risk related to development of the metabolic syndrome.

60. Pre-eclampsia but not pregnancy-induced hypertension is a risk factor for diabetic nephropathy in type 1 diabetic women.

Gordin D, Hiilesmaa V, Fagerudd J et al.

Diabetologia. 2007 50 (3): 516-22.

Aims/Hypothesis Our aim was to study whether pre-eclampsia and pregnancy-induced hypertension are predictors of diabetic nephropathy in type 1 diabetic women. Materials and Methods A total of 203 type 1 diabetic women, who were pregnant between 1988 and 1996 and followed at Department of Obstetrics and Gynaecology in Helsinki, were re-assessed after an average of 11 years within the nationwide, multi-centre Finnish Diabetic Nephropathy Study. Diabetic nephropathy was defined as microalbuminuria, macroalbuminuria or end-stage renal disease. Results Patients with prior pre-eclampsia had diabetic nephropathy more often than patients with a normotensive pregnancy (diabetic nephropathy vs normal albumin excretion rate: 41.9% vs 8.9%; p < 0.001), whereas patients with a history of pregnancy-induced hypertension did not (10.3% vs 8.9%; p = 0.81). CHD was proven prevalent in patients with a history of pre-eclampsia than in patients with a normotensive pregnancy (12.2% vs 2.2%; p = 0.03). Pre-eclampsia (odds ratio [OR] 7.7, 95% CI 1.6-36.1; p = 0.01) and HbA(1c) (OR 2.0, 95% CI 1.1-3.8; p < 0.05) were associated with incident diabetic nephropathy even when adjusted for follow-up time, BMI, smoking, diabetes duration and age. Conclusions/Interpretation These data suggest that a history of pre-eclamptic pregnancy but not pregnancy-induced hypertension is associated with an elevated risk of diabetic nephropathy.

61. SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes.

Lin HY, Wang CL, Hsiao PJ et al.

Diabetes. 2007 Jan 17; [Epub ahead of print].

Objective SUMO4 mRNA is recently found to be mainly expressed in the kidney and M55V variant of SUMO4 may induce higher NF-kappaB activity. Because NF-kappaB is known to mediate the development of diabetic nephropathy, we exmined the association between SUMO4 M55V variant and severity of diabetic nephropathy. Research Design and Methods We recruited a total of 430 patients with type 2 diabetes. He M55V (rs237025, 16A>G) polymorphism of SUMO4 was genotyped by real time-PCR and urine albumin concentration was measured by radioimmunoassay. Results The frequencies of SUMO4 AA, GA, and GG were 52.6%, 40.7% and 6.7% in the normoalbuminuric group; 45.5%, 47.3% and 7.1% in the microalbuminuric group; 36.9%, 46.2% and 16.9% in the macroalbuminuric group, respectively. We detected a significant linear trend for SUMO4 genotype between macroalbuminuric and normoalbuminuric group. The mean urine albumin/creatinine ratio (42.3 +/- 108.82 mg/mmol) in GG group was significantly higher than in AA (14.9 +/- 51.49 mg/mmol) and in GA (17.0 +/- 43.74 mg/mmol) groups. Multivariate logistic regression analysis showed SUMO4 M55V variant to be independently associated with the severity of diabetic nephropathy. Conclusions This study indicates that the SUMO4 gene M55V variant is associated with severity of diabetic nephropathy in patients with type 2 diabetes.

62. Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes:

UKPDS 76.

Calle R, McCarthy MI, Banerjee P et al.

Diabetologia. 2006 49 (12): 2892-9.

Aims/Hypothesis Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. Methods We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and incidences of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3 374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazard models, adjusted for sex, ethnicity and other known or putative risk factors. Results rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p = 0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR = 1.31 [95% CI 1.11-1.54g, p = 0.001) but less likely to double creatinine levels during folow-up (RR = 0.49 [95% CI 0.27-0.89], p = 0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. Conclusions/Interpretation We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

63. Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients.

Buraczynska M, Ksiazek P, Baranowicz-Gaszczyk I et al.

Nephrol Dial Transplant. 2006 Nov 22; [Epub ahead of print].

Background Diabetic microvascular complications are the major causes of morbidity and early mortality in diabetes. Vascular endothelial growth factor (VEGF) is a potent multifunctional cytokine which plays a key role in the pathogenesis of diabetic microvascular complications. We examined the possible association of the VEGF gene polymorphisms with diabetic nephropathy and retinopathy in type 2 diabetes patients. Methods Genotyping of the VEGF gene insertion/deletion (I/D) and +405 polymorphisms was done by the polymerase chain reaction (PCR) and restriction fragment lenght polymorphism methods. A total of 426 patients with type 2 diabetes and 493 healthy subjects were genotyped. The frequency of VEGF alleles and genotype distribution were compared in diabetic and control group. Results The distribution of the VEGF DD genotype was significantly different in patients with diabetic retinopathy compared with healthy controls, entire diabetic group and patients with no complications (44 vs. 23, 30 and 21%, respectively; P < 0.01). Such differences were not observed in the diabetic nephropathy group. The odds ratio for the D allele was 2.27 (95% CI 1.59-3.25). The multivariate logistic regression analysis revealed that the D allele of the VEGF gene I/D polymorphism was an idependent risk factor of retinopathy, (P < 0.001). The VEGF +405 genotype was not associated with diabetic complications in type 2 diabetes patients. Conclusion Our study suggest that the I/D polymorphism in the promoter region of the VEGF gene is associated with retinopathy but not nephropathy in type 2 diabetes patients. The multivariate logistic regression analysis showed that the D allele of the VEGF polymorphisms an independent risk factor of diabetic retionpathy after controlling for other clinical variables.

64. Effects of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy.

Boger CA, Stubanus M, Haak T et al.

Nephrol Dial Transplant. 2007 22 (1): 154-62.

Background The MTHFR C677T single mucleotide polymorphism TT genotype is associated with increased levels of plasma homocysteine and possibly an effect on cardiovascular mortality. We evaluated the effect of C677T genotype on mortality in a large end-stage renal disease (ESRD) cohort. Methods C677T genotype was determined in 439 Caucasians with end-stage diabetic nephropathy (DNP) (cases) recruited from 30 dialysis centres in Southern Germany. A total of 482 type 2 diabetes patients without DNP (no microalbuminuria) at inclusion served as a genotype control collective. Patients were prospectively followed for 4 years. Primary endpoint was all-cause mortality. Results In contrast to controls, the genotype distribution in cases was not in Hardy-Weiberg equilibrium (HWE, P = 0.003), due to a less expected of patients with the TT genotype. The requirements of HWE were met in cases with < 2 years dialysis therapy prior to study inclusion (n = 219). TT genotype was associated with a decreased body mass index (P = 0.002) and long diabetes duration in dialysis patients (P = 0.03). However, TT genotype was not associated with an increased risk of all-cause or cardiac mortality in the total dialysis collective or the subgroup. Also, we observed no association of MTHFR genotype with cardiovascular morbidity in cases or controls (P > 0.05), or with an increased rate of progression to novel microalbuminuria. Conclusion MTHFR 677TT genotype was significantly underrepresented in patients with ESRD in our study, but was not associated with premature mortality in these patients. We found no evidence for survival bias due to C677T genotype in the ESRD cohort, or bias due to genetically determined accelerated progression to novel microalbuminuria in the controls. However, we cannot exclude that the TT genotype protects from progression from microalbuminuria to more advanced stages of DNP, or that TT genotype is associated with premature mortality before a patient progress to ESRD.

65. Proteome analysis of serum from type 2 diabetics with nephropathy.

Kim HJ, Cho EH, Yoo JH et al.

J Proteome Res. 2007 6 (2): 735-43.

Diabetic nephropathy (DN) is a renal disease which develops as a consequence of diabetes mellitus. Microalbuminuria is the earliest clinical sign of DN. There are no specific diagnostic biomarkers for type 2 diabetics with nephropathy other than microalbuminuria and macroalbuminuria. However, microalbuminuria does not constitute a sole independent for type 2 diabetics with nephropathy, and thus, another screening method, such as a biomarker assay, is required in order to diagnose it more correctly. Therefore, we have utilized two.dimensional electrophoresis (2-DE) to identify human serum protein markers for the more specific and accurate prediction of progressive nephropathy in type 2 diabetes patients, via comparison of the serum proteome in three experimental groups: type 2 diabetes patients without microalbuminuria (DM, n = 30), with microalbuminuria (MA, n = 29), and with chronic renal failure (CRF, n = 31). As a result, proteins which were differentially expressed with statistical significance (p < 0.05) in MA and CRF groups as compared to those in DM group were selected and identified by ESI-Q-TOF MS/MS. Among these identified proteins, two proteins which might be useful as diagnostic biomarkers of type 2 diabetics with nephropathy were verified by Western blootting: extracellular glutathione peroxidase (eGPx) and apolipoprotein (ApoE) were found to exhibit a progressive reduction in MA and CRF groups. Notably, eGPx was further verified by ELISA using DM (n = 100) and MA (n = 96) patient samples. Collectively, our results that the proteins identified in this study may constitute potential biomarkers for the diagnosis of type2 diabetics with nephropathy.

66. Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: An observational follow-up study.

Araki S, Haneda M, Koya D et al.

Diabetologia. 2007 Jan 16; [Epub ahead of print].

Aims / Hypothesis The early identification of type 2 diabetic patients at risk of developing microalbuminuria - an independent risk factor for renal and cardiovascular diseases - is important to improve the patient’s outcome. We investigated whether serum levels of IL-18, a proinflammatory cytokine, were a predictor of early renal dysfunction. Materials and Methods A total of 249 Japanese type 2 diabetic patients without overt poroteinuria were enrolled in an observational follow-up study (median follow-up 7 years), and their stage of diabetic nephropathy was classified and their estimated glomerular filtration rate (eGFR) was calculated annually. Results At baseline, serum levels of IL-18 were higher in subjects with microalbuminuria (n = 76) than in those with normoalbuminuria (n = 173). Elevated serum levels of IL-18 were associated with the progression of nephropathy to a higher stage in normoalbuminuric subjects (118 [interquartile range 91-159] ng/l vs 155 [interquartile range 121-205] ng/l, p = 0.003), but not in microalbuminuric subjects (154 [interquartile range 113-200] ng/l vs 160 [interquartile range 101-190] ng/l, p = 0.50). The adjusted risk for developing microalbuminuria was 3.6 (95% CI 1.2-10.4) in normoalbuminuric subjects with serum IL-18 levels above the median (>/= 134.6 ng/l), and was significantly enhanced in those urinary AERs at the upper end of the normal range (7.5 mug/min 300 m/g) over 10 years. Control subjects (n = 31) were matched to case subjects (1:1) according to diabetic duration, age, sex, and BMI but remained normoalbuminuric (albumin-to creatinine ratio < 30 mg/g) over the same 10 years. Surface-enhanced laser desorption/ionization time-of-flight mass spectometry (SELDI-TOF MS) was performed on baseline urine samples, and trains (14 cases: 14 controls) and validation (17:17) sets were tested. Results At baseline, A1C levels differed between case and control subjects. SELDI-TOF MS detected 714 urine protein peaks. Of these, a 12-peak proteomic signature correctly predicted 89% of cases of diabetic nephropathy (93% sensitivity, 86% specificity) in the training set. Applying this same signature to the independent validation set yielded an accurycy rate of 74% (71% sensitivity, 76% specificity). In multivariate analyses, the 12-peak signature was independently associated with subsequent diabetic nephropathy when applied to the validation set (odds ratio [OR] 7.9 [95% CI 1.5-43.5], P = 0.017) and the entire dataset (14.5 [3.7-55.6], P = 0.001), and A1C levels were no longer significant. Conclusions Urine proteomic profiling identifies normoalbuminuric subjects with type 2 diabetes who subsequently develop diabetic nephropathy. Further studies are needed to characterize the specific proteins involved in this early prediction.

69. Relationship between total oxidant status and severity of diabetic nephropathy in type 2 diabetic patients.

Aslan M, Sabuncu T, Kocyigit A et al.

Nutr Metab Cardiovasc Dis. 2007 Feb 21, [Epub ahead of print].

Background and Aim Data on oxidative stress in type 2 diabetic patients with diabetic nephropathy is scant. The objective of this study was to investigate possible associations between total oxidant status (TOS) and the severity of diabetic nephropathy in type 2 diabetic patients by using a novel automated measurement method. Methods and Results Thirthy-six patients with diabetic nephropathy (group 1), 25 diabetic patients without nephropathy (group 2) and 30 controls (group 3) were enrolled. Serum total antioxidant capacity (TAC), TOS levels and oxidative stress index (OSI) were determined. The severity of the disease was determined with microalbuminuria levels. TAC was lower, while TOS and OSI were higher in group 1 than in group 3 (P < 0.01, P < 0.001, P < 0.001; respectively). There were no statistically significant differences between group 2 and group 3 with respect to TAC, TOS and OSI (all P > 0.05). Group 1 had higher TOS and OSI than group 2 (both P < 0.05), but was no statistically significant with respect to TAC. Significant correlations were observed between microalbuminuria levels, and TAC, TOS and OSI levels (t = -0.616, P < 0.001; r = 0.488, P < 0.01; r = 0.567, P < 0.001; respectively). Conclusion Our results suggest that oxidative stress is increased in patients with diabetic nephropathy compared to diabetic patients without nephropathy and this increase seems to be related to the severity of microalbuminuria levels.

70. Cortisol secretion in patients with type 2 diabetes: Relationship with chronic complications.

Chiodini I, Adda G, Scillitani A et al.

Diabetes Care. 2007 30 (1): 83-8.

Objective The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-,age., and BMI-matched nondiabetic subjects. Research Design and Methods In all subjects, we evaluated ACTH at 8:00 a.m. in basal conditions and serum cortisol levels at 12:00 p.m. (F24) and at 9:00 a.m. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n = 53) or presence (group 2, n = 117) of diabetes complications. Results In group 2, UFC (125.2 +/- 4.6 nmol/24 h) and F24 (120.6 +/- 4.1 nmol/l) were higher than in group 1 (109.2 +/- 6.8 nmol/24 h, P = 0.057, and 99.7 +/- 6.1 nmol/l, P = 0.005, respectively) and in nondiabetic patients (101.7 +/- 5.9 nmol/24 h, P = 0.002, and 100.3 +/- 5.3 nmol/l, P = 0.003, respectively). In diabetic patients, the number of complications was associated with F24 (R = 0.345; P < 0.0001) and diabetes duration (R = 0.39; P < 0.0001). Logistic regression analyses showed that the presence of diabetes complications was significantly associated with F24, sex, duration of diabetes, and glycated hemoglobin. Conclusions In type 2 diabetic subjects, hypothalamic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.

71. Anemia in diabetes: Marker or mediator of microvascular disease?

Thomas MC.

Nat Clin Pract Nephrol. 2007 3 (1): 20-30.

Anemia is a common finding in patients with diabetes due to the high burden of chronic kidney disease in this population. Anemia is more prevalent and is found earlier in patients with diabetes than in those with kidney disease from other causes. The increased risk of anemia in diabetes propbably reflects changes in the renal tubulointerstitium associated with diabetic kidney disease, which disrupt the decline interaction between interstitial fibroblasts, capillaries and tubular cells required for normal hemopioetic function. In particular, the uncoupling of the hemoglobin concentration from renal erythropoietin synthesis seems to be the key factor underlying the development of anemia. Systemic inflammation, functional hematinic deficiences, erythropoietin resistance and reduced red cell survival also drive anemia in the setting of impaired renal compensation. Although anemia can be considered a marker of kidney damage, reduced hemoglobin levels independently identify diabetic patients with an increased risk of microvascular complications, cardiovascular disease and mortality. Nevertheless, a direct role in the development of progression of diabetic complications remains to be clearly estabilshed and the clinical utility of correcting anemia in diabetic patients has yet to be demonstrated in randomized controlled trials. Correction of anemia certainly improves performance and quality of life in diabetic patients. In the absence of additional data, treatment should be considered palliative, and any functional benefits must be matched against costs to the patient and health system.

72. Diagnosing diabetic nephropathy by (1) H NMR metabonomics of serum.

Makinen VP, Soininen P, Forsblom C et al.; On behalf of the FinnDiane Study Group.

MAGMA. 2006 Dec 15; [Epub ahead of print].

Object The most severe complication of type 1 diabetes (T1DM) is diabetic nephropathy. It is associated with a high risk of cardiovascular complications and premature death and requires early detection to be efficiently treated. The clinical practice to diagnose diabetic nephropathy is also a non-optimal and tedious set up based on albumin excretion rate in multiple overnight or 24h urine samplaes. Conversely, in this study, these independent diagnostic data are used to provide a realistic testing case for applying (1) H NMR metabonomics of serum in a diagnostic fashion. Materials and Methods 182 T1DM and 21 non-diabetic (non-T1DM) individuals were studied. The (1) H NMR of serum at 500 MHz was targeted at two molecular windows: lipoprotein lipids and low-molecular-weight metabolites. Results T1DM and non-T1DM individuals were exclusively separated by (1) H NMR. For diabetic nephropathy diagnosis in the T1DM patients, (1) H NMR data (and clinical biochemistry data) gave a sensitivity of 87.1% (83.9%) and a specificity of 87.7% (95.9%). The predictive values of positive and negative test were 89.0% (95.5%) and 83.6% (79.2%), respectively. Conclusions (1) H NMR metabonomics clearly distinguishes metabolic characteristics of T1DM and appears approximately as good a means to diagnose diabetic nephropathy from serum as an advanced set of biochemical variables.

73. The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: Results from Metascreen, a multicenter diabetes clinic-based survey.

[No authors listed].

Diabetes Care. 2006 29 (12): 2701-7.

Objective We aimed at assessing the degree of association and the predictive power of the metabolic syndrome with regard to clinically detectable complications in patients with diabetes. Research Design and Methods Metascreen is a cross-sectional survey of metabolic syndrome and clinically detected diabetes complications performed in 8 497 patients (7 859 with type 2 diabetes and 638 with type 1 diabetes) randomly chosen in 176 diabetes outpatients clinics throughout Italy. The metabolic syndrome was defined according to either the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or the Unternational Diabetes Federation (IDF) diagnostic criteria. Multivariate analyses of the association (s) between either AHA/NHLBI or IDF metabolic syndrome and clinical complications were performed. Receiver-operator characteristic (ROC) curves were constructed to compare the predictive power of the two sets of diagnostic criteria of the metabolic syndrome. Results Either definition of the metabolic syndrome was an independent statistical indicator of the presence of nephropathy and neuropathy (P < 0.02-0.01) in type 1 diabetes and all complications (P < 0.0001), including cardiovascular disease and retinopathy, in type 2 diabetes. For each complications, the ROC curves based on either AHA/NHLBI or IDF metabolic syndrome were similar to each other and to the ROC curves constructed with all continous traits compounding the metabolic syndrome. Conclusions The metabolic syndrome, defined according to AHA/NHLBI or IDF diagnostic criteria, is an independent clinical indicator and may be involved in the pathogenesis of both macro- and microvascular complications of diabetes.

74. The new KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and CKD.

Nelson RG, Tuttle KR.

Blood Purif. 2007 25 (1): 112-4.

Background/Aims The National Kidney Fundation (NKF) recently published new guidelines and clinical practice recommendations for the diagnosis and management of patients with diabetes and chronic kidney disease (CKD). Methods Guidelines were developed using an evidence-based approach. When sufficient evidence was lacking, recommendations were developed that reflect expert opinion. Results Giudelines describe the process for screening and diagnosis of kidney disease in the setting of diabetes and the management of hyperglycemia, hypertension, dyslipidemia, and nutrition. Recommendations describe the management of albuminuria in the normotensive diabetic patient and the potential value of albuminuria as a marker of the treatment efficacy; the impact of diabetes and CKD in special populations; the importance of behavioral self-mamagement; and the value of intensive multifaceted intervention in these high risk patients. Conclusions The new guidelines and recommendations update and extend the scope of the NKF’s Disease Outcomes Quality Initiative (KDOQI (TM)).

75. Inverse association between lipid levels and mortality in men with chronic kidney disease who are not yet on dialysis: Effects of case mix and the malnutrition-inflammation-cachexia syndrome.

Kovesdy CP, Anderson JE, Kalantar-Zadeh K.

J Am Soc Nephrol. 2007 18 (1): 304-11.

High total cholesterol is associated with lower mortality in dialysis patients, but the relationship between lipid levels and mortality in patients who have chronic kidney disease (CKD) and are not yet on dialysis is poorly described. This study examined the association between lipid levels and all-cause and cardiovascular mortality in 986 male patients (age 67.4 +/- 10.9 yr; race 23.7% black) who had CKD and were not yet on dialysis. Associations were determined in fixed-covariate and time-dependent Cox models, before and after adjusment for components of case mix and surrogate for malnutrition-inflammation-cachexia syndrome (MICS). Lower total cholesterol quartiles were associated with higher all-cause mortality in a fixed-covariate model that was adjusted for age, race, and body mass index (hazard ratio [95% confidence interval] for cholesterol < 153, 153 to 182, and 183 to 215 versus > 215 mg/dl> 1.91 [1.35 to 2.69], 1.36 [0.96 to 1.92], 1.10 [0.78 to 1.57]; P < 0.001 for trend), but this association was attenuated after adjusment for case mix (P = 0.023 for trend) and abolished after additonal adjusment for MICS (P = 0.14 for trend), with time-dependent Cox models showing similar results. Similar tendencies also were detected in the association between levels of LDL cholesterol with total and cardiovascular mortality and triglycerides with all-cause mortality in both fixed-covariate and time-dependent analyses. Lower lipid levels are associated with higher mortality in patients who have moderate and advanced CKD and are not yet on dialysis. This inverse association is explained in part by case-mix characteristics and the presence of surrogate for MICS.

76. The outcome of heart transplant recipients following the development of end-stage renal disease: Analysis of the Canadian Organ Replacement Register (CORR).

Alam A, Badovinac K, Ivis F et al.

Am J Transplant. 2007 7 (2): 461-5.

End-stage disease is a significant complication of heart transplantation (HTx), but our understanding of dialysis outcomes in HTx recipients remains limited. We performed a retrospective analysis looking at dialysis mortality in HTx recipients as compared to a matched dialysis cohort. We also examined outcomes with respect to kidney transplantation (KTx) in these cohorts. 2709 incident HTx recipients were captured from the Canadian Organ Replacement Register between 1981- and 2002. The incidence of dialysis after HTx was 3.9% (n = 105) and carried a greater crude mortality compared to HTx recipients not requiring dialysis (56.2% vs 35.9%, p < 0.001). Compared to the matched dialysis cohort, survival of HTx patients on dialysis was also significantly worse (19% vs 40%, p = 0.003). In those receiving a KTx, survival did not differ between the two cohorts; however, in those that did not receive a KTx the survival was signficantly lower in the dialysis post-HTx group compared to the matched dialysis cohort (15.7% vs 35.2%, p < 0.025). Our analysis suggest mortality on dialysis following HTx is greater than would be expected from a similar dialysis population, and KTx may abrogate some of this increased risk. Attention should be placed on preventing chronic kidney disease progression following HTx.

77. Poor prognosis of heart transplant patients with end-stage renal failure.

Villar E, Boissonnat P, Sebbag L et al.

Nephrol Dial Transplant. 2007 Jan 31; [Epub ahead of print].

Background Chronic kidney disease (CKD) and end-stage renal failure (ESRF) are major complications after a heart transplant. The aim of this study is to compare survival in heart transplant (HT) vs non-heart transplant (non-HT) patients starting dialysis. Methods Survival was studied among the 539 newly dialysed patients between 1 January 1995 and 31 Dcember 2005 in our Department. All patients were prospectively followed from the date of first dialysis up to death or 31 December 2005. Multivariate survival analysis adjusted on baseline characteristics was performed with the Cox model. Results There were 21 HT patients and they were younger than non-HT patients at first dialysis: 58.6 +/- 11.6 vs 63.0 +/- 16.2 years (P = 0.09). Calcineurin inhibitor nephrotoxicity was the main cause of ESRF in HT patients (47.6%). Crude 1, 3 and 5-year survival rates in HT and in non-HT patients were as follows: 76.2%, 57.1%, 28.6% and 79.1% 58.7%, 46.7% (P = 0.2). The adjusted hazard ratio of death in HT vs non-HT patients was 2.27 [1.33-3.87], P = 0.003. Sudden death was the main cause of death in HT patients, in 33.3% vs l0.4% in non-HT patients (P = 0.01). Five HT patients benefited from renal transplant. They were all alive at the end of the study period, while one patient among the 16 remaining on dialysis survived. Conclusion HT patients with CKD who reached ESRF have a poor outcome after starting dialysis in comparison with other ESRF patients. Improvement in renal function management in the case of CKD is needed in these patients and non-nephrotoxic immunosuppressive regimens have to be evaluated. Renal transplant should be the ESRF treatment of choice in HT patients.

78. Determinants of renal function in pediatric heart transplant recipients: Long-term follow-up study.

Sachdeva R, Blaszak RT, Ainley KA et al.

J Heart Lung Transplant. 2007 26 (2): 108-13.

Background Renal insufficiency (RI) is a known complications in heart transplant recipients. We sought to determine the prevalence and risk factors for RI in pediatric heart transplant recipients over a long-term follow-up period. Methods The study cohort included 77 pediatric heart transplant recipients (35 girls, 18 African Americans) who had a minimum follow-up of 1 year. Data were obtained from pre-transplant evaluation and at 1, 6 and 12 months post-transplant and annually thereafter. Factors evaluated for their influence on renal function included duration of listing, age at transplant, gender, race, cardiac diagnosis, use of assist devices, inotropic support, rejection episodes and use of calcineurin inhibitors. Results The median age at transplant was 2 years, with a median follow-up duration of 5.1 years. RI was prevalent in 33% pre-transplant, and in l7%, 21% and 25.9% at 1, 3 and 5 years post-transplant, respectively. Two patients developed end-stage renal disease requiring long-term dialysis, with 1 eventually receiving a renal transplant. Significant risk factors for RI were African-American race (p = 0.04), younger age at transplant (p = 0.007), duration of losting (p < 0.0001) and calcineurin inhibitor level (p = 0.003). RI at 6 months post-transplant predicted chronic kidney disease at 5 years (odds ratio = 9). Conclusions The prevalence of RI increased during a median follow-up of years in this pediatric heart transplant cohort. African-American race, younger age at transplant, longer duration of listing, high level of calcineurin inhibitors and RI at 6 months were important determinants of RI. These patients should be followed-up carefully with early referral to a pediatric nephrologist if they develop chronic kidney disease.

79. The impact of renal function on the long-term clinical course of patients who underwent percutaneous coronary intervention.

Papafaklis MI, Naka KK, Papamichael ND et al.

Catheter Cardiovasc Interv. 2007 69 (2): 189-97.

Objectives To determine the impact of the level of kidney function on the extended (> 5 years) long-term clinical course of patients undergoing percutaneous coronary intervention (PCI). Background Chronic kidney disease (CKD) has been significantly associated with an increased in-hospital and 1-year mortality following PCI. Methods In this single-centre retrospective study, glomerular filtration rate (GFR) at baseline was estimated in 317 patients not on dialysis, who underwent successful PCI between mid-1995 and mid-1999. baseline demographic and angiographic characteristics, and long-term major adverse cardiac events and symptoms were compared for patients with GFR >/= 60 ml/min/.73 m (2) (normal or mildly impaired renal function) and GFR /= 6 weeks of enalapril (10 mg PO), losartan (100 mg PO), or eprosartan (600 mg PO). Patients as compared with control subjects (n = 82) had higher mean arterial pressure (113 +/- 13 versus 89 +/- 7 mm Hg), MSNA (31 +/- 13 versus 19 +/- 7 bursts per minute), and log plasma renin activity (2.67 +/- 0.36 versus 2.40 +/- 0.32 fmol/L per second; all P < 0.001). During angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (n = 31), mean arterial pressure (115 +/- 11 to 100 +/- 9 mm Hg) and MSNA (33 +/- 11 bursts per minute) decreased (both P < 0.01) but were still higher than in control subjects (both P < 0.01). Multiple regression analysis identified age and plasma renin activity as predictive for MSNA. In conclusion, sympathetic hyperactivity occurs in a substantial proportion of hypertensive CKD patients. Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment reduces but does not normalize MSNA.

6. Insulin resistance, inflammatory biomarkers, and adipokines in patients with chronic kidney disease: Effects of angiotensin II blockade.

de Vinuesa SG, Goicoechea M, Kanter J et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S206-12.

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and not diabetes administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data thet were obtained fro 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml × mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 91 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl, P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the dmnistration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ABR therapy.

7. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy.

Jin HM, Pan Y.

Nephrol Dial Transplant. 2007 Feb 17; [Epub ahead of print].

Background A growing body of evidence supports the concept that treatment with the newer angiotensin type-1 receptor blockers (ARBs) improves glucose homeostasis under condition it is impaired. Controversy exists, however, regarding the ability of losartan, an older ARB, to exert comparable improvement. The present study was undertaken to evaluate the effects of losartan on glucose homeostasis in subjects with type 2 diabetes and nephropathy. Methods Twenty-seven subjects with type 2 diabetic nephropathy were enrolled in this prospective, randomized, controlled study. Losartan (100mg daily) or the calcium channel blocker amlodipine (10 mg daily) was administered for a period of 3 months. Fasting blood glucose, serum insulin and C-peptide concentrations were measured at baseline and at the end of the study. Oral glucose tolerance test were performed to evaluate insulin sensitivity and beta-cell responsiveness. Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR). Results Fasting blood glucose, HbA1c, AUC glucose, and urinary protein values were significantly decreased in the losartan group as compared the amlodipine group (P < 0.05). Furthermore, C-peptide concentrations, the insulin sensitivity index, and the insulin-to-glucose ratio were significantly increased after 3 months of therapy with losartan as compared to amlodipine (P < 0.05). Reductions of fasting insulin concentrations and HOMA-IR were also observed for the losartan group; however, reductions were not significant when compared with the amlodipine group. Conclusion In addition to reducing urinary protein excretion, losartan at 100 mg daily increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetic nephropathy.

8. Health economic implications of irbesartan treatment versus standard blood pressure control in patients with type 2 diabetes, hypertension and renal disease: A Hungarian analysis.

Palmer AJ, Valentine WJ, Ray JA et al.

Eur J Health Econ. 2007 Jan 20; [Epub ahead of print].

To perform a health economic analysis on treatment with irbesartan in patients with type 2 diabetes and hypertension. A Markov model was adapted to the Hungarian setting to stimulate renal deterioration from the development of microalbuminuria to nephropathy, doubling of serum creatinine, end-stage renal disease (ESRD) and all-cause mortality. Outcomes for two treatments were evaluated: (1) a placebo regimen of standard antihypertensive mediactions, and (2) the addition of irbesartan 300 mg administered daily, with both treatment initiated after developing microalbuminuria. Outcomes were discounted at 5% annually to correspond with national guidelines. Treatment with irbesartan was estimated to improve undiscounted life expectancy by 0.89 +/- 0.05 years, reduce the cumulative incidence of ESRD by 7.5 +/- 0.4%, and reduce lifetime costs by Hungarian Forint (HUF) 519 993 +/- 40 814, compared to placebo. Irbesartan was projected to improved life expectancy and reduce costs compared to placebo in the Hungarian setting in hypertensive patients with type 2 diabetes and microalbuminuria.

9. Irbesartan treatment reduces biomarkers of inflammatory activity in patients with type 2 diabetes and microalbuminuria: An IRMA 2 Substudy.

Persson F, Rossing P, Hovind P et al.

Diabetes. 2006 55 (12): 3550-5.

The impact of irbesartan treatment on biomarkers of low-grade inflammation, endothelial dysfunction, growth factors, and advanced glycation end products (AGEs) during the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study was evaluated. IRMA 2 was a 2-year multicenter, randomized, double-blind trial in patients comparing irbesartan (150 or 300 mg once daily) verus placebo. The primary end point was onset of overt nephropathy. A subgroup (n = 269, 68%) was analyzed for biomarkers at baseline and after 1 and 2 years. High-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, fibrinogen, adhesion molecules, transforming growth factor-beta, and AGE peptides were assessed. Irbesartan treatment yielded significantly changes in hs-CRP (based on generalized estimating equation regression coefficient) with a 5.4% decrease per year versus a 10% increase per year in the placebo group (P < 0.001). Fibrinogen decreased 0.059 g/l per year from baseline versus placebo’s 0.059 g/l increase per year (P = 0.027). IL-6 showed a 1.8% increase per year compared with placebo’s 6.5% increase per year (P = 0.005). Changes in IL-6 were associated with changes in albumin excretion (P = 0.04). There was no treatment effect on the other biomarkers. Irbesartan (300 mg once daily) reduces low-grade inflammation in this high-risk population, and this may reduce the risk of micro- and macrovascular disease.

10. Ca2+ channel subtypes and pharmacology in the kidney.

Hayashi K, Wakino S, Sugano N et al.

Circ Res. 2007 100 (3): 342-53.

A large body of evidence has accrued indicating that voltage-gated Ca (2+) channel subtypes, including L-, Z-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca (2+) channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca (2+) channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type C (2+) channels and suggest that it potentially causes glomerular hypertension. In contrast, recently developed Ca (2+) channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca (2+) channels and elicit vasodilation of afferent and efferent arterioles, which suggest the presence of T-type Ca (2+) channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type C (2+) channels mediate aldosterone release as well as its effect on renal efferent arteriolar tone. Furthermore, T-type CCBs are reported to exert inhibitory action on inflammatory process and renin secretion. Similarly, N-type Ca (2+) channels are present in nerve terminals, and the inhibition of neurotransmitter release by N-type CCBs (eg, cilnidipine) elicits dilation of afferent and efferent arterioles and reduce glomerular pressure. Collectively, the kidney is endowed with a variety of C (2+) channel subtypes, and the inhibition of these channels by their specific CCBs leads to variable impact on renal microcirculation. Furthermore, multifaceted activity of CCBs on T- and N-type Ca (2+) channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.

11. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy.

Matsumoto S, Takebayashi K, Aso Y.

Metabolism. 2006 55 (12): 1645-52.

Angiotensin II can influence adipocytokine levels in adipose tissue, but the association between aldosterone, which mediates the effect of angiotensin II, and adipocvytokines has yet to be fully elucidated. This study was designed to investigate the effect of spironolactone, a representative aldosterone blocker, on adipocytokines such as adiponectin, visfatin, plasminogen activator inhibitor (PAI)-1 and tumor necrosis factor alpha in patients with type 2 diabetic nephropathy: the study included 33 patients, 22 of whom were randomly assigned to the spironolactone (50 mg/d) group and 11 to the amlodipine (2.5 mg/d) group. Data were collected at baseline and after 3 months of treatment and compared with baseline data for 25 age-matched healthy subjects. A significant decrease in plasminogen activator inhibitor 1 in the spironolactone group was observed (22.6 +/- 13.4 to 19.2 +/- 11.3 ng/mL, P = 0.0323), but this did not occur in the amlodipine group. Adiponectin and visfatin levels did not change in the spironolactone and amlodipine groups, but significant increases in these adipocytokines were found in a subgroup of patients in the spironolactone group with glycated hemoglobin A (1c) (HbA (1c) ) 8.0% or greater (11.8 +/- 6.4 to 13.3 +/- 7.4 mug/mL, P = 0.0344; and 1.39 +/- 0.92 to 2.26 +/- 0.76 ng/mL, P = 0.0397), respectively). The tumor necrosis factor alpha level at baseline exceeded the lower detection limit of the assay in only 6 patients in the spironolactone group, and no change occured in these patients. Moreover, neither spironolactone nor amlodipine therapy caused a change in high-sensitivity C-reactive protein or soluble CD40 ligand, but a significant decrease in the level of brain natriuretic peptide was found in the spironolactone group only. Furthermore, significant increases of HbA (1c), creatinine, potassium, and aldosterone levels and plasma renin activity, and a decrease in urinary albumin excretion were also observed in the spironolactone group. The number of patients with HbA (1c) 8.0% or greater increased after spironolactone treatment. A significant decrease in systolic but not in diastolic blood pressure was observed in both treatment groups. In conclusion, our data suggest that in patients with type 2 diabetes mellitus complicated by diabetic nephropathy, spironolactone can decrease plasminogen activator inhibitor 1 and brain natriuratic peptide levels in addition to urinary albumin excretion, and systolic blood pressure, and that in patients with poor glycemic control, spironolactone can increase the levels of adiponectin and visfatin. However, the significant elevation of HbA (1c) levels by spironolactone should be emphasized.

12. Beta-blockers in the management of chronic kidney disease.

Bakris GL, Hart P, Ritz E.

Kidney Int. 2006 70 (11): 1905-13.

The sympathetic nervous system modulates renal function through its receptors namely beta1 (cardiac output and renin release), alpha1 (systemic and renovascular constriction), and beta2 renovascular dilation. Sympathetic overactivity is commonly seen in chronic kidney disease (CKD) and is an important contributor to increasing the risk of cardiovascular events as well as increasing renal disease progression. Recent evaluations of drug use in people with CKD shows a remarkably low percentage of patients receiving beta-blockers, especially in more stage CKD when cardiovascular risk is higher. This is in large part due to tolerability of these agents. Moreover, water-soluble beta-blockers such as atenolol and metoprolol are dialyzable and require supplementation to avoid exacerbation of arrhythmias following dialysis. Newer vasodilating beta-blockers have better tolerability and different effects on renal hemodynamics as well as metabolic variables. These effects are related to the relative alpha1-blocking effect of agents such as carvedilol and labetalol, with carvedilol having relatively greater alpha-blocking effects. Few studies evaluate beta-blockers on cardiovascular risk in CKD patients. Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This paper reviews the animal and clinical trial data that evaluate beta-blockers in CKD highlighting the vasodilating beta-blockers. It is apparent that greater use of this drug class for blood pressure control would further enhance reduction of risk of heart failure, the most common cause of death in the first year of starting dialysis.

13. Effect of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease.

Goicoechea M, de Vinuesa SG, Lahera V et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S231-5.

Although substantial evidence suggest that treatment of dyslipidemia with statins reduces mortality and morbidity that are associated with cardiovascular disease, only a few studies have examined the efficacy of statins on inflammatory and fibrinolytic status in patents with chronic kidney disease (CKD). A 6-mo, prospective, randomized study was designed to assess the efficacy of atorvastatin in reducing circulating inflammatory and fibrinolytic parameters in patients with CKD. Sixty-six patients with CKD (stages 2, 3, and 4) and LDL choseterol levels >/= mg/dl were randomly assigned (2:1) to receive 20 mg/d atorvastatin (n = 44) or nonatorvastatin therapy (n = 22). Lipid profile, renal functio, fibrinolytic balance (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1), and inflammatory markers (C-reactive protein [CRP], IL-1beta, IL-6, and TNF-alpha) were measured before and 6 mo after atorvastatin was added to treatment. Twenty-five age-matched individuals with normal renal function (estimated GFR > 90 ml/min) were used as healthy control subjects. Patients with CKD had higher CRP, IL-1beta, TNF-alpha, and IL-6 levels than age-matched population with normal renal function. t-PA concentration was higher in patients with CKD (P = 0.000). Plasminogen activator inhibitor-1 values were comparable in all patients. Total cholesterol and LDL cholesterol were significantly reduced only in patients who received atorvastatin. In addition to the hypolipidemic effect, atorvastatin treatment signficantly reduced inflammatory parameters: CRP (median 4.1 to 2.9; P = 0.015), TNF-alpha (6.0 +/- 2.7 to 7.7 +/- 2.4; P = 0.046), and IL-1beta levels (1.9 +/- 0.7 to 1.2 +/- 0.7; P = 0.001). These parameters remained unchanged in patients who were not treated with atorvastatin. Fibrinolytic parameters were not modified by atorvastatin treatment. Patiens with CKD showed higher levels of inflammatory parameters and t-PA levels than age-matched healthy control subjects. Atorvastatin treatment, in addition to its beneficial effect on cholesterol levels, improved the inflammatory state of these patients without modifying fibrinolytic balance.

14. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: A subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study.

Athyros VG, Mikhailidis DP, Liberopoulos EN et al.

Nephrol Dial Transplant. 2007 22 (1): 118-27.

Background Metabolic syndrome (MetS) is associated with increased risk for both vascular and chronic kidney disease. Whether statins ameliorate these risks is not established. Methods This post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD). Evaluation (GREACE) examines the effect of statins on estimated glomerular filtration rate (e-GFR) and serum uric acid (SUA) levels and their relation to vascular events in CHD patients with MetS. MetS patients were divided into two groups: Group A (n = 365) received lifestyle advice, target-driven treatment with statins (mainly atorvastatin) and treatment for hypertension and elevated glucose. Group B (n = 347) received the same except for statin. Patients without MetS were divided into those who received treatment similar to Group A and Group B [Group C (n = 504) and D (n = 384), respectively]. All patients were followed for 3 years. Results A total of 12.1% of patients in Group A experienced a vascular event vs 28% in Group B; risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20-0.64, P < 0.0001, while in those withoput MetS (group C vs Group D), the respective RR was 0.59, 95% CI 0.41-0.79, P < 0.0001. In Group A, e-GFR increased by 13.7% and SUA levels fell by 8.9%m while in Group B e-GFR was reduced by 5.8% and SUA increased by 4.3% (P < 0.005). Stepwise regression analysis showed that these changes were independently related to vascular events. Conclusion Among CHD patients, those with MetS benefited more from statin treatment than those without MetS. This benefit could be partially attributed to favourable changes in e-GFR and SUA levels probaly induced by statin treatment.

15. Lipid metabolism in chronic kidney disease: The role of statins in cardiovascular risk.

Wanner C, Drechsler C, Krane V.

J Ren Nutr. 2007 17 (1): 75-8.

In the general population, the relation between lipids and cardiovascular disease is clearcut, whereas it is highly controversial in chronic kidney disease (CKD) patients. This primarily due to diverging results of retrospective observational trials. This study design often encounters confounding, especially in renal disease patients. Even if analyses are corrected for multiple influences, there might be unknown confounders changing the results. Prospective randomized trials assure that groups are comparable except for the intervention used. Confounding is eliminated by randomization. Nevertheless, the lipid discussion was restarted when two randomized, placebo-controlled, intervantional trials on lipid-lowering therapy in renal patients have been published (Assessment of Lescol in Renal Transplantation and 4D Study [Atorvastatin in patients with type 2 diabetes on hemodialysis]). Surprisingly, both showed no significant reduction of the primary endpoint by statin therapy. In addition to other factors, this might be due to an altered pathogenesis of atherosclerosis in renal patients where multiple nontraditional cardiovascular risk factors are to be mentioned and different characteristics of cardiovascular disease with a high proportion of sudden cardiac death are present. This review will focus on dyslipidemia in renal failure and its treatment. The data published so far is summarized and grouped according to the different stages of CKD.

16. Lipid changes and statins in chronic renal insufficiency.

Ritz E, Wanner C.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S226-30.

It has been known for a lonmg time that chronic kidney disease (CKD) is associated with dyslipidemia, but the full extent of abnormalities had been appreciated only recently, because routine laboratory tests fail to disclose the entire spectrum of lipid abnormalities. Lipids, particularly HDL cholesterol, are predictive of cardiovascular events, but a paradoxic inverse relation between cholesterol concentration and cardiovascular death has been noted in uremic patients. This currently is thought to be explained by the confounding effect of microinflammation and possibly calcification, but this is not definitely proved. Several retrospective analyses that included patients with mild or moderate CKD documented benefit from lowering of cholesterol by statins. In contrast, the Die Deutsche Diabetes Dialyse (4D) study and a small Scandinavian study failed to show a benefit from lowering of cholesterol by statins in ESRD. Pathomechanistically it is posible that nonclassical pathomechanisms override statin-sensitive mechanisms as also suggested by the observation that statins fail to reduce carotid intima-media thickening. Although, experimentally, exposure to lipids (particularly oxidized lipids) aggravates progression, data on the effect of statins on progression in patients with CKD are not definite. The most likely explanation is that the impact of numerous confounders obscures their effect on progression. The increase in urinary protein excretion of patients who are treated with statins had been a cause of concern, but the underlying mechanism (i.e. interfenece with proximal tubular reabsorption of protein) meanwhile has been well documented.

17. Stain therapy in renal disease: Harmful or protective.

Rocher L.

Curr Atheroscler Rep. 2007 9 (1): 18-24.

Chronic kidney disease (CKD) creates one of the highest-risk atherosclerotic states that can occur in human beings. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) had gained widespread acceptance in the general population for the purposes of lowering low-density lipoprotein choesterol (LDL-C) and reducing the future risk of myocardial infarction, stroke, and cardiac death. In patients with CKD, these benefits are believed to be enjoyed to the same or greater degrees. Reduction in LDL-C with statins may be associated with a reduced progression of CKD. Importantly, recent studies suggest statins are associated with a reduction in rates of acute renal failure after cardiopulmonary bypass surgery and exposure to iodinated contrast. In patients with end-stage renal disease (ESRD), recent data suggest that the annual rate of coronary artery calcification can be attenuated or reduced with LDL-C reduction. However, two large trials demonstrating LDL-C reduction with statins and with these drugs have failed to demonstration a reduction in cardiovascular events in ESRD. Thus, the potential benefits of statins and LDL-C reduction in CKD have to considered in light of evidence suggesting a reduced benefit if any, in patients with ESRD. In addition, studies suggest that there are higher adverse drug effects with statins in CKD.

18. Rosiglitazone prevents advanced glycation endproducts-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1.

Yu X, Li C, Li X et al.

Toxicol Sci. 2007 Jan 29; [Epub ahead of print].

In the development of diabetic nephropathy, advanced glycation end products (AGEs) play a causative role via induction of extracellular matrix (ECM) accumulation. Plasminogen activator inhibitor 1 (PAI-1), as a major inhibitor of plasminogen activator that plays an important role in degrading ECM, was found to significantly increase in renal fibrotic diseases. Activation of peroxisome proliferator-activated receptor (PPAR) gamma prevented diabetic nephropathy. The present study, therefore, was to define whether or not AGE-induced renal ECM accumulation and renal dysfunction are mediated by up-regulation of PAI-1 expression and whether or not PPAR gamma agonist can attenuate these AGE effects via suppressing PAI-1 expression. Rats were given AGEs alone by i.v. injection at 100 mg/kg daily with or without oral supplementation of PPAR gamma agonist rosiglitazone (RGZ) at 2 mg/kg daily for six weeks. Results showed that AGEs induced a renal ECM accumulation, as shown by increases in Periodic Acid-Schiff positive materials, fibronectin and type IV collagen (Col IV) contents in glomeruli, and a mild renal dysfunction, as shown by an increase in urinary proteins. AGEs also caused an increase in PAI-1 expression and a decrease in plasminogen activator bioactivity in the kidney. Treatment with RGZ significantly ameliorated AGE-induced renal ECM accumulation, proteinuria, and PAI-1 up-regulation. Direct exposure of rat mesangial cells to AGEs in vitro induced increases in fibronectin and Col IV syntheses along with an increase in PAI-1 expression, effects significantly attenuated by RGZ. Pre-incubation of PAI-1 antibody to AGE-treated mesangial cells completely prevented AGE-induced fibronectin and Col-IV production. These results suggest that up-regulation of PAI-1 expression plays a critical role in AGE-induced renal ECM accumulation. Renal protection of RGZ from AGEs may be associated with the suppression of PAI-1 expression through PPAR-dependent and independent mechanisms.

19. An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis.

Agarwal AK, Silver MR, Reed JE et al.

J Intern Med. 2006 260 (6): 577-85.

Objective To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). Subjects This open-label study enrolled subjects > or = 18 years of age who had glomerular filtration rate > or = 15 and < or = 60 mL min (-1)/1.73 m(2), had Hb 11.0-13.0 g dL (-1), and were receiving Q2M darbepoetin alfa. Design Subjects were switched to QM darpepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or = 11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. Results The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or = 11.0 g dL (-1) during evaluation was achieved by 76% of the 150 subjects who received at least one of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL (-1). Eghty-five percent of 129 subjects who completed the study (95% CI: 78%. 91%) had Hb > or = 11.0 g dL (-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 12.4 mug (106.2, 140.0). Darbepoetin alfa administered QM was well tolerated in study subjects. Conclusion Darbepoetin alfa administered QM maintained Hb in study subjects with CKD not receiving dialysis.

20. Nutritional and inflammatory status influence darbepoetin dose in pre-dialysis elderly patients.

Neves PL, Morgado E, Faisca M et al.

Int Urol Nephrol. 2006 Dec 7; [Epub ahead of print].

Anaemia is a common finding in elderly patients particularly in those with chronic kidney disease. Effective correction of anaemia improves survival and quality of life. The association between anaemia and a poor nutritional status as well as the presence of inflammation has already been documented. The aim of our study was to assess the impact of the nutritional and inflammatory status on darbepoetin dose requirements of elderly patients followed in a ’’Chronic Kidney Disease’’ outpatient clinic. We included 71 elderly patients (age >/= 65 years) in a ’’Chronic Kidney Disease’’ oupatient clinic. Creatinine Clearence (CrCl) was estimated according to the Cockroft-Gault equation. Nutritional status was evaluated by biochemical and anthropometric parameters. Tumour Necrosis Factor-alpha (TNF-alpha), Interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP) were used as biomarkers of inflammation. Our patients (56% males) with a mean age of 76.2 +/- 6.6 years followed for 33.1 +/- 43.6 months. Mean eCrCl was 13.5 +/- 7.2 ml/min/1.73 m (2). All patients were under supplemental iron therapy and 74.7% needed darbepoetin (0.762 +/- 0.6 (mug/kg/week) to correct anaemia. Among several variables regressed on darbepoetin dose, in a multiple regression model, only Hb, IL-6 and TNF-alpha levels and SGA score predicted the need for higher doses of darbepoetin (r = 0.677; r (2) = 0.459). In conclusion, in our pre-dialysis elderly patients, markers of a poor nutritional status (SGA and albumin) and inflammation (IL-6 and TNF-alpha) independently predicted the use of higher doses of darbepoetin to correct anaemia.

21. Stabilization of glomerular filtration rate in advanced chronic kidney disease: A two-year follow-up of a cohort of chronic kidney disease patients stages 4 and 5.

Serrano A, Huang J, Ghossein C et al.

Adv Chronic Kidney Dis. 2007 14 (1): 105-12.

This study examined whether stabilization of the glomerular filtration rate (GFR) is possible in patients with advanced chronic kidney disease (CKD), managed in a CKD clinic. A cohort of 82 patients with stages 4 and 5 CKD was followed for a period of 2 years after initiation of erythropoietin for anemia to determine the GFR and the frequency of primary outcomes (dialysis, transplantation, or death). GFR, calculated by the abbreviated Modification of Diet in Renal Disease formula, was determined every 3 months. After 24 months, 35 subjects (43%) developed a primary outcome. Controlled for other risk factors, the risk of having a primary outcome increased 19.7% for every unit that the GFR decreased (95% confidence interval [CI], 11.9%-26.8%, P < 0.001) and decreased 21.7% for every unit that the hemoglobin increased (95% CI, 0.58%-38.4%, P < 0.001). Blacks had a 3.1 times higher risk (95% CI, 1.4-6.9, P = 0.006) of developing a primary outcome than other ethnicities. In subjects who did not develop primary outcomes (n = 47 or 57%), GFR remained unchanged (19.5 +/- 9.1 at the end of the study 20.8 +/- 5.3 mL/min/1.73 m (2) at the baseline, P = 0.16). The standardized mortality rate was 4.75 and 9.77 per 100 person-year for stages 4 and 5, respectively. We conclude that stabilization of GFR over a 2-year period can be achieved in many patients with advanced CKD treated with erythropoietinin in a CKD clinic. Although the precise reason for the stabilization of GFR cannot be elucidated from this study, our data are ’’proof of concept’’ that CKD outcomes can be improved in a CKD clinic setting.

22. New approaches to the management of anemia of chronic kideny disease: Beyond Epogen and Infed.

Rastogi A, Nissenson AR.

Kidney Int Suppl. 2006 (104): S14-6.

Anemia is a common and debilitating condition seen worldwide but is specially common and severe in patients with chronic kidney disease (CKD) (peritubular cells being the source of erythropoietin) and cancer (secondary to myelosuppressive treatment). Before introduction of the first erythropoiesis-stimulating agent (ESA), recombinant human erthropoietin (rHuEPO), in the late 1980s, blood transfusion and anabolic steroids were the mainstay of treatment. Even though rHuEPO changed the way anemia was managed in patients with renal disease, it does have its limitations including efficacy, duration of activity, route of administration and concomitant iron deficiency, and inflammation. There are several innovative agents including hypoxia-inducible factor stabilizers and erythropoietin-mimetic peptides that are being developed to overcome some of these limitations of rHuEPO and are currently in various stages of clinical testing. Iron deficiency is also very common in patients with CKD because of impaired absorption and mobilization of iron and increased demands for iron when ESAs are administered. There are several novel agents including ferumoxytol, dialysate iron, and iron oligosaccharide that are being evaluated to manage iron deficiency in this patients population.

23. Iron therapy for renal anemia: How much needed, how much harmful?

Horl WH.

Pediatr Nephrol. 2007 Jan 6; [Epub ahead of print].

Iron deficiency is the most common cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in end-stage renal disease (ESRD) patients. Iron deficiency can easily be corrected by intravenous iron administration, which is more effective than oral iron supplementation, at least in adult patients with chronic kidney disease (CKD). Iron status can be monitored by different parameters such as ferritin, transferrin saturation, percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin content, but an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis. Parenteral iron therapy is not without acute and chronic adverse events. While provocative animal and in vitro studies suggest induction of inflammation, oxidative stress, and kidney damage by available parenteral iron preparations, several recent clinical studies showed the opposite effects as long as intravenous iron was adequately dosed. Thus, within the recommended international guidelines, parenteral iron administration is safe. Intravenous iron therapy should be withheld during acute infection but not during inflammation. The integration of ESA and intravenous iron therapy into anemia management allowed attainment of target hemoglobin values in the majority of pediatric and adult CKD and ESRD patients.

24. Oxidative stress in uremia: The role of anemia correction.

Lahera V, Goicoechea M, de Vinuesa SG et al.

J Am Soc Nephrol. 2006 17 (12 Suppl 3): S 174-7.

Patients with chronic kidney disease (CKD) are prone to develop cardiovascular disorders. Numerous reports have shown the association between uremia and oxidative stress, which increases patients’ risk for cummulative injury to multiple organs. Anemia is a common and disabling feature of CKD and seems to be a main cause of oxidative stress; correction of anemia represents an effective approach to reduce oxidative stress, and consequently, cardiovascular risk. There is increasing evidence that correction of anemia with erythropoiesis-stimulating agents could protect from oxidative stress in patients with CKD and ESRD. However, iron deficiency frequently complicates anemia in patients with CKD, and ferrous iron cation is a co-factor that is needed for hydroxyl radical production, which can promote cytotoxicity and tissue injury. This has raised a justifiable concern that prescription of intravenous iron may exacerbate oxidative stress and, hence, endothelial dysfunction, inflammation, and progression of cardiovascular disease, which are widely known consequences of CKD. Correction of anemia represents an effective approach to reduce oxidative stress and, consequently, cardiovascular risk. Iron deficiency is a common cause of resistance to erythropoiesis-stimulating agents, and the overall risk-benefit ratio favors use of intravenous iron to treat iron deficiency in patients with CKD. Consecutive or combined treatment with intravenous iron and erythropoiesis-stimulating agents clearly is beneficial for patients with CKD and iron deficiency, and anemia and could contribute to prevent the risk for cardiovascular events in these patients.

25. Target level for hemoglobin correction in patients with diabetes and CKD: Primary results of the Anemia Correction in Diabetes (ACORD) Study.

Ritz E, Laville M, Bilous RW et al.; Anemia Correction in Diabetes Study Investigators.

Am J Kidney Dis. 2007 49 (2): 194-207.

Background Patients with diabetes and anemia are at high risk of cardiovascular disease. The Anemia CORrectionin Diabetes (ACORD) Study aimed to investigate the effect of anemia correction on cardiac structure, function, and outcomes in patients with diabetes with anemia and early diabetic nephropathy. Methods One hundred seventy-two patients with type 1 or 2 diabetes mellitus, mild to moderate anemia, and stage 1 to 3 chronic kidney disease were randomly assigned to attain a target hemoglobin (Hb) level of either 13 to 15 g/dL (130 to 150 g/L; group 1) or 10.5 to 11.5 g/dL (105 to 115 g/L; group 2). The primary end point was change in left ventricular mass index (LVMI). Secondary end points included echocardiographic variables, renal function, quality of life, and safety. Results Median Hb level and LVMI were similar in groups 1 and 2 (Hb, 11.9 and 11.7 g/dL [119 and 117 g/L]; LVMI, 113.5 and 112.3 g/m (2), respectively). At study end, Hb levels were 13.5 g/dL (135 g/L) in group 1 and 12.1 g/dL (121 g/L) in group 2 (P < 0.001). No significant differences were observed in median LVMI at month 15 between study groups (group 1, 112.3 g/m (2); group 2, 116.5 g/m (2) ). Multivariate analysis showed a nonsignificant decrease in LVMI (P = 0.15) in group 1 versus group 2. Anemia correction had no effect on the rate of decrease in creatinine clearence, but resulted in significantly improved quality of life in group 1 (P = 0.04). There were no clinically relevant differences in adverse events between study groups. Conclusion In patients with diabetes with mild to moderate anemia and moderate left ventricular hypertrophy, correction to an Hb target of 13 to 15 g/dL (130 to 15o g/L) does not decrease LVMI. However, normalization of Hb level prevented an additonal increase in left ventricular hypertrophy, was safe, and improved quality of life.

26. Mortality and target haemoglobin concentration in anaemic patients with chronic kidney disease treated with erythopoietin: A meta-analysis.

Phrommintikul A, Haas SJ, Elsik M et al.

Lancet. 2007 369 (9559): 381-8.

Background Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease. Methods We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trilal registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks. Findings We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p = 0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p = 0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p = 0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, was not significant in the random effects model (1.31, 0.97-1.78; p = 0.075). The incidence of myocardial infarction was much the same in the two groups. Interpretation To target haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

27. Therapeutic potential of TGF-beta inhibition in chronic renal failure.

Gagliardinin E, Benigni A.

Expert Opin Biol Ther. 2007 7 (3): 293-304.

Chronic kidney disease are emerging as a worlwide public health problem. The progression of kidney disease closely correlates with the accumulation of extracellular matrix leading to glomerulosclerosis and tubulointerstitial injury. Transforming growth factor (TGF)-beta has been identified as a key mediator of kidney matrix accumulation. Overexpression of TGF-beta isoforms and their receptors was observed in a variety of renal diseases in both animals and humans. Given its crucial role in fibrotic kidney disease, TGF-beta has been recently considered as a possible target in the management of chronic renal diseases. This review discusses the role of TGF-beta in renal fibrosis and provides an overview of the strategies that, when interfering with TGF-beta expression and signalling, could be employed as new renoprotective treatments.

28. CD36 is a novel potential anti-fibrogenic target in albumin-induced renal proximal tubule fibrosis.

Yang YL, Lin SH, Chuang LY et al.

J Cell Biochem. 2007 Jan 16; [Epub ahead of print].

Albumin is not only risk factor for diabetic nephropathy (DN), but also a therapeutic target. Hence, scientists have long sought ways to elicidate the interaction between albumin and diabetic renal tubule fibrosis. CD36, a surface receptor for thrombospondin-1, has been reported to interact with latents transforming growth factor-beta1 (TGF-beta1) and activate its fibrogenic bioactivity. This study elucidates the interactions between CD36 and renal tubule fibrosis. LLC-PK1 cell were applied to represent renal proximal tubule cells. The expression of CD36 was evaluated by flow cytometry. Fibronectin was assayed by Western blot and enzyme-linked immunosorbent assay (ELISA). Bioactive TGF-beta1 was assayed by ELISA. We demonstrated that albumin was shown significantly to inhibit cell growth without affecting hypertrophy status since protein content and cell size remained unaffected under albumin treatment. Moreover, albumin dose-dependently (0, 1, or 10 mg/ml) enhanced the secretion of bioactive TGF-beta1 and fibronectin with the upregulation of CD36. Intriguingly, CD36 siRNA, a potent silencer for CD36 effectively suppressed the albumin-induced increase in CD36, TGF-beta1, and even fibronectin level. Accordingly, albumin is a pro-fibrinogenic factor for proximal tubule cells since albumin per se markedly upregulated the expression of TGF-beta1 and fibronectin. Most importantly, CD36 may mediate albumin-induced cellular fibrosis since CD36 siRNA appeared to have anti-fibrosis effects. This work suggest that CD36 is a novel and potential therapeutic target for diabetic renal tubule fibrosis.

29. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis.

Tan X, Li Y, Liu Y.

J Steroid Biochem Mol Biol. 2007 Jan 4; [Epub ahead of print].

Vitamin D, especially its most active metabolite 1,25-dihydroxyvitamin D (3) or calcitriol, is essential in regulating a wide variety of biologic processes, such as calcium homeostasis, immune modulation, cell proliferation and differentiation. Clinical studies show that the circulating level of calcitriol is substantially reduced in patients with chronic renal insufficiency. Administration of active Vitamin D results in significant amelioration of renal dysfunction and fibrotic lesions in various experimental models of chronic kidney diseases. Active Vitamin D elicits its renal protective activity through multiple mechanisms, such as inhibiting renal inflammation, regulating renin-angiotensin system and blocking mesangial cell activation. Recent studies indicate that calcitriol induces anti-fibrotic hepatocyte growth factor expression, which in turn blocks the myofibroblastic activation and matrix production in interstitial fibroblasts. Furthermore, in vivo and in vitro studies demonstrate that active Vitamin D effectively blocks tubular epithelial to mesenchymal transition (EMT), a phenotypic conversion process that plays a central role in the evolution of renal interstitial fibrosis. Together, it is becoming increasingly clear that a high level of active Vitamin D may be obligatory in the maintenance of normal structure and function. Thus, supplementation of active Vitamin D could be a rational strategy for the therapeutics of chronic kidney diseases.

30. Arteriosclerosis and vascular calcification in chronic kidney disease (CKD) patients.

Masho Y, Shigematsu T.

Clin Calcium. 2007 17 (3): 354-9.

Chronic kidney disease (CKD) patients are belonging to high risk patients to atherosclerosis with vascular calcification. These are well recognized advanced arteriosclerosis with vascular medial calcification, with high risk of cardiovascular death. With basic investigated results, the mechanism of vascular clacification is making clear. A lot of various which participate in calcification have been specified. Especially, in long term dialysis patients, the very high grade vascular calcification with advanced atherosclerosis is common with calcium/phosphate/PTH and skeletal problem. This CKD related metabolic bone disorder (CKD-MBD) highly induced and progressed vascular calcification. Participates in vascular calcification. It is extremely important in order to prevent vascular calcification to manage serum phosphorus, serum calcium and parathyroid function within the suitable range. In addition, hyperphosphatemia is becoming the powerful risk factor for patients’ survival. The new powerful phosphate binder is developing. The beneficial effect of the new agent of patients’ survival is now focused.

31. Drug insight: Vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease.

Brown AJ, Slatopolsky E.

Nat Clin Pract Endocrinol Metab. 2007 3 (2): 134-44.

Secondary hyperparathyroidism commonly develops in patients with chronic kideny disease (CKD) in response to high phosphate, low calcium and low 1alpha, 25-dihydroxyvitamin D (3) (calcitriol) levels. High levels of parathyroid hormone (PTH) accelerate bone turnover, with efflux of calcium and phosphate that can lead to vascular calcification. Treatment of secondary hyperparathyroidism with calcitriol and calcium-based phosphate binders can produce hypercalcemia and oversuppression of PTH, which results in adynamic bone that cannot buffer calcium and phosphate levels, and increased risk of vascular calcification. PTH levels must, therefore, be reduced to within a range that supports normal bone turnover and minimizes etopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia (and have reduced calcemic activity) are a safer treatment for secondary hyperparathoidism than calcitriol; these agents enhance the survival of patients with CKD. Several such analogs are now in use, and analogs with even greater selectivity than those currently used are in development. Parathyroid glands express both 25-hydroxylase and 1alpha-hydroxylase, which suggest that these enzymes might suppress parathyroid function by an autocrine mechanism. The risk of hypercalcemia with vitamin D analog therapy is reduced by the introduction of non-calcium-based phosphate binders and cinacalcet; furthermore, recent trials indicate that eraly intervention with vitamin D analogs in stage 3 and 4 CKD can correct PTH levels, and could prevent renal bone disease and prolong patient survival.

37. Management of chronic kidney disease mineral-bone disorder.

Fadem SZ, Moe SM.

Adv Chronic Kidey Dis. 2007 14 (1): 44-53.

Chronic kidney disease mineral-bone disorder (CKD-MBD) is a systemic disorder of abnormal serum levels of mineral-related biochemistries, abnormal bone, and extraskeletal calcifications. Although we have gained understanding on how these components are interelated, our therapeutic tools remain focused on only one aspect of CKD-MBD at a time. However, the management of these disorders is also interrelated; treatment may help one aspect of the disorder but cause or accelerate another. As such, management remains a major challenge to nephrologists and requires balancing risk and benefit of the various available therapies. Our challenge for the decade ahead is to determine which combinations of therapy can be used safely together to prevent morbidity and mortality in CKD. Furthermore, the pathophysiology that sets these events into motion begins well before the onset ESRD. Future therapies and guidelines should, therefore, also emphasize the need for earlier detection and management of CKD, shaped by the results of valid clinical trials.

33. Metabolic bone disease in chronic kidney disease.

Martin KJ, Gonzalez EA.

J Am Soc Nephrol. 2007 18 (3): 875-85.

Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskeletal consequences. Detailed research in that past 4 decades has uncovered many of the mechanisms that are involved in the initiation and maintenance of the disturbances of bone and mineral metabolism and has been translated successfully from ’’bench to bedside” so that efficient therapeutic strategies now are available to control the complications of disturbed mineral metabolism. Recent ephasis is on the need to begin therapy early in the course of CKD. Central to the assessment of disturbances in bone and mineral metabolism is the ability to make an accurate assessment of the bone disease by noninvasive means. This remains somewhat problematic, and although measurements of parathyroid hormone are essential, recently recognized difficulties with these assays make it difficult to provide precise clinical practice for the various stages of CKD at the present time. Further research and progress in this area continue to evaluate the appropriate interventions to integrate therapies for both the skeletal and extraskeletal consequences with a view toward improving patient outcomes.

34. A new era in phosphate binder therapy: What are the options?

Salusky IB.

Kidney Int Suppl. 2006 (105): S10-5.

Dietary restriction of phosphorus and current dialysis prescription are unable to maintain phosphorus levels within the recommended range (2.7-5.5 mg/dl) in patients with advanced chronic kidney disease (CKD). Therefore, phosphate binders that limit the absorption of dietary phosphorus are commonly prescribed for these patient group. The first phosphate binders were introduced more than 30 years ago and included aluminium salts; however, although effective binders, the aluminium accumulation in the central nervous system, and hematopoietic cells. In subsequent years, calcium salts, namely calcium carbonate and calcium acetate, became the most widely used phosphate binders; however, increasing evidence now suggests that prolonged use of these agents increase the total body calcium load, induces adynamic bone, and potentially increases the risk of cardiovascular and soft tissue calcification. Sevelamer is the first phopshate-binding agent that is non-absorbed, calcium-free, and metal-free. To date, this agent has been shown to effectively control serum phosphorus levels in patients with CKD. It may also attenuate coronary and aortic calcification and has a number of other beneficial effects on lipid metabolism and inflammation among others. Lanthanum carbonate is another new agent that is reported to provide similar phosphate control to calcium-based phosphate binders but concerns that the long-term administration of such compound may lead to tissue accumulation may limit its use.

35. The relationship between Sevelamer HCl and vascular calcification.

Uemura K, Kakuta T, Saito A.

Clin Calcium. 2007 17 (3): 392-8.

The Kidney Disease Outcomes Quality Initiative (K/DOQI) issued ’’Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease’’, in which it is recommended that the level of intact parathyroid hormone (i-PTH) should be kept at 150 – 300 pg/mL, the serum phosphorus (P) level at 3.5 - 5.5 mg/dL, and the serum calcium (Ca) level within the normal range of laboratory values (8.4 - 9.5 mg/mL, as close to lower limit as possible). In developing these guidelines, the K/DOQI apparently considered the recently established fact that control of Ca, P and PTH influences not only the development of bone lesions but also patient prognostic factors such as arteriosclerosis, ectopic calcifiaction, and cardiovascular complications, as well as the development of various vitamin D products and analogues and new P adsorbents. The Japanese guidelines also emphasize the control of P and Ca, rather than PTH. Therefore phosphorous control is a primary goal in the care of patients with end-stage renal disease. We inspect the relationship between vascular calcification and Sevelamer HCl, a non-aluminium, non-calcium, non-absorbed phosphate binder.

36. Pleiotropic effects of the non-calcium phosphate binder sevelamer.

Nikolov IG, Joki N, Maizel J et al.

Kidney Int Suppl. 2006 (105): S16-23.

The number of chronic kidney disease (CKD) patients and related adverse outcomes has dramatically increased worldwide in the past decade. Therefore, numerous experimental and clinical studies have recently addressed the underlying mechanisms, in particular the marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of potentially noxious calcium overload. Sevelamer hydrichloride is a phosphate binder that offer an effective control of hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the clearence of some uremic toxins.

37. Risedronate, an effective treatment for glucocorticoid-induced bone loss in CKD patients with or without concomitant active vitamin D (PRIUS-CKD).

Fujii N, Hamano T, Mikami S et al.

Nephrol Dial Transplant. 2006 Nov 23; [Epub ahead of print].

Background Recent post hoc analysis proved the efficacy and tolerability of risedronate in osteoporotic patients with renal impairment, but the combination of active vitamin D in chronic kidney disease (CKD) patients taking glucocorticoids remains unknown. Methods We conducted a prospective study enroling 114 CKD patients (creatinine clearence >/= 30 ml/min/1.73 m(2) receiving glucocorticoid therapy for >/= 6 months. Eighty-eight subjects who had received active vitamin D (aVD) were randomly assigned a group treated with aVD only (group A), or to a group also receiving risedronate 2.5 mg/day (group B). The remaining patients (group C) received risedronate only. Results After 1 year 100 subjects were analysed. Risedronate was effective on the lumbar spine, but not on the femoral neck. The lumbar bone mineral density (BMD) significantly increased by 2.8 and 2.5% in groups B and C, respectively, but decreased by 1.0% in group A. Serum N-terminal telopeptides of type I collagen (S-NTX) and bone alkaline phosphatase (ALP) fell significantly in groups B and C at 3 and 6 months, respectively, while in group A S-NTX remained unchanged and bone ALP significantly increased. There was no significant difference between groups A and C regarding BMD and bone markers. The reduction rate of S-TNX (bone ALP) at 6 months predicted the increase in lumbar BMD at 1 year with a sensitivity of 73% (34%) and a specificity of 46.2% (100%). Conclusions Risedronate is effective in increasing BMD with or without aVD in CKD patients receiving long-term glucocorticoid therapy. Bone markers are of some use in predicting the response to anti-resorptive therapy.

38. Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function.

Shoji T, Wada A, Inoue K et al.

Nephron Clin Pract. 2006 105 (3): c 99-107.

Aims We studied whether adding the spherical adsorptive carbon AST-120 to conventional treatments is effective in ihibiting progression of chronic kidney disease (CKD) at the moderate decrease in renal function. Methods 43 CKD patients with moderately impaired renal function indicated by glomerular filtration rate (GFR) of 20-70 ml/min as measured by non-radiolabeled iothalamate clearence method were enrolled in the study. 26 patients showing a decrease of GFR by 5 ml/min during a 1-year observation period were randomized to receive ongoing treatments only (control group, 12 cases) or with AST-120 co-administered with ongoing treatment (AST-120 group, 14 cases). The intervention period was 1 year and the change in GFR was the primary evaluation variable. Results The mean changes of GFR per months (DeltaGFR) in the intervention period were not significantly different between both groups. However, when comparing the DeltaGFR in the observation and intervention periods for each group, the rate of decline was significantly retarded (p < 0.001) in the AST-120 group while no significant difference was observed in the control group. Conclusion These results suggest that co-administration of AST-120 with conventional treatment retards decline in renal function in CKD patients with moderate decrease in renal function.

39. Effect of dietary protein restriction on the progression of kidney disease: Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study.

Levey AS, Greene T, Sarnak MJ et al.

Am J Kidney Dis. 2006 48 (6): 879-88.

Background The long-term effect of a low-protein diet on the progression of chronic kidney disease is unknown. We evaluated effects of protein restriction on kidney failure and all-cause mortality during extended follow-up the Modification of Diet in Renal Disease Study. Methods Study A was a randomized controlled trial from 1989 to 1993 of 585 patients with predominantly nondiabetic kidney disease and a moderate decrease in glomerular filtration rate (25 to 55 ml/min/1.73 m (2) [0.42 to 0.92 mL/s/1.73 m (2)]) assigned to a low- versus usual-protein diet (0.58 versus 1.2 g/kg/d). We used registries to ascertain the development of kidney failure (initiation of dialysis therapy or transplantation) or a composite of kidney failure and all-cause mortality through December 31, 2000. We used Cox regression models and intention-to-treat principles to compute hazard ratios for the low- versus usual-protein diet, adjusted baseline glomerular filtration rate and other factors previously associated with the rate of decrease in glomerular filtration rate. We estimated hazard ratios for the entire follow-up period and then, in time-dependent analyses, separately for 2 consecutive 6-year periods of follow-up. Results Kidney failure and the composite outcome occured in 327 (56%) and 380 patients (65%), respectively. After adjusment for baseline factors, hazard ratios were 0.89 (95% confidence interval [CI], 0.71 to 1.12) and 0.88 (95% CI, 0.71 to 1.08), respectively. Adjusted hazard ratios for both outcomes were lower during the first 6 years (0.68; 95% CI, 0.51 to 0.93 and 0.66; 95% CI, 0.50 to 0.87, respectively) than afterward (1.27; 95% CI, 0.90 to 1.80 and 1.29; 95% CI, 0.94 to 1.78; interaction P = 0.008 and 0.002, respectively). Limitations include lack of data for dietary intake and clinical conditions after conclusion of the trial. Conclusion The efficacy of a 2- to 3-year intervention of dietary protein restriction on progression of nondiabetic kidney disease remains inconclusive. Future studies should be include a longer duration of intervention and follow-up.

40. Pharmacological therapy for Wegener’s granulomatosis.

White ES, Lynch JP.

Drugs. 2006 66 (9): 1209-28.

Abstract Wegener’s granulomatosis (WG) is the most common pulmonary granulomatous vasculitis and was a uniformly fatal disease prior to the identification of efficacious pharmacological regimens. The pathogenesis of WG remains elusive but proteinase 3-specific anti-neutrophil cytoplasmic antibodies may be involved. Histologically, WG is defined by the trial of small vessel necrotising vasculits, ’geographic’ necrosis and granulomatous inflammation. Organ involvement characteristically includes the upper and lower respiratory tracts and kidney, but virtually any organ can be involved. The severity of the disease varies, ranging from asymptomatic disease to fulminant, fatal vasculitis. Simlarly, the degree of organ involvement is highly variable: WG may be limited to a single organ (typically the lungs or upper respiratory tract), or may be systemic. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids, with induces complete remission in the majority of patients, is considered standard therapy. Since approximatelly 50% of patients experience a relapse following discontionuation of therapy, alternative regimens designed to maintain remissions after using cyclophosphamide and corticosteroids are usually necessary. This ’induction maintenance’ approach to treatment has emerged as a central premise in planning therapy for patients with WG. A number of trials have evaluated the efficacy of less toxic immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil) and antibacterials (e.g. cotrimoxazole [trimethoprime/sulfamethoxazole]) for treating patients with WG, resulting in the identification of effective alternative regimens to induce or maintain remission in certain sub-populations of patients. Given the efficacy of methotrexate (for early systemic WG) and cotrimoxazole (in WG limited solely to the upper airways) to induce remissions, and the relatively decreased associated morbidity compared with cyclophosphamide, these alternative regimens are preferred in appropriate patients. Similarly, therapeutic options to maintain disease remission that are less toxic cyclophosphamide should be offered following induction of remission unless a specific contraindication exist. By following this premise, the development of cyclophosphamide-induced morbidities (e.g. haemorrhagic cystitis, uroepithelial cancers and prolonged myelosuppression) may be minimised. Recent investigation has focussed on other immunomodulatory agents (tumour necrosis factor-alfa inhibitors [infliximab and etanercept] and anti-CD20 antibodies [rituximab]) for treating with WG. However, the current data are conflicting and difficult to interpret. As a result, these newer agents cannot be recommended for routine use until vigorous clinical study confirms their efficacy.

41. Fifteen-year remission of a steroid-resistant nephrotic syndrome sustained by cyclosporine A.

Drube J, Geerlings C, Taylor R et al.

Pediatr Nephrol. 2007 Jan 18; [Epub ahead of print].

Many children with a late steroid-resistant nephrotic syndrome (SRNS) and focal glomerulosclerosis have a poor prognosis and enter end-stage renal failure (ESRF) within five years. Reports are scarce on the long-term follow-up of patients entering remission while receiving immunosuppression therapy after steroids have failed. A two-year-old boy with focal and segmental glomerulosclerosis having both late steroid and cyclophosphamide resistance entered complete remission of the SRNS two years after starting induction therapy with cyclosporine A (CSA). During the 15-year follow-up, the patient experienced five relapses during CSA maintenance therapy. All relapses were successfully treated within 10 days by intravenous methylprednisolone pulses in addition to CSA. The relapses were accompained by a drop in the glomerular filtration rate (GFR). At the age of 18 years, the patients had grade II chronic kidney disease (GFR = 61 ml/min/1.73 m (2)). At the age of 14 years, mycophenolate mofetil (MMF) was added to the maintenance therapy and the CSA dosage was reduced. Two renal biopsies at the ages of 10 and 18 years failed to detect CSA nephrotoxicity. We conclude that children with SRNS may have long-term benefit from a combination therapy using intravenous methylprednisolone pulses and CSA.

42. Efficacy and safety of ’rescue therapy’ with mycophenolate mofetil in resistant primary glomerulonephritis - - A multicenter study.

Segarra A, Amoedo ML, Garcia JM et al.

Nephrol Dial Transplant. 2007 Feb 20; [Epub ahead of print].

Background Sudies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessment of efficacy and optimal dose. Method This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearence. Results Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2.0 g /day). Mean (SD) treatment time to remission was 141.5 (+/- 61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased ( P < 0.01), whereas proteinuria (P < 0.01), serum LDL-cholesterol (P < 0.01) and mean blood pressure (P < 0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. Conclusions MMF monotherapy causes moderate decrease in proteinuria in > 50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.

43. High-dose therapy in patients with plasma cell dyscrasias and renal dysfunction.

Pineda-Roman M, Tricot G.

Contrib Nephrol. 2007 (153): 182-94.

Multiple myeloma causes a disproportionate amount of the malignancy-related renal insufficiency. Acute renal insufficiency in myeloma patients can occur due to dehydration, hypercalcemia, side effects of medications (NSAIDs) or tumor lysis syndrome in additon to cast nephropathy, amyloidosis and light chain deposition disease. Patients on hemodialysis have traditionally been exclude from antineoplastic therapy due to fear of side effects and lack of studies addressing benefit. Melphalan is the most effective chemotherapeutic agent in myeloma and its PK (pharmacokinetics) are not adversely affected by impaired renal function. Because of more pronounced toxicity of Melphalan 200 mg/m2 conditioning regimen, Melphalan 140 mg/m2 has become the standard of care. 24% of patients become dialysis-independent at a median of 4 months after autotransplantation. Favorable factors for becoming dialysis independent were duration of dialysis < or = 6 months and pretransplant creatinine clearence > 10 ml/min. While no good are available on the use of thalidomide in the presence of renal failure, it is our experience that severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with creatinine > or = 3 mg/dl. It has become apparent that biphosphanates-zoledronic acid more than pamidronate-cause renal dysfunction. If patients remain dialysis-dependent after autotransplantation, we recommended to delay considering a renal transplant until at least 3 years after first transplant.

44. Current and emerging views and treatments of systemic immunoglobulin light-chain (AL) amyloidosis.

Comenzo RL.

Contrib Nephrol. 2007 (153): 195-210.

Amyloidosis is a disease in which abnormal proteins form toxic intermediates and fibrillar tissue-deposits that compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis. One-third to one-half of patients with systemic AL amyloidosis has renal involvement in the form of glomerular, vascular and interstitial deposits of amyloid causing progressive proteinuria. Less than 5% of AL patients present with renal failure requring dialysis; patients with renal involvement usually present with fatigue, peripheral edema, proteinuria and hypoalbuminemia. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light-chains, measured with the serum light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precusor light chain is eliminated. The most effective treatment for systemic AL is risk-adapted melphalan with peripheral blood stem cell transplant; oral melphalan and dexamethasone is the most effective therapy for patients who are not stem cell transplant candidates although it carries a risk of myelodysplasia and leukemia. Novel therapies currently under study include thalidomide, bortezomib and lenalidomide. With therapy, a majority of patients can achieve long-term durable remissions with stabilization or recovery of organ function. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.

45. Successful treatment of hepatitis B-associated leukocytoclastic vasculitis with lamivudine treatment in a child patients.

Surmali Onay O, Baskin E, Ozcay F et al.

Rheumatol Int. 2007 Jan 25; [Epub ahead of print].

Chronic hepatitis B infection (HBI) has many extrahepatic manifestations such as vasculitis, glomerulonephritis, arthritis, dermatitis, pulmonary disease, and skin manifestations. The mechanism of these manifestations is thought to be immune mediated. Immune-suppressive treatment may enhance viral replication and worsen hepatic disease. Lamivudine is a nucleoside analogue used in chronic HBI treatment that works by suppressing replication of the hepatitis B virus (HBV). Recently, several reports have suggested that lamivudine treats vasculitis associated with HBV infection in adults. However, there are no data in the literature for children. Herein, we report a child with leukocytoclastic vasculitis due to chronic HBI who was successfullly treated with lamivudine.

46. Meta-analysis of antiplatelet therapy for IgA nephropathy.

Taji Y, Kuwahara T, Shikata S et al.

Clin Exp Nephrol. 2006 10 (4): 268-73.

Background Antiplatelet agents have been widely used in the management of immunoglobulin A (IgA) nephropathy in the Japanese population. To systematically evaluate the effects of antiplatelet agents for IgA nephropathy, we conducted a meta-analysis of the published studies. Methods Data sources consisted of MEDLINE, EMBASE, the Cochrane Library, Ityu-shi (Japanese medical database), and bibliographies from the studies. The quality of the studies was evaluated from the intention to treat analysis and allocation concealment, as well as by the Jadad method. Meta-analysis were performed on the outcomes of proteinuria and renal function. Results Seven articles met the predetermined inclusion criteria. The use of antiplatelet agents showed statistically significant effects of proteinuria and renal function. The pooled risk ratio for proteinuria was 0.61 (95% confidence intervals (CI) 0.39-0.94) and for renal function it was 0.74 (95% CI 0.63-0.87). Conclusions Antiplatelet agents resulted in reduced proteinuria and protected renal function in patients with IgA nephropathy. However, studies of high-quality design were rare, and most studies assessed surrogate outcomes. More properly designed studies are needed to reach a definitive assessment of this matter.

47. Agalsidase-beta therapy for advanced Fabry disease: A randomized trial.

Banikazemi M, Bultas J, Waldek S et al.; Fabry Disease Clinical Trial Study Group.

Ann Intern Med. 2007 146 (2): 77-86.

Background Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. Objective To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. Design Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. Setting 41 referral centers in 9 countries. Patients 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. Intervention Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). Measurements The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. Results Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.93). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group. Limitations The study sample was small. Only one third of patients experienced clinical events, and some patients withdrew before experiencing any event. Conclusions Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

48. Gene therapy targeting kidney disease: Routes and vehicles.

Isaka I.

Clin Exp Nephrol. 2006 10 (4): 229-35.

Renal gene therapy may offer new strategies to treat disease of native and transplanted kidneys. Several experimental techniques have been developed and employed using nonviral, viral, and cellular vectors. The most efficient viral vector for in vivo transfection to be adenovirus. In addition, enhanced naked plasmid techniques, such as the hamegglutinating virus in Japan (HVJ)-liposome method, electroporation, the hydrodynamic method, and ultrasound with microbubbles, are promising. Trapping genetically modified macrophages in the inflammed kidneys is an elegant method dor site-specific gene delivery. The choice of delivery vehicle as well as the administration route determines the site of transduction. In conclusion, for both in vivo and ex vivo renal transfection, enhanced naked plasmids, adenoviruses, and modified cell vectors offer the best prospects for effective clinical application. Moreover, the development of safer and nonimmunogenic vectors may realize clinical renal gene therapy in the near future.

49. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL). A randomized comparison of 3 preventive strategies.

Briguori C, Airoldi F, D’Andrea D et al.

Circulation. 2007 Feb 19; [Epub ahead of print].

Background Volume supplementation by saline infusion combined with N-acetylcysteine (NAC) represents an effective strategy to prevent contrast agent-induced nephrotoxicity (CIN). Preliminary data support the concept that sodium bicarbonate and ascorbic acid also may be effective is preventing CIN. Methods and Results Three hundred twenty-six consecutive patients with chronic kidney disease, referred to our institutions for coronary and/or peripheral procedures, were randomly assigned to prophylactic administration of 0.9% saline infusion plus NAC (n = 111), sodium bicarbonate infusion plus NAC (n = 108), and 0.9% saline plus ascorbic acid plus NAC (n = 107). All enrolled patients had serum creatinine >/= 2.0 mg/dL and /or estimated filtration rate < 40 mL./min/1.73 m(-2). Contrast nephropathy risk score was calculated in each patient. In all cases, iodixanol (an iso-osmolar, nonionic contrast agent) was administered. The primary end point was an increase of >/= 25% in the creatinine concentration 48 hours after the procedure (CIN). The amount of contrast media administered (179 +/- 102, 169 +/- 92, and 169 +/- 94 mL, respectively; P = 0.69) and risk scores (9.1 +/- 3.4, 9.5 +/- 3.6, and 9.3 +/- 3.6; P = 0.21) were similar in the 3 groups. CIN occured in 11 of 11 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P = 0.0119 by Fisher exact test versus saline plus NAC group), and 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P = 1.00 versus saline plus NAC group). Conclusions The strategy of volume supplementation by sodium bicarbonate plus NAC seems to be superior to the combination of normal saline with NAC alone or with the addition of ascorbic acid in preventing CIN in patients at medium to high risk.

50. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: A meta-analysis of randomized clinical trials.

Landoni G, Biondi-Zoccai GG, Tumlin JA et al.

Am J Kidney Dis. 2007 49 (1): 56-68.

Background Acute kidney injury is common in critically ill patients. Fenoldopam mesylate is a potent dopamine A-1 receptor agonist that increase blood flow to the renal cortex and outer medulla. Because there is uncertainty about the benefits of fenoldopam in such a setting, we performed a systemic review of randomized-controlled trials of intensive care unit patients or those undergoing major surgery. Methods BioMedCentral, CENTRAL, PubMed, and conference proceedings were searched (updated October 2005). Investigators and external experts were contacted. Two unblinded reviewers selected randomized controlled trials that used fenoldopam in the prevention or treatment of acute kidney injury in postoperative or intensive care patients. Studies involving the prevention of contrast nephropathy or containing duplicate data were excluded from analysis. Two reviewers independently abstracted patients data, treatment characteristics, and outcomes. Results A total of 1 290 patients from 16 randomized studies were included in the analysis. Pooled estimates showed that fenoldopam consistently and significantly reduced the risk for acute kidney disease injury (odds ratio [OR], 0.43, 95% confidence interval [CI], 0.32 to 0.59; P < 0.001), need for renal replacement therapy (OR, 0.54; 95% CI, 0.34 to 0.84; P = 0.007), and in-hospital death (OR, 0.64; 95% CI, 0.45- to 0.91; P = 0.01). These benefits were associated with shorter intensive care unit stay (weighted mean difference, -0.61 days; 95% CI, -0.99 to –0.23; P = 0.002). Sensitivity analyses, test for small-study bias, and heterogeneity assessment further confirmed the main analysis. Conclusion This analysis suggest the fenoldopam reduces the need for renal replacement and mortality in patients with acute kidney injury. A large, multicenter, appropriately powered trial will need to be performed to confirm these results.

51. N-acetylcysysteine and sodium bicarbonate versus N-acetylcysteine and standard hydration for the prevention of radiocontrast-induced nephropathy following coronary angiography.

Schmidt P, Pang D, Nykamp D et al.

Ann Pharmacother. 2006 Dec 26; [Epub ahead of print].

Background Radiocontrast-induced nephropathy (RCIN) is thought to be caused by renal ischemia and direct toxic effects on renal tubular cells brought on by contrast media. The combination of N-acetylcysteine (NAC) and hydration fluids (NaCl 0.9% or 0.45%) has been shown to reduce deterious effects and is commonly given prior to coronary angiography. The use of bicarbonate as the hydration anion has been shown to confer additional RCIN protection compared with that of saline. However, limited data are available regarding whether sodium bicarbonate hydration, proven to be beneficial alone, can further improve outcomes when given with NAC. Objective To compare the incidence of RCIN in patients undergoing coronary angiography after pretreatment with NAC plus sodium bicarbonate hydration or NAC plus standard hydration (NaCl 0.9% or 0.45%). Methods A retrospective, single-center study evaluated 96 patients who underwent coronary angiography from January 2002 to December 2005. Data were collected through electronic chart reviews. Results Forty-seven patients received NAC and sodium bicarbonate for hydration and 49 received NAC and standard hydration. Baseline characteristics between the 2 groups were similar. All patients received at least one 600 mg oral dose NAC before angiography was performed. RCIN was defined impairment of renal function occuring within 72 hours of administering contrast media, indicated by an absolute increase in the serum creatinine level of 0.5 mg/dL or more. A total of 12.2% of the patients receiving NAC and standard hydration developed RCIN, versus 14.9% of the patients in the NAC and sodium bicarbonate group (p = 0.713). Conclusions The additon of sodium bicarbonate to NAC does not to confer additional protection against the development of RCIN. Prospective, randomized, placebo-controlled trial are warranted to definitively determine how this combination compares with NAC and standard hydration in preventing RCIN.

V. TRANSPLANTATION

1. Lymphatic neoangiogenesis in human renal allografts: Results from sequential protocol biopsies.

Stuht S, Gwinner W, Franz I et al.

Am J Transplant. 2007 7 (2): 377-84.

Neoangiogenesis of lymphatic vessels may be important for the cellular immune response in renal transplants. To determine the prevalence and chronology of lymph vessel proliferation and its relation to cellular infiltrates and allograft function, we analyzed sequential protocol biopsies (n = 162), taken at 6, 12 and 26 weeks after transplantation. Biopsies were stained with an antibody against podoplanin and lymphatic vessel density was quantified per square millimeter. The prevalence of lymph vessel-positive biopsies and the lymph vessel density were similar at 6, 12 and 26 weeks after transplantation. Biopsies with acute cellular rejection showed no significantly different lymph vessel density compared to those below the treshold for acute rejection or chronic allograft nephropathy. While lymphatic neoangiogenesis was equally prevalent in biopsies with and without infiltrates, the lymph vessel densitiy was significantly higher in areas with cellular infiltrates than in areas without. Graft function at 1 year after transplantation was better in cases with lymph vessels in their infiltrates compared to cases with lymph vessel-free infiltrates. In conclusion, lymphangiogenesis not only shows a clear association with cellular infiltrates but might also have an impact on the pathogenecity of these cellular infiltrates.

2. Heightened expression of the cytotoxicity receptor NKG2D correlates with acute and chronic nephropathy after kidney transplantation.

Seiler M, Brabcova I, Viklicky O et al.

Am J Transplant. 2007 7 (2): 423-33.

The activating cytotoxicity receptor NKG2D binds to stress-regulated molecules encoded by the major histocompatbility complex class I chain-related (MIC) and UL-16-binding protein (ULBP) / retinoic acid early transcript (RAET) gene family. To assess whether acute allograft rejection leads to an induction of these inducible ligands and their receptor NKG2D, we examined the mRNA profiles in kidney transplant biopsies. Expression levels were correlated with the incidence of acute rejection (aRx) episodes and chronic allograft nephropathy (CAN) proven by histology. Whereas MICA, ULBP1/3 and RAET-E did not display heightened gene expression, elevated levels of NKG2D mRNA could be associated with aRx (p < 0.001). Immunohistology of kidney biopsies diagnosed with aRx related NKG2D+ cells in tubulointerstitial areas positive for CD8+ cells. Most importantly, elevated levels of NKG2D mRNA were associated with restricted long-term graft function assessed by the glomerular filtration rate at 6, 12 and 18 months posttransplantation. Induced NKG2D mRNA expression was still observable in biopsies diagnosed with CAN (p < 0.001), demonstrating a higher sensitivity and specificity compared to CD3, granzyme B and granulysin mRNA measurement. Significant elevated levels of NKG2D mRNA could be further detected in urine sediment prior to aRx, suggesting this receptor as a new candidate marker for the diagnosis of acute and chronic allograft rejection.

3. Role of dendritic cell synthesis of complement in the allospecific T cell response.

Zhou W, Peng Q, Li K et al.

Mol Immunol. 2007 44 (1-3): 57-63.

Although extrahepatic synthesis of complement and particularly C3 has been widely studied in most cells and tissues, new information is emerging on dendritic cells (DCs). This research has shown that mouse bone marrow (BM) derived DCs are able to synthesise C3 and this synthesis has a substantial impact on DC activation, affecting the diverse range of DC functions relevant to the allospecific T cell response. Thus, local production of C3 appears to regulate the capacity of DCs to trigger the primary T cell response against donor alloantigen. Understanding of the key mechanisms by which complement activation modulates DC maturation could lead to the development of therapeutic strategies to down regulate DC activation thus reduce allograft rejection.

4. Expression of the chemokine receptor CCR1 in human renal allografts.

Mayer V, Hudkins KL, Heller F et al.

Nephrol Dial Transplant. 2007 Feb 13; [Epub ahead of print].

Background Chemokines are involved in the recruitment of leukocytes to vascularized allografts. CCR1 is a receptor for various proinflammatory chemokines and CCR1 blockade reduces renal allograft injury in rabbits. The purpose of the study was characterize CCR1-positive cells in human renal allografts. Methods Formalin-fixed, paraffin-embedded allograft nephrectomies (n = 9) and non-involved parts of tumour nephrectomies (n = 10) were studied. Immunohistochemistry for CCR1m CD3 and CD68 was performed on consecutive sections. Double immunofluorescence for CCR1 and CD3, CD20, CD68, DC-SIGN and S100 was used on selected cases. Expression of CCR1 mRNA and the ligands CCL3 and CCL5 was studied in renal allograft biopsies with acute rejection (n = 10), with chronic allograft nephropathy (n = 8) and controls (n = 8). Results CCR1 protein was expressed by circulating cells in glomerular and peritubular capillaries, colocalizing with CD68. In renal allografts CCR1-positive cells were present within glomerular tufts, but only scattered CCR1-positive cells were found in tubulointerstitial infiltrates. CCR1 did not colocalize with the majority of CD68-positive cells in the interstitium. The small number of CCR1-positive interstitial cells were identified as CD20- or DC-SIGN-positive by double immunofluorescence. CCR1 mRNA was significantly increased in renal biopsies with acute allograft rejection (P < 0.001), and with chronic allograft nephropathy (P < 0.05), it correlated with expression of CCL3 and CCL5, and with serum-creatinine. Conclusions CCR1 mRNA expression was associated with renal function in allografts. CCR1 protein expression was restricted to monocytes, CD20-positive B cells and DC-SIGN-positive dendritic cells. Thus most interstitial macrophages were CCR1 negative, which may relate to down-regulation after migration into the interstitium in human renal allografts.

5. Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome.

Worthington JE, McEwen A, McWilliam LJ et al.

Transplantation. 2007 83 (4): 398-403.

Background We carried out a retrospective study of C4d staining in paraffin sections from renal transplant biopsies to determine the association between C4d staining, donor-specific antibodies (DSA), histological features, and graft outcome. Methods We studied 92 patients who had been biopsied for graft dysfunction. Biopsies classified using Banff 97 criteria and features suggestive of antibody-mediated rejection were noted. Paraffin sections were stained with a polyclonal antibody using an immunoperoxidase technique. The presence of DSA in concurrent sera was determined by enzyme-linked immunosorbent assay and clinical data were reviewed. Results Of the 92 cases, 15% showed diffuse and 24% showed focal C4d positivity. The grafts failed in 26% of the diffuse (P < 0.025), 23% of the focal, and 7% of the negative group at between one month and 15 years posttransplantation. Only patients in the group with diffuse C4d positivity had concurrent DSA (five cases, P < 0.001). Of the five DSA-positive patients, three had type II acute rejection and two of these transplants subsequently failed. The remaining two had chronic allograft nephropathy with features of alloimmune injury. Only two of the nine DSA-negative/C4d-positive transplants had failed at the time of writing, in one case due to recurrent disease. Conclusion We demonstrated a significant association between diffuse C4d staining, production of DSA, and graft failure. Although the concurrent detection of DSA and C4d positivity is uncommon in our patients, these results indicate that outcome in this group is poor and they may benefit from therapies directed at the humoral response.

6. Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation.

Brandacher G, Cakar F, Winkler C et al.

Kidney Int. 2007 71 (1): 60-7.

The immunomodulatory enzyme indoleamine 2, 3-dioxygenase (IDO) is activated by interferon-gamma (IFN-gamma) and via tryptophan depletion, suppress adaptive T cell-mediated immunity in inflammation, host immune defense, and maternal tolerance. Its role in solid organ transplantation is still unclear. Therefore, we investigated the usefulness of IDO-mediated tryptophan catabolism in the evaluation of kidney allograft rejection. Blood, urine, and tissue samples were collected from 34 renal transplant patients without rejection and from nine patients with biopsy-confirmed episodes of acute rejection (n = 12). Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography. Kynurenine to tryptophan ratio (kyn/trp) was calculated to estimate IDO activity. Immunostaining for IDO was performed on renal biopsies. Neopterin was assessed using radioiminoassay. Kyn/trp and neopterin were detectable at low levels in serum of healthy volunteers and were increased in non-rejecting allograft recipients. Serum levels of kyn/trp were higher in recipients with rejection compared to non-rejectors as early as by day 1 post-surgery. Rejection episodes occuring within 13 +/- 5.9 days after transplantation were accompained by elevated kyn/trp in serum (114 +/- 44.5 mumol/mmol, P = 0.001) and urine (126 +/- 65.9 mumol/mmol, P = 0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-gamma-induced increase in IDO activity. Immunstaining showed upregulation of IDO in rejection biopsies, localized in tubular-epithelial cells. Non-rejected grafts displayed no IDO expression. Acute rejection is associated with simultaneously increased serum and urinary kyn/trp in patients after kidney transplantation. Thus, IDO activity might offer a novel non-invasive means of immunomonitoring of renal allografts.

7. Pretransplant soluble CD30 level has limited effect on acute rejection, but affects graft function in living donor kidney transplantation.

Kim MS, Kim HJ, Kim SI et al.

Transplantation. 2006 82 (12): 1602-5.

Background Serum soluble CD30 (sCD30) levels might be a useful marker of immunologic status in pre transplant (Tx) recipients. We retrospectively correlated preTx sCD30 levels (high versus low) on postTx graft survival, incidence of acute rejection, and graft function using stored preTx serum. Methods Of 254 recipients who undrewent kidney Tx, 120 recipients were enrolled under the uniform criteria (living donor, age > 25 years, viral hepatitis free, diabetes free). Results The preTx sCD30 was not significantly associated with differences in graft survival rate duringg 47.5 +/- 11.4 months of follow-up (P = 0.5901). High sCD30 (> or = 115 U/ml) was associated with a higher incidence of clinically or pathologically defined acute rejection than low sCD30, but the difference was not statistically significant (33.9% vs. 22.4%, P = 0.164). The response rate to antirejection therapy in patients with high sCD30 was inferior to those with low sCD30, but also was not statistically significant (33.3°vs. 7.7%, P = 0.087). However, mean serum creatinine levels in high sCD30 patients at one month, one year, and three years postTx were significantly different from those with low sCD30 (P < 0.05). In multiple regression analysis, acute rejection episodes, donor age, kidney weight/recipient body weight ratio, and preTx sCD30 levels were independent variables affecting the serum creatinine level three years postTx. Conclusion PreTx sCD30 level has a limited effect on the incidence of acute rejection and response to antirejection treatment, but inversely and independently affects serum creatinine level after living donor kidney transplantation.

8. Inflammation and endothelial activation are linked to renal function in long-term kidney transplantation.

Cottone S, Palermo A, Vaccaro Fet al.

Transpl Int. 2007 20 (1): 82-7.

The aim of this study was to investigate the relationships between inflammation and adhesion molecules in long-term kidney transplantation. We measured serum concentrations of tumor necrosis factor-alpha (TNF-alpha) and intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) in 35 renal transplant recipients (mean age of transplantation 5 +/- 3 years) and in 35 chronic renal insufficiency (CRI) patients; twenty-six healthy subjects were enrolled as controls. Transplanted showed higher values than controls of TNF-alpha (O < 0.0001), ICAM-1 (P < 0.0001), and VCAM-1 (P < 0.0001). CRI group as well exhibited higher concentrations than controls of TNF-alpha (P < 0.0001), ICAM-1 (P < 0.0001), and VCAM-1 (P < 0.0001). Transplanted and CRI patients had similar blood pressure and renal function levels, and TNF-alpha, ICAM-1, and VCAM-1 were not significantly different in the two groups. In transplanted group ICAM-1, VCAM-1, and TNF-alpha correlated negatively and independently with glomerular filtration rate (GFR) -P < 0.00001 for all. TNF-alpha as well correlated with ICAM-1 and VCAM-1 (P < 0.001, respectively). In CRI group, TNF-alpha correlated with serum creatinine, ICAM-1, and VCAM-1 (P = 0.01 for all). In conclusion, in long-term renal transplantation, the level of kidney function and both inflammation and endothelial activation are closely related. In fact, the multiple regression analysis demonstrated that the level of kidney insufficiency and the levels of of the studied molecules were independently associated.

9. Endothelial dysfunction and fetuin A levels before and after kidney transplantation.

Caglar K, Yilmaz MI, Saglam M et al.

Transplantation. 2007 83 (4): 392-7.

Background Endothelial dysfunction (ED) has a major role in the cardiovascular outcome of patients with chronic kidney disease (CKD). The aim of this study was to investigate the relation between fetuin A levels and ED in kidney transplant recipients. Methods Forty-two living donor kidney transplant recipients, 21 (11 male) on cyclosporine A and 21 (10 male) on tacrolimus-based regimens, were studied. Forty-two (21 male) healthy subjects were enrolled as controls. Fetuin A, highly sensitive C-reactive protein (hsCRP) levels, brachial artery endothelium-dependent vasodilation (FMD), nitroglycerine mediated dilation (NMD), and carotid intima-media thickness (CIMT) were measured before transplantation and on the 30th and 90th days postransplant. Results Pretransplantation serum fetuin A concentrations and FMD values of patients were significantly lower than those of the controls (P < 0.001 for both). These were significantly increased in the 30th and 90th days posttransplantation. There was a significant positive correlation between fetuin A and FMD levels both before and after kidney transplantation (r = 0.534, r = 0.576; respectively, P < 0.001 for both). Carotid intima-media thickness and hsCRP levels decreased after transplantation (P < 0.001 for all). According to the regression analysis, fetuin A, intact parathyroid hormone, and hsCRP levels were the independent determinants of FMD. Conclusion The results of the present study suggest taht low serum fetuin A levels in CKD may contribute to impaired endothelial function in CKD. Future studies should clarify the role of fetuin A levels in cardiovascular outcomes of CKD.

10. Renal tubular acidosis after kidney transplantation--incidence, risk factors and clinical implications.

Keven K, Ozturk R, Sengul S et al.

Nephrol Dial Transplant. 2007 Jan 8; [Epub ahead of print].

Background Renal tubular acidosis (RTA) is a non-anion metabolic acidosis and is generally mild and asymptomatic in kidney recipients. Although calcineurin inhibitors, suboptimal allograft function, donor age and acute rejection have been associated with RTA, no detailed study has been conducted to investigate the prevalence and clinical implications of RTA in long-term kidney recipients. Methods In this cross-sectional study, we enrolled 109 patients (74 males, 35 females) for the study [patients with glomerular filtration rate (GFR) < 30 ml/min/1.73 m(2), unstable allograft function, diarrhoea, and respiratory disease were excluded]. Thirty-six patients (33%) were found to have RTA on the basis of plasma bicarbonate, arterial pH, urine and serum anion gap measurements. Results Deceased donor transplantation [P = 0.034, 95% confidence interval (CI): 1.10-13.27], female gender (P = 0.017, 95% CI: 1.23-8.50), and lower GFR (55.8 +/- 19.4 in RTA and 66.1 +/- 15.9 ml/min/1.73 m (2) in non-RTA, P = 0.002, 95% CI: 1.10-13.27) were independent risk factors for RTA. Also, C-reactive protein was found to be higher in the RTA group (2.7 +/- 1.5 vs 2.0 +/- 2.5 mg/dl, P = 0.03), while no difference was noticed in body mass index or serum albumin. Analysis of the prevalence of osteoporosis and osteopenia in patients with RTA and without RTA, respectively, revealed no difference in frequency of osteoporosis (33% vs 31%) or osteopenia (33% vs 47%). Conclusion Although long-term kidney recipients have a relatively high prevalence of RTA, it is usually mild and subclinical. Further studies are need to clarify long-term effects of RTA in kidney recipients.

11. Comparison of early renal function parameters for the prediction of 5-year graft survival after kidney transplantation.

Schnuelle P, Gottmann U, Koppel H et al.

Nephrol Dial Transplant. 2007 22 (1): 235-45.

Background Early graft function (EGF) has an enduring effect on the subsequent course after kidney transplantation. This study compares quantitative parameters of EGF for the prediction of graft survival. Methods We involved 300 consecutive transplant recipients from deceased donors from 1989 to 2005. Urine output during 24 h post-transplant (UO), and serum creatinine after 1 week (Cr7) were taken for explanatory variables. We generated Kaplan-Meier (K-M) estimates of graft survival, by quintiles of the explanatory variable. Cox regression was applied to control for various recipient factors. Results K-M survival estimates indicate a threshold effect and UO and Cr7, which can dissect the risk of graft failure. The threshold referring to the 2nd quintile correspond to a UO > 630 ml and a Cr7 < 2.5 mg/dl and were associated with a proportional hazard ratio of 0.52 (95% CI 0.33-0.84) and 0.34 (95% CI 0.18-0.65), respectively. Combining both of the parameters predicted a 5-year graft survival probability > 90%, according to a hazard ratio of 0.21 (95% CI 0.09-0.46). Requirement of dialysis post-transplant lost its discriminatory power and was not a significant explanatory variable in the multivariate analysis. Conclusion Routine parameters for monitoring of EGF display a threshold effect allowing accurate prediction of 5-year graft survival at the earliest point in time. The quantitative threshold levels for an optimum discriminatory power require validation in a larger, preferably multicentre database.

12. Urine cytology screening for polyoma virus infection following renal transplantation: The Oxford experience.

Thamboo TP, Jeffery KJ, Friend PJ et al.

J Clin Pathol. 2006 Dec 8; [Epub ahead of print].

Aims Polyoma virus nephropathy (PVN) has a high incidence of irreversible injury and graft failure. Here we review the first year of a monthly urine cytology screening service, introduced to identify renal transplant patients at risk of PVN, at an early, potentially treatable, stage. Methods and Results Monthly urine samples (n = 392) were received from 97/108 transplant recipients in 2005; of 56 patients with follow-up > 6 months, 20% and 9% had significant (> 10 decoy cells/cytospin) and non-significant positive cytology respectively. The first positive urine samples occured most commonly in the second and third month post-transplantation and patients with significantly positive samples had higher 3 and 6-month serum creatinine levels than patients with negative urine cytology (p < 0.01). Four patients with positive urine cytology had a subsequent positive plasma BK virus PCR; 3/97 patients had biopsy-proven PVN, all in the third month, 1-6 weeks after first positive urine samples. Conclusions Significant PV viruria is common following renal transplantation with onset usually within the first 3 months. Viruria is associated with worse graft function at 3 and 6 months. The time between urine positivity and clinical PVN is short. More frequent early urine screening would be required to achieve clinical benefit.

13. The older living kidney donor: Part of the solution to the organ shortage.

Gill JS, Gill J, Rose C et al.

Transplantation. 2006 82 (12): 1662-6.

Background Strategies to increase kidney transplantation are urgently needed. Methods We studied all (n = 73 073) first kidney-only transplant recipients in the United States between 1995 and 2003 to determine the incidence and outcomes of living donor transplantation as a function of donor age. Because 90% of living donors were < 55 years, we defined older living donors as > or == 55 years. Factors associated with transplantation from older living donors and the association of living donor age with allograft function and survival were determined. Results Recipients of older age, female gender, white race, and preemptive transplants had a higher odds of older living donor transplantation. Older living donor transplantation was more likely from spousal donors rather than blood relatives, and more likely when a husband was the donor. The glomerular filtration rate (GFR) one year transplantation decreased with increasing donor age (P < 0.001). Graft survival from living donors > or = 55 years was 85% and 76% at three and five years (compared to 89% and 82% with living donors < 55 years, and 82% and 73% with deceased donors < 55 years). In a multivariate model, the risk or graft loss with living donors 55-64 years was similar to that with deceased donors < 55 years, while recipients from living donors 65-69 years (HR = 1.3, 95% CI: 1.1-1.7) and > 70 years (HR = 1.7, 95% CI: 1.1-2.6) had a higher relative risk of graft loss. Conclusions Outcomes are excellent with living donors < 65 years. Expanded use of older living donors may help meet the demand for transplantation.

14. Successful transplantation of kidneys from deceased donors with acute renal failure: Three-year results.

Anil Kumar MS, Khan SM, Jaglan S et al.

Transplantation. 2006 82 (12): 1640-5.

Background Kidneys from deceased donors with acute renal failure (ARF) are generally not accepted for transplantation because of the expected poor outcome. This prospective study examined the utilization of kidneys from donors with ARF for transplantation and the outcomes. Methods Fifty-five kidneys from donors with ARF were transplanted. The outcomes was compared with concurrent and matched 55 recipients of standard criteria donor (SCD) kidneys and 55 expanded criteria donor (ECD) kidneys. ARF kidneys were accepted from donors aged < 50 years, a negative history for kidney disease, and a negative pretransplant biopsy for chronic structural changes. The immunosuppreession was similar in all three groups. The outcome measurements included three-year patient and graft survival, biopsy-proven acute rejection (BPAR), subclinical acute rejection (SCAR), and chronic allograft nephropathy (CAN), serum creatinine, and creatinine clearence. Results Three-year patients and graft survival was 90% and 9% in ARF group, 100% and 89% in SCD group and 83% and 66% in ECD group. BPAR and SCAR were comparable in the groups but CAN was significantly higher in ECD group. Mean serum creatinine levels were 1.9 +/- 1.1, 1.9 +/- 0.9, and 2.2 +/- 1.3 mg/dl and mean creatinine clearence were 66 +/- 15, 68 +/- 14, and 58 +/- 10 in ARF, SCD, and ECD groups, respectively (SCD and ARF vs. ECD P = 0.04). Conclusions Trasnplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expanded the donor pool to overcome the current acute shortage of kidneys.

15. Transplant tourism: Outcomes of United States residents who undergo kidney transplantation overseas.

Canales MT, Kasiske BL, Rosenberg ME.

Transplantation. 2006 82 (12): 1658-61.

Background Although international commerce in kidney transplantation is a reality, little is known about U.S. residents who travel abroad for kidney transplantation. Methods We retrospectively reviewed tthe clinical outcomes of patients who were evaluated at the University of Minnesota Medical Center or Hennepin County Medical Center, but then surreptitiously underwent kidney transplantation overseas. Results We identified 10 patients who underwent kidney transplantation outside the United States between September 16, 2002 and June 30, 2006 and then returned for care in our programs. Eight were transplanted in Pakistan (all Somali), one was transplanted in China (Chinese), and one was transplanted in Iran (Iranian). All but one had a living donor. Mean age was 36.8 +/- 12.5 years with median follow-up of 2.0 years (range 0.4-3.7). Three patients communicated their intent to travel abroad before transplantation. Induction immunosuppressive therapy (if any) was available in 3/10, and initial maintenance immunosuppression was known in 5/10. Complications were primarily inffectious, with six potentially life-threatening infections in four patients. At least follow-up, mean serum creatinine was 1.13 +/- 0.34 mg/dL, acute rejection occured in 2/10 grafts failed due to acute rejection, and 9/10 patients were alive. Conclusions Kidney function and graft survival were generally good after surreptitious overseas kidney transplantation. Major problems included incomplete perioperative information communicated to the posttransplant care facility and a high incidence of posttransplant infections.

16. Surgically relevant normal and variant renal parenchymal and vascular anatomy in preoperative 16-MDCT evaluation of potential laparoscopic renal donors.

Raman SS, Pojchamarnwiputh S, Muangsomboon K et al.

AJR Am J Roentgenol. 2007 188 (1): 105-14.

Objective Using16-MDCT, we describe and quantify the frequency and types of renal anatomic variants and findings relevant for preoperative evaluation and surgical planning for potential laparoscopic renal donors. Material and Methods On 16-MDCT, 126 consecutive potential donors scanning before contrast administration and after i.v. power injection of nonionic contrast material during the arterial, nephrographic, and excretory phases. On a 3D workstation, CT images were evaluated retrospectively in consensus by three abdominal imagers. The number and branching pattern of bilateral renal arteries and veins, including anomalies of the inferior vena cava and lumbar-gonadal axis, were categorrized along with the frequency of incidental findings of the renal parenchyma and collecting system. Results Major arterial variants including supernumerary and early branching arterias were present in 16% and 21%, respectively, of left kidneys and 22% and 15%, respectively, of right kidneys. Major and minor venous variants were detected in 11% and 58% of left kidneys and 24% and 3% of right kidneys. Late confluence of the venous trunk was identified in 17% of left kidneys and 10% of right kidneys. Incidental parenchymal and urothelial abnormalities, most commonly cysts and calyceal calcifications, were identified in 30% of the kidneys. Other relevant incidental findings included focal infarcts, cortical scars, atrophic scarred kidney, and bilateral papillary necrosis. Urothelial variants included bilateral simple ureteroceles and rightsided complete duplicated system. Conclusion 16-MDCT angiography and urography allow confident detection and classification of a variety of anatomic and incidental anomalies relevant to the preoperative selection of potential laparoscopic renal donors and to surgical planning.

17. Stable T-cell reactivity after successful tapering of azathioprine in HLA-identical living-related kidney transplant recipients despite minor histocompability antigen mismatches.

Gerrits JH, van de Wetering J, Postma S et al.

Nephrol Dial Transplant. 2006 Dec 1; [Epub ahead of print].

Background Human leukocyte antigen (HLA)-identical living-related (LR) kidney transplant recipients often receive the standard regimen of immunosuppression. We wondered whether these patients should be exposed to the side effects of these drugs any longer. Safe tapering of immunosuppression should not result in rejection and high donor-directed T-cell responses. In the present study, we investigated the effect of tapering azathioprine (AZA) on T-cell reactivity. Methods Fifteen HLA-identical LR kidney transplant recipients receiving a median of 150 mg/day AZA and 5-10 mg/day prednisone were trapered to a median of 50mg/day AZA. Donor-, third-party and tetanus toxoid (TET)-reactivity were determined in interferon (IFN)-gamma and interleukin (IL)-13 Elispot assays, which reflect the T-helper (Th) 1 and T-helper (Th) 2 response. Results After the tapering of AZA, none of the patients developed acute rejection and the renal function remained stable, even at 1-year follow-up. He frequency of donor-secific IFN-gamma and IL-13 producing cells (pc) was low. Tapering of AZA did not influence the frequency of both IFN-gamma and Il-13 pc. Also, the reactivity against third-party cells and TET remained unchanged. Conclusions The AZA-dose can be safely reduced in recipients of an HLA-identical LR kidney transplant without affecting kidney function and without increasing T-cell response directed against donor or other antigens.

18. Living related kidney transplantation without calcineurin inhibitors: Initial experience in a Mexican center.

Martinez-Mier G, Mendez-Lopez MT, Budar-Fernandez LF et al.

Transplantation. 2006 82 (11): 1533-6.

We performed a prospective randomized trial comparing sirolimus/mycophenolate mofetil (MMF)/prednisone to cyclosporine/MMF/prednisone and selected induction therapy with basiliximab. Twenty patients received sirolimus (10 mg loading doses followed by 3 mg/m body surface area/day, keeping 24-hr trough levels at 10-15 ng/mL for six months and 5-10 ng/mL thereafter. Twenty-one patients began cyclosporine (4 to 8 mg/kg/day, keeping 12-hour trough levels at 150-300 ng/mL for 6 months and 100-200 ng/mL afterwards). Mean follow up was 15.8 months. One-year patient and graft survival was similar in both groups (> 90%). Acute rejection rate was 16.6% in the sirolimus group and 5.2% in the cyclosporine group (P = NS). There were no differences in mean serum creatinine between groups. No patients who received basiliximab and had sirolimus target levels suffered acute rejection at one year. The sirolimus group had a significantly higher cholesterol and triglycerides. A calcineurin inhibitor-free regimen using sirolimus produces comparable one-year transplant outcomes in living related kidney transplants compared to a calcineurin inhibitor regimen.

19. Calcineurin inhibitor-free protocols: Risks and benefits.

Barbari AG, Stephan AG, Masri MA.

Saudi J Kidney Dis Transpl. 2007 18 (1): 1-23.

The nephtotoxic and extra-renal adverse effects associated with calcineurin inhibitor (CNI) therapies appear to have a negative impact on long-term graft survival. Several CNI minimization protocols have been recently studied. These protocols involve either early CNI avoidance or CNI withdrawal. CNI withdrawal strategies are associated with a significant improvement in renal function and graft survival on both a short and long-term basis. Delayed and progressive withdrawal appears to be safer. Maintaining a high mycophenolate mofetil (MMF) or sirolimus (SIR) exposure minimizes the risk of acute rejection. CNI avoidance regimens using maintenance mono-therapy or combination therapies without induction appear to be immunologically risky and unsafe. In contrast, the combination of SIR + MMF with induction therapy reduces markedly the incidence of acute rejection and chronic allograft nephropathy (CAN). Two year patients and graft survival levels were comparable. CAN as well as the incidence and the risk for cancer in addition to blood pressure profiles and uric acid levels were owerall lower in the SIR-based treatment. In contrast, hyperlipidemia, delayed wound healing, lymphocele, arthralgias, thrombocytopenia and study protocol deviations were reported more frequently in the SIR-maintenance protocols. Long-term follow-ups are definitely needed to determine whether these avoidance strategies will result in a significant improvement in long-term patient and graft survival. Outcome differences among various protocols within the same CNI elimination strategy are probably related to study design, patient selection criteria, immunosuppression monitoring methods, indications for graft biopsies, environmental, and both genetic and ethnic factors. All monitoring techniques are unreliable short of a graft biopsy. Preliminary results on drug lymphocyte binding may offer new guidelines for tailoring immunosuppression. Whether these protocols based on SIR or SIR + MMF can also be extended to high risk patients is currently unknown. These encouraging results allow speculation but with caution that the use of the combination of non-nephrotoxic immunosuppression such as SIR and MMF, might change dramatically the natural course of CAN and may influence long-term patient survival.

20. Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy?

Courtney AE, McNamee PT, Nelson WE et al.

Nephrol Dial Transplant. 2006 21 (12): 3550-4.

Background IgA nephropathy (IgAN) is a frequent cause of end-stage renal disease (ESRD) and recurrent disease causes deterioration and graft loss in transplant recipients. No definitive management is known to reduce the risk or severity of recurrent IgAN, and the evidence to support the use of renin-angiotensin system blockade in such patients is limited. Methods All 1137 renal transplant performed at the Belfast City Hospital over a 27-year period were reviewed. A total of 75 patients with ESRD due to biopsy-proven IgAN were identified; 39 of them had been prescribed an angiotensin-converting enzyme inhbitor (ACEi) or angiotensin-II type I receptor blocker (ARB). Results The two groups were well-matched in terms of demographic details, immunosuppressive regimens and duration of follow-up (median 65 months, range 18-261 months). The 5- and 10-year graft survivals were higher in those prescribed ACEi/ARB therapy compared with those who were not, although these differences did not reach statistical significance (92.9 vs 86.5%; P = 0.34 and 81.6 vs 72.7%; P = 0.32, respectively). These results were similar when censored for death with a functioning graft. In the group where an ACEi/ARB was not prescribed, all four with biopsy-proven recurrent IgAN progressed to ESRD, compared with three out of nine in the group treated an ACEi/ARB. Conclusions In transplant recipients with ESRD due to biopsy-proven IgAN, a trend towards improved 5-year and 10-year graft survival was seen in those prescribed ACEi/ARBs. All with recurrent IgAN in their grafts who were not treated with ACEi/ARB therapy progressed again to ESRD.

21. Chronic allograft nephropathy in paediatric renal transplantation.

Alexander SI, Fletcher JT, Nankivell B.

Pediatr Nephrol. 2007 22 (1): 17-23.

Chronic allograft nephropathy (CAN) is now the leading cause of renal transplant loss in paediatric transplant recipients. Despite improvement in immunosuppression, which have significantly reduced the incidence of acute rejection, the rates of chronic kidney loss have remained unchanged in paediatric transplant patients over the last 20 years. Chronic allograft nephropathy is a pathological diagnosis of which the key features are tubular atrophy and interstitial fibrosis. More consistent definition and grading of these through the Banff classification have allowed more rigorous study of the development of chronic allograft nephropathy along with further identification of specific lesions associated with the underlying aetiologies. While initially thought to be primarily due to immune injury, it is now evident that CAN is the end result of a variety of immune and non-immune injuries including ischaemia reperfuson injury, calcineurin inhibitor (CNI) toxicity and infections. Protocol biopsy studies have demonstrated rates of CAN development in children similar those in adults with comparable underlying pathological processes. This review outlines the current knowledge of CAN within the context of paediatric renal transplantation.

22. Establishing the molecular pathways involved in chronic allograft nephropathy for testing new noninvasive diagnostic markers.

Mas V, Maluf D, Archer K et al.

Transplantation. 2007 83 (4): 448-57.

Background Chronic allograft nephropathy (CAN) is a cause of graft loss. The multistage processes that result in CAN are poorly understood. Noninvasive assays for detecting allograft dysfunction and predicting long-term outcomes are a priority in transplantation (Tx). Methods Renal tissue from kidney transplant patients (KTP) with CAN (n = 11) and normal kidneys (NK; n = 7) were studied using microassays. Markers resulting from the microarray analysis (transforming growth factor [TGF]-beta, epidermal growt factor receptor [EGFR], angiotensin [AGT]) were tested in urine (Ur) and peripheral blood (PB) samples from the CAN patients (collected at the biopsy time) using reverse-transcriptase real-time polymerase chain reaction. Ur and PB samples from long-term KTP with stable renal function (SRF; n = 20) were used as control. Results Assuming unequal variances between CAN and NK, using a false discovery rate of 0.005, and running 1000 of all possible permutations, 728 probe sets were differentially expressed. Genes related to fibrosis and extracellular matrix deposition (i.e., TGF-beta, laminin, gamma 2, metalloproteinses-9, and collagen type IX alpha 3) were up-regulated. Genes related to immunoglobulins, B cells, T-cell receptor, nuclear factor of activated T cells, and cytokine and chemokines receptors were also upregulated. EGFR and growth factor receptor activity (FGFR) 2 were downregulated in CAN samples. AGT, EGFR, and TGF-beta levels were statistically different in urine but not blood samples of CAN patients when compared to KTP with SRF (P < 0.001, P = 0.04, and P < 0.001, respectively). Conclusions Genes related to fibrosis, extracellular matrix deposition, and immune response were found up-regulated in CAN. Markers resulting from the microarray analysis were differentially expressed in Ur samples of the CAN patients and in concordance with the microarray profiles.

23. Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab.

Hristea D, Hadaya K, Marangon N et al.

Transpl Int. 2007 20 (1): 102-5.

A 22-year-old patient whose primary kidney disease was focal segmental glomerulosclerosis (FSGS) developed severe recurrence of proteinuria (up to 5-7 g/24 h) immediately after a haploidentic living donor kidney transplantation despite pre-operative plasmapheresis. The immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil, basiliximab and steroids. He underwent 10 plasmapheresis sessions in the first 3-week post-transplantation. In addition, he received 2 i.v. doses of rituximab (RTX) 600 mg (375 mg/m (2)) on days 7 and 15. Proteinuria decreased below nephrotic range at day 14 and serum creatinine returned progressively to normal values. A short course of oral cyclophosphamide (100 mg/d) was administered between days 22 and 40 and three additonal plasmapheresis sessions on days 34, 39 and 49. This strategy allowed obtaining sustained full remission of the nephrotic syndrome (NS) and excellent graft function, which persist over 2 years after transplantation. No notable adverse events related to RTX or plasmapheresis were observed. This case suggest that RTX associated with plasmapheresis may be an effective treatment of recurrent NS because of FSGS.

24. Anti-CD20 monoclonal antibody (rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patients.

Gallon L, Chhabra D.

Am J Transplant. 2006 6 (12): 3017-21.

Idiopathic membranous nephropathy (MN) remains the most common histologic entity associated with adult-onset nephrotic syndrome. The therapy for IMN is challenging. Steroids and various other immunosuppressive agents hav been tried in IMN; however, current agents have not altered the course of IMN, are nonspecific and can be very toxic. In native kidneys affected by IMN, rituximab, a monoclonal antibody against the B-cell surface antigen CD20, has been shown to reduce proteinuria and prevent disease progression. In this report, we describe a 39-year-old white male with end-stage renal disease secondary to IMN that, 4 months post living unrelated kidney transplant, developed recurrent IMN with 18 g/day of proteinuria. In additon to angiotensin converting enzyme inhibitor and statins, the patient was treated with 4 weekly doses of 375 mg/m (2) of rituximab with significant reduction in proteinuria, a corresponding increase in serum albumin and improvement in hypercholesterolemia. At 3 years post-transplant, his kidney function remains stable with 0.5 g/day of proteinuria.

25. Antivirals for the treatment of polyomavirus BK replication.

Rinaldo CH, Hirsch HH.

Expert Rev Anti Infect Ther. 2007 5 (1): 105-15.

Antiviral drugs with specific activity against polyomavirus replication have not been developed in the past. This deficiency has become fully apparent with the emergence of polyomavirus-associated nephropathy in kidney-transpalnt recipients, with a prevalence rate of up to 10%. In most cases, high BK virus replication in tubular epithelial cells causes significant cytopathology, leading to permanently impaired renal allograft function and return to hemodialysis within 6-60 months. In 5-10% of allogenic bone marrow/hematopoietic stem cell transplant recipients, high-level BK virus replication in the ureter/bladder mucosa has been associated with postengraftment hemorrhagic cystitis, which appears to involve significant immunopathology. Thus, in view of the increasing clinical need, a number of drugs have been studied in small case series. We review the antiviral strategies explored to date and specifically discuss available in vivo and in vitro data on cidofovir, leflunomide, fluoroquinolones and intravenous immunoglobulins, regarding mechanism, administration, dosing and outcome and provide a perspective on future therapy options.

26. Inhibitory effect of gamma interferon on BK virus gene expression and replication.

Abend JR, Low JA, Imperiale MJ.

J Virol. 2007 81 (1): 272-9.

BK virus (BKV) is widely accepted to be the causative agent of polyomavirus nephropathy. In immunocompromised individuals, especially kidney transplant recipents, BKV can replicate in kidney epithelial cells, causing loss of renal function and eventual destruction of the graft. Advances in immunosuppressive therapies may be partially responsible for the increasing incidence of polyomavirus nephropathy among transplant recipients by more effectively eliminating components of the immune system, such as gamma interferon (IFN-gamma)-producing lymphocytes, that keep BKV infections at a subclinical level. In this study, we investigated the role of IFN-gamma in regulating lytic infection by BKV. Treatment with IFN-gamma inhibited the expression of the viral early protein large tumor antigen (TAg) and the late protein VP1 in a dose-dependent manner. We detected 1.6- and 12-fold reductions in TAg transcripts at 48 and 96 h postinfection, respectively, with 250 U/ml IFN-gamma, suggesting that IFN-gamma-mediated inhibition occurs at the level of transcription. Furthermore, IFN-gamma inhibited the level of viral progeny production as much as 50-fold at a multiplicity of infection (MOI) of 0.5 and 80-fold at an MOI of 0.1. The inhibitory effects of IFN-gamma were similar for three different strains of BKV examined. These results indicate an important role for IFN-gamma in regulating BKV lytic infection.

27. Cell mediated immunity (CMI) and post transplant viral infections - - role of a functional immune

assay to titrate immunosuppression.

Gautam A, Fischer SA, Yango AF et al.

Int Immunopharmacol. 2006 6 (13-14): 2023-6.

Cell mediated immunity (CMI) was assessed by the ImmuKnow assay in 12 patients after kidney transplantation, who presented with viral infection. Treatment included lowering of immunosuppression in all cases and antiviral treatment if indicated. The assay was repeated during the follow-up. The ImmuKnow assay at time of presentation of viral infections was 56.8 +/- 58.2 (range 3-178; median 22) ATP ng/ml. With the clearence of viral infection and lowering of immunosuppression, the assay showed an increase in the level of CMI at 194.5 +/- 118.9 (range 53-409; median 150) ATP ng/ml. There was viral clearence or stabilization in all cases and there was no indicate of allograft rejection. The ImmuKnow assay of CMI can be used to titrate initial immunosuppression reduction and its subsequent increase, in patients with viral infection after transplantation.

28. Risk factors for development of new-onset diabetes mellitus after kidney transplantation.

Shah T, Kasravi A, Huang E et al.

Transplantation. 2006 82 (12): 1673-6.

Background New-onset diabetes mellitus after kidney transplantation (NODM) is an important co morbid condition that is associated with inferior graft and patient survival. The objective of this study was to identify donor, recipient and transplant factors, and choices of immunosuppression associated with development of NODM using Organ Procurement Transplant Network/United Network of Organ Sharing database (OPTN/UNOS). Methods From January 2004 to December 2005, 15 309 adult kidney transplants alone with a least on follow-up report as of March 2006 were identified in the OPTN/UNOS database. Among these, 1 581 patients developed NODM during the follow-up period. We examine the risk fators of NODM using multivariate Cox regression analysis using the time to diagnosis of NODM as a time-varying end point. Other events such as graft loss, patient death, and lost to follow-up were censored. Results NODM was reported in 10% in our study population with mean follow-up time of 306 days. After adjusting for other known factors, independent factors associated with the development of NODM included recipient age (29% increase of relative risk [RR] for every 10-year age increment), obesity (RR = 1.39 for body mass index [BMI] 25-30 and RR = 1.85 for BMI > 30 vs BMI < 25), tacrolimus use (RR = 1.50), hepatitis C virus (HCV) positivity (RR = 1.42), and African-American recipients (RR = 1.32). Alemtuzumab was associated with a lower risk of NODM (RR = 0.52). Discussion Using OPTN/UNOS database, we identified risk factors for development of NODM. Some of these factors potentially modifiable, including obesity, HCV infection, and the use of tacrolimus. Clinical trials are needed to assess whether modifying these ’’modifiable risk factors’’ will indeed prevent NODM.

29. Cancer incidence before and after kidney transplantation.

Vajdic CM, McDonald SP, McCredie MRE et al.

JAMA. 2006 (296): 2823-31.

Context Immune suppression after organ transplantation is associated with a markedly increased risk nonmelanoma skin cancer and a few virus-associated cancers. Although it is generally accepted that other cancers do not occur at increased rates, there have been few long-term population-based cohort studies performed. Objective To compare the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression: during dialysis and during end-stage kidney disease before renal replacement therapy (RRT). Design, Setting, and Participants A population-based cohort study of 28 855 patients with end-stage kidney disease who received RRT, with 273 407 person-years of follow-up. Incident cancers (1982-2003) were ascertained by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Main Outcome Measure Standardized incidence ratios (SIRs) of cancer, using age-specific, sex-specific, calendar year-specific, and state/territory-specific population cancer incidence rates. Results The overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1236; SIR, 3.27, 95% confidence interval [CI], 3.09-3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27-1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08-1.25). After transplantation, cancer occured at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology. Concluisions Kidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites. Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.

30. KSHV after an organ transplant: Should we screen?

Marcelin AG, Calvez V, Dussaix E.

Curr Top Microbiol Immunol. 2007 (312): 245-62.

The incidence of Kaposi sarcoma (KS) related to Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) after organ transplantation is 500-1000 times greater than in the general population, and its occurence is associated with immunosuppressive therapy. The reported incidence of posttransplant KS ranges from 0.5% to 5%, depending on the patient’s country of origin and the type of organ received, mainly after renal transplantation. Posttransplant KS is caused by two possible mechanisms: KSHV reactivation in patients who were infected before the graft and KSHV contamination from the infected organ’s donor to the recipient. KSHV reactivation appears to play a greater role in the risk of KS than incident infection. However, some studies, with findings based not only on serological data but also on molecular tracing of the viral infection, have shown that organ-related transmission of KSHV could be more common than previously thought and associated in some cases with severe KSHV-related disease. Precise estimate of KSHV seroprevalence in the organ donor and recipient population in different countries are lacking. However, studies have reported seroprevalences among donors and recipients that are similar to those among the general population of the country considered. Many studies have suggested the potential utility of screening of KSHV antibodies among organ donors and recipients. However, to date the results of these studies have argued in favor of KSHV screening, even in low-KSHV infection prevalence countries, not to exclude the graft but to have the KSHV status information in order to have the opportunity to monitor, clinically and biologically, patients at risk for KSHV-related disease development. The detection of KSHV antibodies could be done in the days after the transplantation and the result transmitted to the physicians retrospectively. In conclusion, the question of screening donors and recipents for KSHV, even in low-KSHV infection prevalence countries, is still debated, and prospective studies are needed to evaluate the benefit of pre- and posttransplantation strategies.

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