CLINICALNEPHROLOGY07
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. ÁRILIS 1. – JÚNIUS 30.
GYŐR, 2007. JÚLIUS 1.
C O N T E N T S
Part One
SECTIONS
I. EPIDEMIOLOGY
II. ETIOPATHOGENESIS
III. CLINICAL PRESENTATION
IV. TREATMENT
V. TRANSPLANTATION
TITLE OF PUBLICATIONS – AUTHORS – PUBLICATIONS
Part One
I. EPIDEMIOLOGY
1. Association between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: Case-control, haplotype, and family-based study in three European populations.
Hadjadj S, Tarnow L, Forsblom C, Kazeem G, Marre M, Groop PH, Parving HH, Cambien F, Tregouet DA, Gut IG, Theva A, Gauguier D, Farral M, Cox R, Matsuda F, Lathrop M, Hager-Vionnet N.
J Am Soc Nephrol. 2007 18 (4): 1284-91.
2. Resequencing of genes for transforming growth factor beta1 (TGFB1) type 1 and 2 receptors (TGFBR1, TGFBR2), and association analysis of variants with diabetic nephropathy.
McKnight AJ, Savage DA, Patterson CC, Sadlier D, Maxwell AP.
BMC Med Genet. 2007 Feb 23; [Epub ahead of print].
3. Association of TGFbeta1, TNFalpha, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians.
Prasad P, Tiwari AK, Kumar KM, Ammini AC, Gupta A, Gupta R, Thelma BK.
BMC Med Genet. 2007 Apr 12;
4. Study on the mitochondrial DNA variation in patients with type 2 diabetes mellitus.
Ji J, Lu J, Ye W, Hu X, Wang D.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 24 (2): 167-72.
5. Early chronic kidney disease in Aboriginal and non-Aboriginal Australian children: Remoteness, socioeconomic disadvantage or race?
Haysom L, Williams R, Hodson E, Roy LP, Lyle D, Craig JC.
Kidney Int. 2007 Feb 21; [Epub ahead of print].
6. Epidemiology of renal disease in children in the region of Southern Croatia: A 10-year review of regional renal biopsy databases.
Bazina M, Glavina-Durdov M, Scukanec-Spoljar M, Bazina A, Vukojevic K, Ljutic D, Saraga M.
Med Sci Monit. 2007 13 (4): CR172-6.
7. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population - - the Ohasama study.
Nakayama M, Metoki H, Terawaki H, Ohkubo T, Kikuya M, Sato T, Nakayama K, Asayama K, Inoue R, Hashimoto J, Totsune K, Hoshi H, Ito S, Imai Y.
Nephrol Dial Transplant. 2007 Mar 29; [Epub ahead of print].
8. Epidemiologic and clinical factors associated with chronic kidney disease among Asian Americans and Native Hawaiians.
Mau MK, West MR, Shara MN, Efird JT, Alimineti K, Saito E, Sugihara J, Ng R.
Ethn Health. 2007 12 (2): 111-27.
9. Prevalence and characteristics of a family history of end-stage renal disease among adults in the United States population: Reasons for Geographic and Racial Differences in Stroke (REGARDS) Renal Cohort Study.
McClellan W, Speckman R, McClure L, Howard V, Campbell RC, Cushman M, Audhya P, Howard G, Warnock DG.
J Am Soc Nephrol. 2007 18 (4): 1344-52.
10. Kidney disease mortality - - Michigan, 1989 – 2005.
Centers for Disease Control and Prevention (CDC).
MMWR Morb Mortal Wkly Rep. 2007 56 (10): 225-7.
11. Causes and consequences of chronic kidney disease: Implications for managed health care.
Weiner DE.
J Manag Care Pharm. 2007 13 (3): 1-9.
12. Wegener’s granulomatosis in New Zealand: Evidence for a latitude-dependent incidence gradient.
O’Donnell JL, Stevanovic VR, Frampton C, Stamp LK, Chapman PT.
Intern Med J. 2007 37 (4): 242-6.
13. Community-based screening for chronic kidney disease among populations older than 40 years in Beijing.
Zhang L, Zuo L, Xu G, Wang F, Wang M, Wang S, Lv J, Liu L, Wang H.
Nephrol Dial Transplant. 2007 22 (4): 1093-9.
14. Prevalence of Balkan endemic nephropathy has not changed since 1971 in the Kolubara region in Serbia.
Bukvic D, Maric I, Arsenovic A, Jankovic S, Djukanovic L.
Kidney Blood Press Res. 2007 30 (2): 117-23.
15. Country as the primary risk factor for renal amyloidosis in familial mediterranean fever.
Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalcinkaya F, Ozen S, Majeed H, Ozdogan H, Kastner D, Booth D, Ben-Chetrit E, Pugnere D, Michelon C, Seguret F, Gershoni-Baruch R; International Study Group for Phenotype-Genothype Correlation in Familial Mediterranean Fever Members of the International Study Group for Phenotype-Genotype Correlation in FMF are shown in Appendix A.
Arthritis Rheum. 2007 56 (5): 1706-12.
16. Genome-wide scans for diabetic nephropathy and albuminuria in multi-ethnic populations: The Family Investigation of Nephropathy and Diabetes.
Iyengar SK, Abboud HE, Goddard KA, Saad MF, Adler SG, Arar NH, Bowden DW, Duggirala R, Elston RC, Hanson RL, Ipp E, Kao WH, Kimmel PL, Klag MJ, Knowler WC, Meoni LA, Nelson RG, Nicholas SB, Pahl MV, Parekh RS, Quade SR, Rich SS, Rotter JI, Scavini M, Schelling JR, Sedor JR, Sehgal AR, Shah VO, Smith MW, Taylor KD, Winkler CA, Zager PG, Freedman BI.
Diabetes. 2007 Mar 15; [Epub ahead of print].
17. Racial differences in trends of end-stage renal disease, by primary diagnosis - - United States, 1994-2004.
Centers for Disease Control and Prevention (CDC).
MMWR Morb Mortal Wkly Rep. 2007 56 (11): 253-6.
18. SCreening for Occult REnal Disease (SCORED): A simple prediction model for chronic kidney disease.
Bang H, Vupputuri S, Shoham DA, Klemmer PJ, Falk RJ, Mazumdar M, Gipson D, Colindress RE, Kshirsagar AV.
Arch Intern Med. 2007 167 (4): 374-81.
19. Use of albumin creatinine ratio and urine albumin concentration as a screening test for albuminuria in an Indo-Asian population.
Jafar TH, Chaturverdi N, Hatcher J, Levey AS.
Nephrol Dial Transplant. 2007 Apr 3; [Epub ahead of print].
20. A population-based, prospective study of blood pressure and risk for end-stage renal disease in China.
Reynolds K, Gu D, Muntner P, Kusek JW, Chen J, Wu X, Duan X, Chen CS, Klag MJ, Whelton PK, He J.
J Am Soc Nephrol. 2007 May 2; [Epub ahead of print].
21. Risk factors for mortality among patients with diabetes: The Translating Research Into Action for Diabetes (TRIAD) Study.
McEwen LN, Kim C, Karter AJ, Haan MN, Ghosh D, Lantz PM, Mangione CM, Thompson TJ, Herman WH.
Diabetes Care. 2007 Apr 27; [Epub ahead of print].
22. The metabolic syndrome and chronic kidney disease in a Southeast Asian cohort.
Kitiyakara C, Yamwong S, Cheepudomwit S, Domrongkitchaiporn S, Unkurapinun N, Pakpeankitvatana V, Sritara P.
Kidney Int. 2007 71 (7): 693-700.
23. Chronic kidney disease and mortality and morbidity among patients with established cardiovascular disease: A West of Ireland community-based cohort study.
Glynn LG, Reddan D, Newel J, Hinde J, Buckley B, Murphy AW.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
II. ETIOPATHOGENESIS
1. Congenital cytomegalovirus infection: A cause of renal dysplasia?
Chan M, Hecht J, Boyd T, Rosen S.
Pediatr Dev Pathol. 2007 Mar 22; [Epub ahead of print].
2. Cryoglobulinemia related to hepatitis C virus infection.
Dore MP, Fattovich G, Sepulveda AR, Realdi G.
Dig Dis Sci. 2007 52 (4): 897-907.
3. Autosomal dominant polycystic kidney disease.
Torres VE, Harris PC, Pirson Y.
Lancet. 2007 369 (9569): 1287-301.
4. Correlation between mRNA expression level of the mutant COL4A5 gene and phenotypes of XLAS females.
Wang Y, Zhang H, Ding J, Wang F.
Exp Biol Med (Maywood). 2007 232 (5): 638-42.
5. Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases.
Rana K, Tonna S, Wang YY, Sin L, Lin T, Shaw E, Mookerjee I, Savige J.
Pediatr Nephrol. 2007 22 (5): 652-7.
6. Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?
Zhang KW, Tonna S, Wang YY, Rana K, Padavarat S, Savige J.
Pediatr Nephrol. 2007 22 (5): 645-51.
7. Toll-like receptors: Emerging concepts in kidney disease.
Anders HJ, Schlondorff D.
Curr Opin Nephrol Hypertens. 2007 16 (3): 177-83.
8. BMP in the kidney: Signaling, function and pathophysiological significance.
Hanai J.
Clin Calcium. 2007 17 (5): 704-10.
9. Mast cells and inflammatory kidney disease.
Blank U, Essig M, Scandiuzzi L, Benhamou M, Kanamaru Y.
Immunol Rev. 2007 217 (1): 79-95.
10. The mast cell IgG receptors and their roles in tissue inflammation.
Malbec O, Daeron M.
Immunol Rev. 2007 217 (1): 206-21.
11. Mechanisms of disease: The complement system in renal injury - - new ways of looking at an old foe.
Brown KM, Sacks SH, Sheerin NS.
Nat Clin Pract Nephrol. 2007 3 (5): 277-86.
12. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions.
Woltman AM, de Fijter JW, Zuidwijk K, Vlug AG, Bajema IM, van der Kooij SW, van Ham V, van Kooten C.
Kidney Int. 2007 Mar 14; [Epub ahead of print].
13. Physiologic and pathophysiologic roles of lipid mediators in the kidney.
Hao CM, Breyer MD.
Kidney Int. 2007 Mar 14; [Epub ahead of print].
14. Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes.
Asanuma K, Campbell KN, Kim K, Faul C, Mundel P.
Proc Natl Acad Sci U S A. 2007 May 30; [Epub ahead of print].
15. Kidney growth during catabolic illness: What it does not destroy makes it grow stronger.
Franch HA.
J Ren Nutr. 2007 17 (3): 167-72.
16. Kidney growth, hypertrophy and the unifying mechanism of diabetic complications.
Satriano J.
Amino Acids. 2007 Apr 19; [Epub ahead of print].
17. Fibrillogenic amylin evokes the apoptosis of human mesangial cells.
Peng A, Liu ZH, Zhou H, Zhu MY, Li LS.
Diabetes Res Clin Pract. 2007 Apr 5; [Epub ahead of print].
18. Role of matrix metalloproteinases in renal pathophysiologies.
Catania JM, Chen G, Parrish AR.
Am J Physiol Renal Physiol. 2007 292 (3): F905-11.
19. The (pro) renin receptor: Pathophysiological roles in cardiovascular and renal pathology.
Nguyen G.
Curr Opin Nephrol Hypertens. 2007 16 (2): 129-33.
20. Human T and natural killer cells possess a functional renin-angiotensin system: Further mechanisms of angiotensin II-induced inflammation.
Jurewicz M, McDermott DH, Sechler JM, Tinckam K, Takakura A, Carpenter CB, Milford E, Abdi R.
J Am Soc Nephrol. 2007 18 (4): 1093-102.
21. The emerging role of angiotensin-converting enzyme-2 in the kidney.
Burns KD.
Curr Opin Nephrol Hypertens. 2007 16 (2): 116-21.
22. Vascular endothelium summary statement I: Health promotion and chronic disease prevention.
Hooper WC, Catravas JD, Heistad DD, Sessa WC, Mensah GA.
Vascul Pharmacol. 2007 46 (5): 315-7.
23. Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease.
Bellini MH, Figueira MN, Piccoli MF, Marumo JT, Cedoroglo MS, Neto MC, Dalboni MA, Batista MC, Goes MA, Schor N.
Nephrology (Carlton). 2007 12 (3): 289-93.
24. Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?
Stenvinkel P, Karimi M, Johansson S, Axelsson J, Suliman M, Lindholm B, Heimburger O, Barany P, Alvestrand A, Nordfors L, Qureshi AR, Ekstrom TJ, Schalling M.
J Intern Med. 2007 261 (5): 488-99.
25. The past, presence and future of ADMA in nephrology.
Kielstein JT, Fliser D.
Nephrol Ther. 2007 3 (2): 47-54.
26. Vascular calcification and fetuin-A deficiency in chronic kidney disease.
Westenfeld R, Jachnen-Dechent W, Ketteler M.
Trends Cardiovasc Med. 2007 17 (4): 124-8.
27. Transthyretin amyloidoses.
Magy-Bertrand N.
Rev Med Interne. 2007 28 (5): 306-13.
28. Mechanism of beta (2)-microglobulin-related amyloid fibril formation in CKD.
Yamamoto S, Kazama JJ.
Clin Calcium. 2007 17 (5): 740-4.
29. Phenylalanine and tyrosine metabolism in chronic kidney failure.
Kopple JD.
J Nutr. 2007 137 (6): 1586S-90S.
30. Disorders of bone and mineral metabolism in CKD: CKD-MBD as a new entity.
Tsukamoto Y.
Clin Calcium. 2007 17 (5): 660-4.
31. Streptococcal exotoxin B increases interleukin-6, tumor necrosis factor alpha, interleukin-8 and transforming growth factor beta-1 in leukocytes.
Viera N, Pedreanez A, Rincon J, Mosquera J.
Pediatr Nephrol. 2007 May 25; [Epub ahead of print].
32. Activation of the lectin complement pathway in post-streptococcal acute glomerulonephritis.
Hisano S, Matsushita M, Fujita T, Takeshita M, Iwasaki H.
Pathol Int. 2007 57 (6): 351-7.
33. Collapsing glomerulopathy: An inflammatory podocytopathy?
Barisoni L, Nelson PJ.
Curr Opin Nephrol Hypertens. 2007 16 (3): 192-5.
34. Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis.
Mezzano S, Droguett A, Burgos ME, Aros C, Ardiles L, Flores C, Carpio D, Carvajal G, Ruiz-Ortega M, Egido J.
Nephrol Dial Transplant. 2007 Apr 1; [Epub ahead of print].
35. Adult and paediatric patients with minimal change nephrotic syndrome show no major alterations in glomerular expression of sulphated heparan sulphate domains.
Wijnhoven TJ, Geelen JM, Bakker M, Lensen JF, Rops AL, Kramer AB, Navis G, van den Hoven MJ, Van der Vlag J, Berden JH, Wetzels JF, van den Heuvel LP, Monnens LA, van Kuppevelt TH.
Nephrol Dial Transplant. 2007 May 25, [Epub ahead of print].
36. TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurence of idiopathic membranous nephropathy.
Thibaudin D, Thibaudin L, Berthoux P, Mariat C, Filippis JP, Laurent B, Alamartine E, Berthoux F.
Kidney Int. 2007 71 (5): 431-7.
37. Membranous nephropathy is developed under Th2 environment in chronic graft-versus-host disease.
Nakashima H.
Med Hypotheses. 2007 Mar 28; [Epub ahead of print].
38. Dense deposit disease is not a membranoproliferative glomerulonephritis.
Walker PD, Ferrario F, Joh K, Bonsib SM.
Mod Pathol. 2007 20 (6): 605-16.
39. The genetics of IgA nephropathy.
Beerman I, Novak J, Wyatt RJ, Julian BA, Gharavi AG.
Nat Clin Pract Nephrol. 2007 3 (6): 325-38.
40. Variants of the ST6GALNAC2 promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy.
Li GS, Zhu L, Zhang H, Lv JC, Ding JX, Zhao MH, Shen Y, Wang HY.
Hum Mutat. 2007 May 4; [Epub ahead of print].
41. Identification and characterization of CMP-NeuAc:GalNAc-IgA1 alpha2, 6-Sialyltransferase in IgA1-producing cells.
Raska M, Moldoveanu Z, Suzuki H, Brown R, Kulhavy R, Andrasi J, Hall S, Vu HL, Carlsson F, Lindahl G, Tomana M, Julian BA, Wyatt RJ, Mestecky J, Novak J.
J Mol Biol. 2007 369 (1): 69-78.
42. The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy (Review Article).
Barrat J, Smith AC, Feehally J.
Nephrology (Carlton). 2007 12 (3): 275-84.
43. Differential binding characteristics of native monomeric and polymeric immunoglobulin A1 (IgA1) on human mesangial cells and the influence of in vitro deglycosylation of IgA1 molecules.
Gao YH, Xu LX, Zhang JJ, Zhang Y, Zhao MH, Wang HY.
Clin Exp Immunol. 2007 148 (3): 507-14.
44. Underglycosylation of IgA in IgA nephropathy: More than a diagnostic marker?
Roos A, van Kooten C.
Kidney Int. 2007 71 (11): 1089-91.
45. T-cell homing receptor expression in IgA nephropathy.
Batra A, Smith AC, Feehally J, Barratt J.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
46. Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients.
Kobori H, Katsurada A, Ozawa Y, Satou R, Miyata K, Hase N, Suzaki Y, Shoji T.
Biochem Biophys Res Commun. 2007 Apr 26; [Epub ahead of print].
47. Soluble fibrin formation in the mesangial area of IgA nephropathy.
Liu N, Mori N, Iehara N, Uemura K, Fukastu A, Kita T, Matsuda M, Ono T.
Clin Exp Nephrol. 2007 11 (1): 71-6.
48. Hypothesis - - haptoglobin genotype and diabetic nephropathy.
Nakhoul FM, Miller-Lotan R, Awaad H, Asleh R, Levy AP.
Nat Clin Pract Nephrol. 2007 3 (6): 339-44.
49. Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via upregulation of MAP kinase phosphatase-1 (MKP-1).
Wahab NA, Cox DJ, Witherden AS, Mason RM.
Biochem J. 2007 May 10; [Epub ahead of print].
50. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
Lindmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlondorff D, Cohen CD.
J Am Soc Nephrol. 2007 18 (6): 1765-76.
51. Pathogenesis of extra efferent vessel development in diabetic glomeruli.
Stout LC, Whorton EB.
Hum Pathol. 2007 May 7;[Epub ahead of print].
52. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy.
Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M.
Diabetes. 2007 May 29; [Epub ahead of print].
53. Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach.
Kankova K, Stejskalova A, Pacal L, Tschoplova S, Hertlova M, Krusova D, Izakovicova-Holla L, Beranek M, Vasku A, Barral S, Ott J.
Diabetologia. 2007 Mar 8; [Epub ahead of print].
54. The relationship of the methylenetetrahydrofolate reductase C677T gene polymorphism in Tuskish type 2 diabetic patients with and without nephropathy.
Eroglu Z, Erdogan M, Tetik A, Karadinez M, Cetinalp S, Kosova B, Gunduz C, Ozgen AG, Yilmaz C.
Diabetes Metab Res Rev. 2007 Mar 12; [Epub ahead of print].
55. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlondorff D, Cohen CD.
J Am Soc Nephrol. 2007 May 2; [Epub ahead of print].
56. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy.
Wong CK, Ho AW, Tong PC, Yeung CY, Kong AP, Lun SW, Chan JC, Lam CW.
Clin Exp Immunol. 2007 Apr 11; [Epub ahead of print].
57. Elevated circulating transforming growth factor beta-1 may explain poorer renal survival in type II diabetics with chronic hepatitis C.
Peterson MC.
Med Sci Monit. 2007 13 (5): RA50-4.
58. Physiologic and pathophysiologic roles of lipid mediators in the kidney.
Hao CM, Breyer MD.
Kidney Int. 2007 71 (11): 1105-15.
59. Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome.
Ramos MV, Fernandez GC, Patey N, Schierloh P, Exeni R, Grimoldi I, Vallejo G, Elias-Costa C, Del Carmen Sasiain M, Trachtman H, Combadiere C, Proulx F, Palermo MS.
Blood. 2007 109 (6): 2438-45.
III. CLINICAL PRESENTATION
1. Useful indicators for performing renal biopsy in adult patients with isolated microscopic haematuria.
Shen P, He L, Jiang Y, Wang C, Chen M.
Int J Clin Pract. 2007 Mar 16, [Epub ahead of print].
2. Can cystatin C replace creatinine to estimate glomerular filtration rate? A literature review.
Zahran A, El-Husseini A, Shoker A.
Am J Nephrol. 2007 27 (2): 197-205.
3. Anemia as a risk factor for kidney function decline in individuals with heart failure.
Bansal N, Tighiouart H, Weiner D, Griffith J, Vlagopoulos P, Salem D, Levin A, Sarnak MJ.
Am J Cardiol. 2007 99 (8): 1137-42.
4. Validation of a predictive risk score for radiocontrast-induced nephropathy following percuatenous coronary intervention.
Skelding KA, Best PJ, Bartholomew BA, Lennon RJ, O’Neill WW, Rihal CS.
J Invasiv Cardiol. 2007 19 (5): 229-33.
5. Paradoxical association between body mass index and mortality in men with CKD no yet on dialysis.
Kovesdy CP, Anderson JE, Kalantar-Zadeh K.
Am J Kidney Dis. 2007 49 (5): 581-91.
6. Impact of haemoglobin concentration and chronic kidney disease in patients with coronary heart disease undergoing percutaneous coronary interventions.
Husemann W, Fobker M, Pohlen M, Bruch C, Hausberg M, Breithardt G, Reinicke H.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
7. An introduction to biomarkers: Applications to chronic kidney disease.
Lemley KV.
Pediatr Nephrol. 2007 Mar 30; [Epub ahead of print].
8. Urinary proteome profiling using microfluidic technology on a chip.
Thongoboonkerd V, Songtawee N, Sritippayawan S.
J Proteome Res. 2007 6 (5): 2011-8.
9. Plasma and urine levels of resistin and adiponectin in chronic kidney disease.
Yaturu S, Reddy RD, Rains J, Jain SK.
Cytokine. 2007 Mar 23; [Epub ahead of print].
10. Low fat adiponectin expression is associated with oxidative stress in non-diabetic humans with chronic kidney disease - impact on plasma adiponectin concentration.
Barazzoni R, Bernardi A, Biasia F, Semolic A, Bosutti A, Mucci M, Dore F, Zanetti M, Guarnieri G.
Am J Physiol Regul Integr Comp Physiol. 2007 Mar 15; [Epub ahead of print].
11. Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: The Mild to Moderate Kidney Disease Study.
Kollerits B, Fliser D, Heig IM, Ritz E, Kronenberg F.
Kidney Int. 2007 Apr 25; [Epub ahead of print].
12. B-type natriuretic peptide concentrations predict the progression of nondiabetic chronic kidney disease: The Mild-to-Moderate Kidney Disease Study.
Spanaus KS, Kronenberg F, Ritz E, Schlapbach R, Fliser D, Hersberger M, Kollerits B, Konig P, von Eckardstein A.
Clin Chem. 2007 May 3; [Epub ahead of print].
13. Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease.
Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, Kato A, Nakamura Y, Suzuki F, Hishida A.
J Am Soc Nephrol. 2007 18 (5): 1558-65.
14. Chronic glomerulonephritis associated with IgG subclass deficiency.
Kamei K, Nakagawa A, Otsuka Y, Nakayama M, Kobayashi S, Matsuoka K, Iijima K.
Pediatr Nephrol. 2007 Apr 17; [Epub ahead of print].
15. Hepatitis C infection with false negative serology in a patient with mixed cryoglobulinemic vasculitis.
Tini GM, Wuscher V, Jeker R.
Dtsch Med Wochenschr. 2007 132 (12): 616-8.
16. Chronic lead poisoning: A ’’forgotten’’ cause of renal disease.
Benjelloun M, Tarrass F, Hachim K, Medkouri G, Benghanem MG, Ramdani B.
Saudi J Kidney Dis Transpl. 2007 18 (1): 83-6.
17. Case-control study of gadodiamide-related nephrogenic systemic fibrosis.
Marckmann P, Skov L, Rossen K, Heaf JG, Thomsen HS.
Nephrol Dial Transplant. 2007 May 4; [Epub ahead of print].
18. Enforcement of the ban on aristolochic acids in Chinese traditional herbal preparations on the Dutch market.
Martena MJ, van der Wielen JC, van de Laak LF, Konings EJ, de Groot HN, Rietjens IM.
Anal Bioanal Chem. 2007 May 8; [Epub ahead of print].
19. Nephrogenic fibrosing dermopathy associated with exposure to gadolium-containing contrast agents - - St. Louis, Missouri, 2002-2006.
Centers for Disease Control and Prevention (CDC).
MMWR Morb Mortal Wkly Rep. 2007 56 (7): 137-41.
20. Carbonated beverages and chronic kidney disease.
Saldana TM, Basso O, Darden R, Sandler DP.
Epidemiology. 2007 May 25; [Epub ahead of print].
21. High incidence of autoantibodies in Fabry disease patients.
Martinez P, Aggio M, Rozenfeld P.
J Inherit Metab Dis. 2007 Apr 24; [Epub ahead of print].
22. Historical perspective of pregnancy in chronic kidney disease.
Hou S.
Adv Chronic Kidney Dis. 2007 14 (2): 116-8.
23. Chronic kidney disease and pregnancy: Maternal and fetal outcomes.
Fischer MJ.
Adv Chronic Kidney Dis. 2007 14 (2): 132-45.
24. Outcome of infants born to women with chronic kidney disease.
Blowey DL, Warady BA.
Adv Chronic Kidney Dis. 2007 14 (2): 199-205.
25. Nutritional management of pregnancy in chronic kidney disease.
Stover J.
Adv Chronic Kidney Dis. 2007 14 (2): 212-4.
26. Pregnancy and contraceptive counseling of women with chronic kidney disease and kidney transplants.
Watnick S.
Adv Chronic Kideny Dis. 2007 14 (2): 126-31.
27. Ethical considerations regarding pregnancy in chronic kidney disease.
Davison SN.
Adv Chronic Kidney Dis. 2007 14 (2): 206-11.
28. How have the past 5 years of research changed clinical practice in paediatric nephrology?
Marks SD.
Arch Dis Child. 2007 92 (4): 357-61.
29. Bone mass, biochemical markers and growth in children with chronic kidney disease: A 1-year prospective study.
Swolin-Eide D, Magnusson P, Hansson S.
Acta Paediatr. 2007 Mar 23; [Epub ahead of print].
30. Sexual function in chronic kidney disease.
Anantharaman P, Schmidt RJ.
Adv Chronic Kidney Dis. 2007 14 (2): 119-25.
31. Therapy insight: Sexual dysfunction in patients with chronic kidney disease.
Finkelstein FO, Shirani S, Wuerth D, Finkelstein SH.
Nat Clin Pract Nephrol. 2007 3 (4): 200-7.
32. Progression of coronary artery calcification in predialysis patients.
Russo D, Corrao S, Miranda I, Ruocco C, Manzi S, Elefante R, Brancaccio D, Cozzolino M, Biondi ML, Andreucci VE.
Am J Nephrol. 2007 27 (2): 152-8.
33. Differential impact of age on verbal memory and executive functioning in chronic kidney disease.
Thornton WL, Shapiro RJ, Deria S, Gelb S, Hill A.
J Int Neuropsychol Soc. 2007 13 (2): 344-53.
34. Association between multidisciplinary care and survival for elderly patients with chronic kidney disease.
Hemmelgarn BR, Manns BJ, Zhang J, Tonelli M, Klarenbach S, Walsh M, Culleton BF.
J Am Soc Nephrol. 2007 18 (3): 993-9.
35. Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage 5.
Murtagh FE, Marsh JE, Donohoe P, Ekbal NJ, Sheerin NS, Harris FE.
Nephrol Dial Transplant. 2007 Apr 4; [Epub ahead of print].
36. Urine biomarkers predict the cause of glomerular disease.
Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM.
J Am Soc Nephrol. 2007 18 (3): 913-22.
37. NOx (nitrite/nitrate) in patients with pediatric nephrotic syndrome.
Kawashima H, Kashiwagi Y, Watanabe C, Sato S, Nishimata S, Takekuma K, Hoshika A, Watanabe Y.
Pediatr Nephrol. 2007 Feb 8; [Epub ahead of print].
38. Immunotactoid glomerulonephritis in a child with HIV infection: A case report.
van Biljon G, Louw M, Dreyer L.
Pediatr Nephrol. 2007 Apr 25; [Epub ahead of print].
39. Nephrotic syndrome preceding psoriasis in children.
Bagga A, Menon S, Hari P, Mantan M, Dinda A.
Pediatr Nephrol. 2007 Apr 25; [Epub ahead of print].
40. Polymyositis associated with focal mesangial proliferative glomerulonephritis with depositions of immune complexes.
Takizawa Y, Kanda H, Sato K, Kawahata K, Yamaguchi A, Uozaki H, Shimizu J, Tsuji S, Misaki Y, Yamamoto K.
Clin Rheumatol. 2007 26 (5): 792-6.
41. Meningococcal disease associated with an acute post-streptococcal complement deficiency.
Daskas N, Farmer K, Coward R, Erlewyn-Lajeunesse M.
Pediatr Nephrol. 2007 22 (5): 747-9.
42. Glomerulonephritis induced by methicillin-resistant Staphylococcus aureus infection that progressed during puerperal period.
Hashimoto M, Nogaki F, Oida E, Tanaka M, Ito-Ihara T, Nomura K, Liu N, Muso E, Fukatsu A, Kita T, Ono T.
Clin Exp Nephrol. 2007 11 (1): 92-6.
43. A 59-kd renal antigen as a new target for rapidly progressive glomerulonephritis.
Audard V, Hellmark T, El Karoui K, Noel LH, Pardon A, Desvaux D, Touchard G, Remy P, Lang P, Sahali D.
Am J Kidney Dis. 2007 49 (5): 710-6.
44. Systemic lupus erythematosus and pregnancy.
Skomsvoll JF, Aasarod K, Salvesen KA, Hoff M, Wallenius M, Rodevand E, Koksvik HS, Gilboe IM, Nossent HC.
Tidsskr Nor Laegeforen. 2007 127 (6): 725-9.
45. Recurrent major infections in juvenile-onset systemic lupus erythematosus - - a close link with long-term disease damage.
Lee PP, Lee TL, Ho MH, Wong WH, Lau YL.
Rheumatology (Oxford). 2007 May 23; [Epub ahead of print].
46. Diffuse alveolar hemorrhage in Colombian patients with systemic lupus erythematosus.
Canas C, Tobon GJ, Granados M, Fernandez L.
Clin Rheumatol. 2007 Mar 22; [Epub ahead of print].
47. Oral 9, Hypocomplementaemic urticarial vasculitis: A rare but important cause of urticaria and angio-oedema.
Roberts C, Rangaraj A, Murphy R.
Br J Dermatol. 2007 Apr 17; [Epub ahead of print].
48. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: Follow-up of a population-based study.
Karstila K, Korpela M, Sihvonen S, Mustonen J.
Clin Rheumatol. 2007 May 10; [Epub ahead of print].
49. Clustering of inflammatory bowel disease with immune mediated diseases among members of a Northern California-Managed Care Organization.
Weng X, Liu L, Barcellos LF, Allison JE, Herrinton LJ.
Am J Gastroenterol. 2007 Apr 16; [Epub ahead of print].
50. Anti-glomerular basement membrane antibody disease with granulomatosus lesions on renal biopsy.
Takahashi M, Otsubo S, Takei T, Sugiura H, Yoshida K, Tamei N, Koike M, Uchida K, Yumura W, Kawamura S, Horita S, Akiba T, Nitta K.
Intern Med. 2007 46 (6): 295-301.
51. Fibrillary glomerulonephritis with small fibrils in a patients with the antiphospholipid antibody syndrome successfully treated with immunosuppressive therapy.
Javaid MM, Denley H, Tagboto S.
BMC Nephrol. 2007 May 9; [Epub ahead of print].
52. Microscopic polyangiitis.
Pagnoux C, Guilpain P, Guillevin L.
Presse Med. 2007 36 (5P2): 895-901.
53. Microscopic polyangiitis presenting with temporal arteritis and multiple cranial neuropathies.
Morinaga A, Ono K, Komai K, Yamada M.
J Neurol Sci. 2007 256 (1-2): 81-3.
54. Wegener’s granulomatosis: Current trends in diagnosis and management.
Erickson VR, Hwang PH.
Curr Opin Otolaryngol Head Neck Surg. 2007 15 (3): 170-6.
55. Clinical features and outcome of pediatric Wegener’s granulomatosis.
Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, Silverman ED.
Arthritis Rheum. 2007 57 (5): 837-44.
56. Wegener’s granulomatosis.
Pagnoux C, Teixeira L.
Presse Med. 2007 36 (5P2): 860-74.
57. Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis.
Yu F, Chen M, Gao Y, Wang SX, Zou WZ, Zhao MH, Wang HY.
Am J Kidney Dis. 2007 49 (5): 607-14.
58. Eye manifestations in patients with perinuclear antineutrophil cytoplasmic antibody-associated vasculitis: Case series and literature review.
Matsuo T.
Jpn J Ophtalmol. 2007 51 (2): 131-8.
59. Long-term outcome of 37 patients with Wegener’s granulomatosis with renal involvement.
Gottenberg JE, Mahr A, Pagnoux C, Cohen P, Mouthon L, Guillevin L; For the French Vasculitis Study Group (FVSG).
Presse Med. 2007 36 (5P1): 771-8.
60. Atypical p-ANCA is not a poor prognostic marker in postinfectious glomerulonephritis.
Waters A, Langlois V, Thorner P, Geary D.
Pediatr Nephrol. 2007 May 4; [Epub ahead of print].
61. Churg-Strauss syndrome.
Lhote F.
Presse Med. 2007 36 (5P2): 875-89.
62. Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate.
Pascual J, Torrealba J, Myers J, Tome S, Samaniego M, Musat A, Djamali A.
Osteoporosis Int. 2007 Apr 3; [Epub ahead of print].
63. Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy.
Heeringa SF, Branten AJ, Deegens JK, Steenbergen E, Wetzels JF.
Nephrol Dial Transplant. 2007 Apr 18; [Epub ahead of print].
64. Post-allogenic haematopoietic stem cell transplantation membranous nephropathy: Clincal presentation, outcome and pathogenic aspects.
Terrier B, Delmas Y, Hummel A, Presne C, Glowacki F, Knebelmann B, Combe C, Lesavre P, Maillard N, Noel LH, Patey-Mariaud de Serre N, Nusbaum S, Radford I, Buzyn A, Fakhouri F.
Nephrol Dial Transplant. 2007 22 (5): 1369-76.
65. Nephrotic syndrome as a clinical manifestation of systemic sclerosis.
Wielosz E, Majdan M, Suszek D, Smarz-Widelska I, Korolczuk A, Korobowicz E.
Rheumatol Int. 2007 Apr 11; [epub ahead of print].
66. C4B deficiency associated with membranoproliferative glomerulonephritis.
Tsuda T, Moriguchi M, Asanuma Y, Imamura S, Toyoda A, Yamada S, Terai C, Suzuki K, Tabei K.
Intern Med. 2007 46 (11): 765-70.
67. Nocardial cerebral abscess associated with mycetoma, pneumonia and membranoproliferative glomerulonephritis.
Elmaci I, Senday D, Silav G, Ekenel F, Balak N, Ayan E, Akinci M, Isik N, Yazici S.
J Clin Microbiol. 2007 Apr 11; [Epub ahead of print].
68. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.
Ding H, He Y, Li K, Yang J, Li X, Lu R, Gao W.
Clin Immunol. 2007 123 (2): 227-34.
69. Association between serum adiponectin levels and arteriolosclerosis in IgA nephropathy patients.
Takahashi M, Otsubo S, Uchida K, Yumura W, Nitta K.
Intern Med. 2007 46 (8): 453-9.
70. Tonsillar focal infectious disease involving IgA nephropathy, pustulosis, and ossification.
Noda K, Kodama S, Suenaga S, Suzuki M.
Clin Exp Nephrol. 2007 11 (1): 97-101.
71. Obesity and kidney disease: A big dilemma.
Kramer H, Luke A.
Curr Opin Nephrol Hypertens. 2007 16 (3): 237-41.
72. Hyperinsulinemia in pediatric patients with chronic kidney disease: The role of tumor necrosis factor-alpha.
Lai HL, Kartal J, Mitsnefes M.
Pediatr Nephrol. 2007 Jun 1; [Epub ahead of print].
73. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes.
Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, Krolewski AS.
J Am Soc Nephrol. 2007 18 (4): 1353-61.
74. Laughter modulates prorenin gene expression in patients with type 2 diabetes.
Hayashi T, Urayama O, Hori M, Sakamoto S, Nasir UM, Iwanaga S, Hayashi K, Suzuki F, Kawai K, Murakami K.
J Psychosom Res. 2007 62 (6): 703-6.
75. The relationship between adrenomedullin, metabolic factors and vascular function in individuals with type 2 diabetes mellitus.
Lim S, Morgenthaler NG, Subramaniam T, Wu YS, Goh SK, Sum CF.
Diabetes Care. 2007 30 (6): 1513-9.
76. Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease.
Hayashi T, Hirano T, Taira T, Tokuno A, Mori Y, Koba S, Adachi M.
Atherosclerosis. 2007 Apr 24; [Epub ahead of print].
77. Relationship between apolipoprotein E polymorphism and nephropathy in type-2 diabetic patients.
Leiva E, Mujica V, Elelmatore I, Orrego R, Diaz G, Prieto M, Arredondo M.
Diabetes Res Clin Pract. 2007 May 2; [Epub ahead of print].
78. Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus: Relation with lipoprotein-associated phospholipase A (2) and effects of simvastatin treatment.
Iwase M, Sonoki K, Sasaki N, Ono S, Higuchi S, Hattori H, Iida M.
Atherosclerosis. 2007 Mar 9; [Epub ahead of print].
79. Serum resistin is associated with the severity of microangiopathies in type-2 diabetes.
Osawa H, Ochi M, Kato K, Yamauchi J, Nishida W, Takata Y, Kawamura R, Onuma H, Takasuka T, Shimizu I, Fujii Y, Ohashi J, Makino H.
Biochem Biophys Res Commun. 2007 355 (2): 342-6.
80. Beer ethanol consumption and plasma homocysteine among patients with type 2 diabetes.
Sakuta H, Suzuki T, Ito T, Yasuda H.
Diabetes Res Clin Pract. 2007 May 21; [Epub ahead of print].
81. Acute and chronic complications of type 2 diabetes mellitus in children and adolescents.
Pinhas-Hamiel O, Zeitler P.
Lancet. 2007 369 (9575): 1823-31.
82. Prevalence of nondiabetic renal disease in diabetic patients.
Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA.
Am J Nephrol. 2007 27 (3): 322-8.
83. Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients with type 2 diabetes mellitus.
Araki SI, Haneda M, Koya D, Hidaka H, Sugimoto T, Isono M, Isshiki K, Chin-Kanasaki M, Uzu T, Kashiwagi A.
Diabetes. 2007 56 (6): 1727-30.
84. Association between diabetic microangiopathy and vascular endothelial function evaluated by flow-mediated vasodilatation in patients with type 2 diabetes.
Suetsugu M, Takebayashi K, Aso Y.
Int J Clin Pract. 2007 61 (6): 920-6.
85. The accuracy of cystatin C and commonly used creatinine-based methods for detecting moderate and mild chronic kidney disease in diabetes.
Macisaac RJ, Tsalamandris C, Thomas MC, Premaratne E, Panagiotopoulos S, Smith TJ, Poon A, Jenkins MA, Ratnaike SI, Power DA, Jerums G.
Diabet Med. 2007 24 (4): 443-8.
86. Estimated glomerular filtration rate, albuminuria and mortality in type 2 diabetes: The Casale Monferrato study.
Bruno G, Merletti F, Bargero G, Novelli G, Melis D, Soddu A, Perotto M, Pagano G, Cavallo-Perin P.
Diabetologia. 2007 Mar 2; [Epub ahed of print].
87. Lipoprotein metabolism in chronic renal insufficiency.
Saland JM, Ginsberg HN.
Pediatr Nephrol. 2007 Mar 28; [Epub ahed of print].
88. Diagnosis and management of renovascular disease and renovascular hypertension.
Bloch MJ, Basile J.
J Clin Hypertens (Greenwich). 2007 9 (5): 381-9.
89. A prospective national study of acute renal failure treated with RRT: Incidence, aetiology and outcomes.
Prescott GJ, Metcalfe W, Baharani J, Khan IH, Simpson K, Smith WC, Macleod AM.
Nephrol Dial Transplant. 2007 May 21; [Epub ahead of print].
90. Patients at high of adverse events from intravenous contrast media after computed tomography examination.
Reddan D.
Eur J Radiol. 2007 Mar 24; [Epub ahead of print].
91. Different types of renal dysfunction in patients with acute myocardial infaction treated with percutaneous coronary intervention.
Kowalczyk J, Lenarczyk R, Kowalski O, Sredniawa B, Musialik-Lydka A, Gasior M, Polonski L, Zembala M, Gumprecht J, Kalarus Z.
J Interv Cardiol. 2007 20 (2): 143-52.
92. Myocardial ultrasound tissue characterization in patients with chronic renal failure.
Salvetti M, Muiesan ML, Paini A, Monteduro C, Bonzi B, Galbassini G, Belotti E, Movilli E, Cancarini G, Agabiti-Rosei E.
J Am Soc Nephrol. 2007 Apr 18, [Epub ahead of print].
IV. TREATMENT
1. Which optimal antihypertensive bitherapy for kidney patients?
Bonne JF, Shahapuni I, Mailliez S, Oprisiu R, Temmar M, Choukroun G, Massy ZA, Fournier A.
Nephrol Ther. 2007 3 (3): 79-88.
2. Proteinuria as a therapeutic target in patients with chronic kidney disease.
Palmer BF.
Am J Nephrol. 2007 27 (3): 287-93.
3. Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor.
Costa-Scharplatz M, van Asselt AD, Bachmann LM, Kessels AG, Severens JL.
Pharmacogenet Genomics. 2007 17 (5): 359-68.
4. No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy - - report from the ItalKid Project database
Ardissino G, Vigano S, Testa S, Dacco V, Paglialonga F, Leoni A, Belingheri M, Avolio L, Ciofani A, Claris-Appiani A, Cusi D, Edefonti A, Ammenti A, Cecconi M, Fede C, Ghio L, Manna AL, Maringhini S, Papalia T, Pela I, Pisanello L, Ratsch IM.
Nephrol Dial Transplant. 2007 May 25; [Epub ahead of print].
5. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria.
Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, Kirschstein M, Linne T.
J Am Soc Nephrol. 2007 18 (6): 1880-8.
6. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: A meta-analysis.
Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J.
Diabet Med. 2007 Mar 15; [Epub ahead of print].
7. Angiotensin-converting enzyme inhbitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease.
Beger AK, Duval S, Manske C, Vazquez G, Barber C, Miller L, Luepker RV.
Am Heart J. 2007 153 (6): 1064-73.
8. Toward better renoprotection: Lessons from angiotensin receptor blockers.
Miyata T, Takizawa S.
Hemodial Int. 2007 11 (2): 164-8.
9. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: Post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial.
Eijkelkamp WB, Zhang Z, Remuzzi G, Parving HH, Cooper ME, Keane WF, Shahinfar S, Gleim GW, Weir MR, Brenner BM, de Zeeuw D.
J Am Soc Nephrol. 2007 18 (5): 1540-6.
10. A randomized trial of the effect of statin and fibrate therapy on arterial function in CKD.
Dogra G, Irish A, Chan D, Watts G.
Am J Kidney Dis. 2007 49 (6): 776-85.
11. Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure.
Baber U, Toto RD, de Lemos JA.
Am Heart J. 2007 153 (4): 471-7.
12. The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: A pooled analysis of double-blind, randomized trials.
Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C, Isaacsohn J.
Int J Cardiol. 2007 117 (1): 64-74.
13. Statins use and hospitalization for sepsis in patients with chronic kidney disease.
Gupta R, Plantinga LC, Fink NE, Melamed ML, Coresh J, Fox CS, Levin NW, Powe NR.
JAMA. 2007 297 (13): 1455-64.
14. Effect of statins on contrast-induced nephropathy in patients with acute myocardial infarction treated with primary angioplasty.
Zhao JL, Yang YJ, Zhang YH, You SJ, Wu YJ, Gao RL.
Int J Cardiol. 2007 Apr 24; [Epub ahead of print].
15. Development, worsening, and improvement of diabetic microangiopathy in older people: Six-year prospective study of patients under intensive diabetes control.
Katakura M, Naka M, Kondo T, Komatsu M, Yamauchi K, Hashizume K, Aizawa T.
J Am Geriatr Soc. 2007 55 (4): 541-7.
16. Combined effect of pioglitazone and simvastatin on urinary liver-type fatty acid-binding protein concentration in diabetic patients with microalbuminuria.
Wei J, Ma C, Li YM.
Diabetologia. 2007 May 23; [Epub ahead of print].
17. The treatment of anemia in chronic kidney disease: Understandings in 2006.
Levin A.
Curr Opin Nephrol Hypertens. 2007 16 (3): 267-71.
18. Nononcologic use of human recombinant erythropoietin therapy in hospitalized patients.
Fischer MA, Morris CA, Winkelmayer WC, Avorn J.
Arch Intern Med. 2007 167 (8): 840-6.
19. Reengineering clinical operations in a medical practice to optimize the management of anemia of chronic kidney disease.
Joy MS, Candiani C, Vaillancourt BA, Chin H, Hogan SL, Falk RJ.
Pharmacotherapy. 2007 27 (5): 734-44.
20. Pyridoxal phosphate prevents progression of diabetic nephropathy.
Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T.
Nephrol Dial Transplant. 2007. Apr 20; [Epub ahed of print].
21. Nutrition assessment and hormonal influences on body composition in children with chronic kidney disease.
Graf L, Candelaria S, Doyle M, Kaskel F.
Adv Chronic Kidney Dis. 2007 14 (2): 215-23.
22. Effect of raloxifene - a selective oestrogen receptor modulator - on kidney function in post-menopausal women with type 2 diabetes: Results from a randomized, placebo-controlled pilot trial.
Hadjadj S, Gourdy P, Zaoui P, Guerci B, Roudaut N, Gautier JF, Chabin M, Mauco G, Ragot R; for the RADIAN (Raloxifene in Diabetic Nephropathy) Study Group.
Diabet Med. 2007 Apr 19; [Epub ahead of print].
23. Doxycycline: A pilot study to reduce diabetic proteinuria.
Naini AE, Harandi AA, Moghtaderi J, Bastani B, Amiran A.
Am J Nephrol. 2007 27 (3): 269-73.
24. Diabetes mellitus does not preclude stabilization or improvement of renal function after stent revascularization in patients with kidney insufficiency and renal artery stenosis.
Silva JA, Potluri S, White CJ, Collins TJ, Jenkins JS, Subramanian R, Ramee SR.
Catheter Cardiovasc Interv. 2007 69 (6): 902-7.
25. Are high-protein, vegetable-based diets safe for kidney function? A review of the literature.
Bernstein AM, Treyzon L, Li Z.
J Am Diet Assoc. 2007 107 (4): 644-50.
26. Effects of a supplemented hypoproteic diet in chronic kidney disease.
Mirescu G, Garneata L, Stancu SH, Capusa C.
J Ren Nutr. 2007 17 (3): 179-88.
27. AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney disease.
Ueda H, Shibahara N, Takagi S, Inoue T, Katsuoka Y.
Ther Apher Dial. 2007 11 (3): 189-95.
28. Nandrolone decanoate as anabolic therapy in chronic kidney disease: A randomized phase II dose-finding study.
Macdonald JH, Marcora SM, Jibani MM, Kumwenda MJ, Ahmed W, Lemmey AB.
Nephron Clin Pract. 2007 106 (3): c125-35.
29. Nutritional effect of nandrolone decanoate in predialysis patients with chronic kidney disease.
Eiam-Ong S, Buranaosot S, Eiam-Ong S, Wathanavaha A, Pansin P.
J Ren Nutr. 2007 17 (3): 173-8.
30. The potential for vitamin D receptor activation in cardiovascular research.
Wu-Wong JR.
Expert Opin Investig Drugs. 2007 16 (4): 407-11.
31. Biological therapies: New treatment options for ANCA-associated vasculitis?
Aries PM, Lamprecht P, Gross WL.
Expert Opin Biol Ther. 2007 (4): 521-33.
32. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis.
Metzler C, Miehle N, Manger K, Iking-Konert C, de Groot K, Hellmich B, Gross WL, Reinhold-Keller E.
Rheumatology (Oxford). 2007 May 22; [Epub ahead of print].
33. Membranous nephropathy: When and how to treat.
Lai KN.
Kidney Int. 2007 71 (9): 841-3.
34. Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: Higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs.
Goumenos DS, Katopodis KP, Passadakis P, Vardaki E, Laikopoulos V, Dafnis E, Stefanidis I, Vargemezis V, Vlachojannis JG, Siamopoulos KC.
Am J Nephrol. 2007 27 (3): 226-31.
35. Steroid-resistant idiopathic childhood nephrosis: Overdiagnosed and undertreated.
Ehrich JH, Geerlings C, Zivicnjak M, Franke D, Geerlings H, Gellermann J.
Nephrol Dial Transplant. 2007 May 15; [Epub ahead of print].
36. Does cyclosporine achieve a real advantage for treatment of idiopathic nephrotic syndrome in children? A long-term efficacy and safety study.
Sheashaa H, Mahmoud I, El-Basuony F, El-Husseini A, Hassan N, El-Baz M, Ahmed NS, Sobh M.
Int Urol Nephrol. 2007 Apr 20; [Epub ahead of print].
37. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.
Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V.
J Am Soc Nephrol. 2007 18 (6): 1899-904.
38. Plasma exchange combined with immunosuppressive treatment in a child with rapidly progressive IgA nephropathy.
Fujinaga S, Ohtomo Y, Umino D, Mochizuki H, Murakami H, Shimizu T, Yamashiro Y, Kaneko K.
Pediatr Nephrol. 2007 22 (6): 899-902.
39. Mycophenolate mofetil treatment for therapy-resistant glomerulopathies.
Sahin GM, Sahin S, Kantarci G, Ergin H.
Nephrology (Carlton). 2007 12 (3): 285-8.
40. Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial.
Praga M, Barrio V, Juarez GF, Luno J.
Kidney Int. 2007 71 (9): 924-30.
41. HIV-associated nephropathy in the era of antiretroviral therapy.
Wyatt CM, Klotman PE.
Am J Med. 2007 120 (6): 488-92.
42. The S1P modulator FTY720 limits matrix expansion acute anti-thy1 mesangioproliferative glomerulonephritis.
Martini S, Kramer S, Loof T, Wang-Rosenke Y, Daig U, Budde K, Neumayer HH, Peters H.
Am J Physiol Renal Physiol. 2007 Mar 13, [Epub ahead of print].
43. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study.
Chanan-Khan AA, Kaufman JL, Mehta J, Rishardson PG, Miller KC, Lonial S, Munshi NC, Schlossman R, Tariman J, Singhal S.
Blood. 2007 109 (6): 2604-6.
44. Endothelin-1 antisense oligonucleotide suppressess the proliferation of glomerular mesangial cells stimulated with angiotensin-II.
Lee JJ, Shin SJ, Chiu YW, Chen HC.
Kaohsiung J Med Sci. 2007 23 (4): 170-5.
45. Glucose responsive insulin production human embryonic germ (EG) cell derivatives.
Clark GO, Yochem RL, Axelman J, Sheets TP, Kaczorowski DJ, Shamblott MJ.
Biochem Biophys Res Commun. 2007 356 (3): 587-93.
46. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes.
Kunter U, Rong S, Boor P, Eitner F, Muller-Newen G, Djuric Z, van Roeyen CR, Konieczny A, Ostendorf T, Villa L, Milovanceva-Popovska M, Kerjaschki D, Floege J.
J Am Soc Nephrol. 2007 18 (6): 1754-64.
47. Prevention of contrast-induced nephropathy in the Emergency Department.
Sinert R, Doty CI.
Ann Emerg Med. 2007 May 17; [Epub ahead of print].
48. The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention: The RENO study.
Recio-Mayoral A, Chaparro M, Prado B, Cozar R, Mendez I, Banerjee D, Kaski JC, Cubero J, Cruz JM.
J Am Coll Cardiol. 2007 49 (12): 1283-8.
V. TRANSPLANTATION
1. Renal pathology in the pediatric transplant patients.
Vogler C, Wang Y, Brink DS, Wood E, Belsha C, Walker PD.
Adv Anat Pathol. 2007 14 (3): 202-16.
2. 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 22 (6): 1720-9.
3. Chronic renal failure in kidney transplant recipients. Do they receive optimum care? Data from the UK renal registry.
Ansell D, Udayaraj UP, Steenkamp R, Dudley CR.
Am J Transplant. 2007 7 (5): 1167-76.
4. Diurnal blood pressure changes one year after kidney transplantation: Relationship to allograft function, histology, and resistive index.
Wadei HM, Amer H, Taler SJ, Cosio FG, Griffin MD, Grande JP, Larson TS, Schwab TR, Stegall MD, Textor SC.
J Am Soc Nephrol. 2007 18 (5): 1607-15.
5. Association of functional heme oxgenase-1 gene promoter polymorphism with renal transplantation outcomes.
Courtney AE, McNamee PT, Middleton D, Heggarty S, Patterson CC, Maxwell AP.
Am J Transplant. 2007 7 (4): 908-13.
6. The impact of living donor kidney transplantation on markers of cardiovascular risk in chronic kidney disease patients.
Bignelli AT, Barberato SH, Aveles P, Abensur H, Pecoits-Filho R.
Blood Purif. 2007 25 (3): 233-41.
7. Time-dependent changes in cardiac growth after kidney transplantation: The impact of pre-dialysis ventricular mass.
Hernandez D, Gonzalez A, Rufino M, Laynez I, Rosa AD, Porrini E, Lacalzada J, Barragan A, Lorenzo V, Torres A.
Nephrol Dial Transplant. 2007 May 17; [Epub ahead of print].
8. Prevalence and determinants of coronary and aortic calcifications assessed by chest CT in renal transplant recipients.
Nguyen PT, Coche E, Goffin E, Beguin C, Vlassenbroek A, Devuyst O, Robert A, Jadoul M.
Am J Nephrol. 2007 27 (4): 329-35.
9. Pseudotumor of gout in the patella of a kidney transplant recipient.
Staub-Zahner T, Garzoni D, Fretz C, Lampert C, Ohlschlegel C, Wuthrich RP, Fehr T.
Nat Clin Pract Nephrol. 2007 3 (6): 345-9.
10. Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosupression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.
Flechner SM, Goldfarb D, Solez K, Modlin CS, Mastroianni B, Savas K, Babineau D, Kurian S, Salomon D, Novick AC, Cook DJ.
Transplantation. 2007 83 (7): 883-92.
11. Combination therapy with ribavirin and amantadine in renal transplant patients with chronic hepattitis C virus infection is not superior to ribavirin alone.
Calanca LN, Fehr T, Jochum W, Fischer-Vetter J, Mullhaupt B, Wuthrich RP, Ambuhl PM.
J Clin Virol. 2007 39 (1): 54-8.
12. Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low-dose cyclosporine A.
Pape L, Ahlenstiel T, Ehrich JH, Offner G.
Pediatr Transplant. 2007 11 (3): 291-5.
13. Sirolimus is not always responsible for new-onset proteinuria after conversion for chronic allograft nephropathy.
Abdurrahman Z, Sarwal M, Millan M, Robertson S, Filler G.
Pediatr Transplant. 2007 11 (3): 336-9.
14. Treatment of patients with chronic hepatitis C before and after renal transplantation.
Tornai I, Matyus J.
Orv Hetil. 2007 148 (11): 489-94.
15. Posttransplant prophylactic intravenous immunoglobulin in kidney transplant patients at high immunological risk: A pilot study.
Anglicheau D, Loupy A, Suberbielle C, Zuber J, Patey N, Noel LH, Cavalcanti R, Le Quintrec M, Audat F, Mejean A, Martinez F, Mamzer-Bruneel MF, Thervet E, Legendre C.
Am J Transplant. 2007 7 (5): 1185-92.
16. Management of growth retardation in pediatric recipients of renal allografts.
Fine RN.
Nat Clin Pract Nephrol. 2007 3 (6): 318-24.
17. Use of rhGH in children with chronic kidney disease: Lessons from NAPRTCS.
Seikaly MG, Salhab N, Warady BA, Stablein D.
Pediatr Nephrol. 2007 May 25; [Epub ahead of print].
18. Early withdrawal of calcineurin inhibitors and rescue immunosuppression with sirolimus-based therapy in renal transplant recipients with moderate to severe renal dysfunction.
Wali RK, Mohanlal V, Ramos E, Blahut S, Drachenberg C, Papadimitriou J, Dinits M, Joshi A, Philosophe B, Foster C, Cangro C, Nogueira J, Cooper M, Bartlett ST, Weir MR.
Am J Transplant. 2007 7 (6): 1572-83.
19. Impact of NOD2/CARD15 haplotypes on the outcome after kidney transplantation.
Kruger B, Boger CA, Schroppel B, Obed A, Hoffmann U, Murphy BT, Fischereder M, Holler E, Banas B, Kramer BK.
Transpl Int. 2007 May 10; [Epub ahead of print].
20. Distribution of donor-specific antibodies in the cortex and the medulla of renal transplants with chronic allograft nephropathy.
Bocrie O, Hussein Aly AA, Guignier F, Funes de la Vega M, Rifle G, Mousson C, Martin L.
Transpl Immunol. 2007 17 (3): 227-9.
21. Thickening of the peritubular capillary basement membrane is a useful diagnostic marker of chronic rejection in renal allografts.
Aita K, Yamaguchi Y, Horita S, Ohno M, Tanabe K, Fuchinoue S, Teraoka S, Toma H, Nagata M.
Am J Transplant. 2007 7 (4): 923-9.
22. Evaluating the accuracy of functional biomarkers for detecting histological changes in chronic allograft nephropathy.
Yilmaz S, Isik I, Afrouzian M, Monroy M, Sar A, Benediktsson H, McLaughlin K.
Transpl Int. 2007 May 22; [Epub ahead of print].
23. Nephrology: Renal transplantation.
Ott U, Steiner T, Schubert J, Wolf G.
Med Klin (Munich). 2007 102 (3): 219-29.
24. Cigarette smoking and chronic allograft nephropathy.
Zitt N, Kollerits B, Neyer U, Mark W, Heininger D, Mayer G, Kronenberg F, Lhotta K.
Nephrol Dial Transplant. 2007 May 21; [Epub ahead of print].
25. Efficiency of rituximab treatment for recurrence of membranous glomerulopathy after renal transplantation.
Weclawiak H, Ribes D, Modesto A, Kamar N, Durand D, Rostaing L.
Nephrol Ther. 2007 3 (2): 65-8.
26. Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosuppression.
Gera M, Griffin MD, Specks U, Leung N, Stegall MD, Fervenza FC.
Kidney Int. 2007 Apr 4; [Epub ahead of print].
27. Polyomavirus-associated nephropathy risk in kidney transplants: The influence of recipient age and donor gender.
Khamash HA, Wadei HM, Mahale AS, Larson TS, Stegall MD, Cosio FG, Griffin MD.
Kidney Int. 2007 Apr 4, [Epub ahead of print].
28. Cross-sectional study of BK virus infection in pediatric kidney transplant recipients.
Fogeda M, Munoz P, Luque A, Morales MD, Bouza E; The BKV Study Group.
Pediatr Transplant. 2007 11 (4): 394-401.
29. Polyomavirus BK-specific cellular immune response to VP1 and large T-anigen in kidney transplant recipients.
Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, Hirsch HH.
Am J Transplant. 2007 7 (5): 1131-9.
30. Human polyomavirus type 1 (BK virus) agnoprotein is abundantly expressed, but immunological ignored.
Leuenberger D, Andresen PA, Gosert R, Binggeli S, Strom EH, Bodaghi S, Rinaldo CH, Hirsch HH.
Clin Vaccine Immunol. 2007 May 30; [Epub ahead of print].
31. Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy.
Bracamonte E, Leca N, Smith KD, Nicosia RF, Nickeleit V, Kendrick E, Furmanczyk PS, Davis CL, Alpers CE, Kowalewska J.
Am J Transplant. 2007 7 (6): 1552-60.
32. BK virus infection, replication, and diseases in pediatric kidney transplantation.
Acott PD, Hirsch HH.
Pediatr Nephrol. 2007 Mar 22; [Epub ahead of print].
33. BK virus subtype IV nephropathy occuring 5 years after kidney transplantation.
Takayama T, Suzuki K, Otsuka A, Furuse H, Mugiya S, Ushiyama T, Han G, Miura K, Horii T, Ozono S.
Clin Exp Nephrol. 2007 11 (1): 102-6.
34. Ureteric and urethral stenosis: A complication of BK virus infection in a pediatric renal transplant patient.
Rajpoot DK, Gomez A, Tsang W, Shanberg A.
…
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 between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: Case-control, haplotype, and family-based study in three European populations.
Hadjadj S, Tarnow L, Forsblom C et al.
J Am Soc Nephrol. 2007 18 (4): 1284-91.
Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [< / = 15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed 244 trios with DN probands and 228 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/Deletion (I/D or rs 1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homgeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmissionto DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN: these findings were no confirmed in a family based association study. This study population is suitable to search for additional candidate genes for DN.
2. Resequencing of genes for transforming growth factor beta1 (TGFB1) type 1 and 2 receptors (TGFBR1, TGFBR2), and association analysis of variants with diabetic nephropathy.
McKnight AJ,Savage DA, Patterson CC et al.
BMC Med Genet. 2007 Feb 23; [Epub ahead of print].
Background Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemilogical evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFbeta1) is a crucial mediator in the pathogenesis of diabetic nephropathy. Methods We investigated the role of five known single nucleotide polymophisms (SNPs) in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272) control (n = 367) collection. The activity of TGFbeta1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2) shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVEtrade mark (dHPLC) technology and confirmed variants by direct capillary sequencing. Allele frequencies determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the chi2 test for contingency tables. Patterns of linkage disequilibrium were estabilished and common haplotypes estimated. Results Fifteen variants were identified in these genes, seven of wich are novel, and putatively functional SNPs were subsequently genotyped using TaqMantrade mark, Invadertrade mark or Pyrosequencing (R) technology. No significant differences (p > 0.1) were found in genotype or allele distributions between cases and controls for any of the SNPs assessed. Conclusion Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population.
3. Association of TGFbeta1, TNFalpha, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians.
Prasad P, Tiwari AK, Kumar KM et al.
BMC Med Genet. 2007 Apr 12; [Epub ahead of print].
Background Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor beta1 (TGFbeta1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFalpha), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediated macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFbeta1, TNFalpha1, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency. Methods Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine > or = 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration > or = 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFbeta1, TNFalpha1, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence interval (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed. Results SNPs Tyr81His and Thr263Ile in TGF beta1 gene were monomorphic, and Arg25Pro in TGF beta1 gene and Delta32 polymorphism in CCR5 gene were minor variants (minor allele frequency < 0.05) and therefore were not considered for case-control analysis. A significant allelic association of 59029>A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04-1.84). In CRI subjects a compound group of genotypes ’’GA and AA” of SNP G>A -800 was found fo confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08-8.50, p = 0.035). Conclusion Of the varoius cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted.
4. Study on the mitochondrial DNA variation in patients with type 2 diabetes mellitus.
Ji J, Lu J, Ye W et al.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 24 (2): 167-72.
Objective To explore the relationship between type 2 diabetes mellitus (T2DM) and the mutations in the fragment of mitochondrial DNA (mtDNA) from nucleotides 3153 to 3551, which have shown high frequency of point mutation. Methods One hundred and ninety-one normal controls and 222 patients with T2DM were screened by polymerase chain reaction-restriction fragment lenght polymorphism (PCR-RFLP), T-A cloning sequencing and denaturated high performance liquid chromatography (DHPLC) techniques. Results The prevalence of mtDNA mutations in the patients group (24.32%) was significantly higher than that in the control group (7.33%) (P < 0.05). Three novel mutations of A3209T, T3253G and A3467C were found, and C3497T was first reported in DM. Onset age, body mass index, fasting blood glucose, HbA1c, high density lipoprotein-cholesterol and diabetic nephropathy could be related to occurence of mtDNA mutations (P < 0.05). Conclusion Mitochondrial DNA mutations might implicate T2DM in Wenzhou population, which should play an important role in the pathogenesis of T2DM.
5. Early chronic kidney disease in Aboriginal and non-Aboriginal Australian children: Remoteness, socioeconomic disadvantage or race?
Haysom L, Williams R, Hodson E et al.
Kidney Int. 2007 Feb 21; [Epub ahead of print].
Indigenous people suffer substantially more end-stage kidney disease (ESKD), especially Australian Aboriginals. Previous work suggests causal pathways beginning early in life. No studies have shown the prevalence of early markers of chronic kidney disease (CKD) in both Indigenous and non-Indigenous children or the association with environmental health determinants - geographic remoteness and socioeconomic disadvantage. Height, weight, blodd pressure, and urinary abnormalities were measured in age- and gender matched Aboriginal and non-Aboriginal children from elementary schools across diverse areas of New South Wales, Australia. Hematuria was defined as >/ = 25 red blood cells/mul (>/= 1+), proteinuria >/= 0.30 g/l (>/= 1+), and albuminuria (by albumin:creatinine) >/= 3.4 mg/mmol. Remoteness and socioeconomic status were assigned using the Accessibility and Remoteness Index of Australia and Socio-Economic Indexes For Areas. From 2002 to 2004, 2266 children (55% Aboriginial, mean age 8.9 years) were enrolled from 37 elementary schools. Overall prevalence of hematuria was 5.5%, proteinuria 7.3%, and albuminuria 7.37.3%. Only baseline hematuria was more common in Aboriginal children (7.1 versus 3.6%; P = 0.002). At 2-year follow up, 1.2% of Aboriginal children had persistent hematuria that was no different from non-Aboriginal children (P = 0.60). Socioeconomic disadvantage and geographical isolation were neighter significant nor consistent risk factors for any marker of CKD. Aboriginal children have no increase in albuminuria, proteinuria, or persistent hematuria, which are more important markers for CKD. This suggest ESKD in Aboriginal people may be preventable during early adult life.
6. Epidemiology of renal disease in children in the region of Southern Croatia: A 10-year review of regional renal biopsy databases.
Bazina M, Glavina-Durdov M, Scukanec-Spoljar M et al.
Med Sci Monit. 2007 13 (4): CR172-6.
Background Epidemiological data on some renal diseases in children are available from world national registries of renal biopsies. However, ther is not published study of biopsy-proven childhood glomerulonephritis in Croatia. This report is the first review of pathohistological data covering a pediatric population over a 10-year period in the Croatian region of Dalmatia. Material/Methods A retrospective study was done on all renal biopsies from 65 chidren under 18 years of age received by the Clinical Hospital Split between 1995 and 2005. The histopathological findings were reviewed the pattern of biopsy-proven glomerulonephritis. Indications for renal biopsy and clinico-pathological correlations were studied. Data on serum creatinine concentration, 24-h proteinuria, hematuria, clinical diagnosis, pathohistological diagnosis, and post-biopsy complications were collected. Results The main indications for biopsy were nephrotic syndrome (41.5%), hematuria with proteinuria (23.1%), and isolated hematuria (12.3%). The most frequent renal disease in decreasing order were mesangioproliferative glomerulonephritis (27.7%), IgA nephropathy (13.8%), and Henoch-Schonlein nephritis (10.8%). Tubulointerstitial nephritis, focal segmental glomerulosclerosis, and endoproliferative glomerulonephritis each accounted for 6.2%. Alport syndrome, fibrillary glomerulonephritis, and minimal change disease were each found in 4.6% of cases. Other forms of glomerulonephritis were rarely found. Conclusions The present data represent the basis for a future Croation registry of Renal Biopsies and are an important contribution to the epidemiology of renal disease in south-eastern Europe. Three cases of fibrillary glomerulonephritis in children with steroid-dependent nephrotic syndrome, not reported other countries’ registries, were also found. The importance of ultrastructural analysis of biopsy specimens is emphasized.
7. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population - - the Ohasama study.
Nakayama M, Metoki H, Terawaki H et al.
Nephrol Dial Transplant. 2007 Mar 29, [Epub ahead of print].
Background Chronic kidney disease (CKD) has been shown to be a risk factor for mortality as well as for morbidity such as cardiovascular disease (CVD) in the general population. However, in the context of CVD events, there is a differencein the incidence of cardiac and stroke events between Western and Asian populations. Although a high prevalence of stroke is a characteristic feature in Japanese populations, it is unclear whether CKD constitutes a risk for stroke events. Methods To clarify this issue, we estimated creatinine clearence and obtain dipstick test from spot-urine samples in 1977 subjects (mean 62.9-years-old, men/women: 731/1246) from a general Japanese population. First symptomatic stroke events and all-cause mortality were analysed according to stratification of kidney function and by positive test for macroalbuminuria using a Cox proportional hazards regression model adjusted for possible confounding factors. Results During the observation period (mean 7.76 years), we recorded 112 events of first symptomatic stroke and 187 deaths (58 cases due to CVD). After adjusment for all variables, we found that increases in relative hazard (RH) for the first symptomatic stroke events were associated with decreasing kidney function (RH, 3.1; 95% CI, 1,24-7.84 in Ccr < 40 ml/min, 1.9; 95% CI, 1.06-3.75 in Ccr 40-70 ml/min, ref in Ccr > 70 ml/min) and with the presence of macroalbuminuria (RH, 1.4; 95% CI, 0.80-2.41). Conclusion Decreased kidney function increased the risk of first symptomatic stroke events in a general Japanese population. The high prevalence of stroke in this population prompts the need for greater public awareness about risks for CKD.
8. Epidemiologic and clinical factors associated with chronic kidney disease among Asian Americans and Native Hawaiians.
Mau MK, West MR, Shara NM et al.
Ethn Health. 2007 12 (2): 111-27.
Objective To examine the association between key susceptibility factors and measures of chronic kidney disease in Asian American and Native Hawaiian participants enrolled in the Hawai’i site of the national Kidney Early Evaluation Program (KEEP-2) study community screening program. Design In 2001-2003, 793 participants from five ethnic groups (Japanese, Native Hawaiian, Chinese, Filipino and Caucasian) were enrolled in the Hawai’i KEEP-2 program. Odds ratios were used as the measure of association and were computed using unconditional logistic regression. Renal susceptibility factors for chronic kidney disease were included in a multivariable model if found to be statistically significant in univariate analysis. The proportion of Hawi’i KEEP-2 study participants manifesting various clinical caracteristics were compared by ethnicity with Japanese as the referent group. Results Significant ethnic differences in the occurence of chronic kidney disease were found, with Japanese having the lowest occurence of chronic kidney disease (18%) and Native Hawaiians the highest (40%). Within each ethnic group, the occurence of chronic kidney disease was associated with a different ethnic-specific clustering of susceptibility factors. Hypertension was associated with chronic kidney disease among four of the five ethnic groups: Japanese, Caucasians, Native Hawaiian and Filipino. Overweight was associated with a decreased occurence of chronic kidney disease among Caucasians, while diabetes and lower educational attainment were associated with increased occurence of chronic kidney disease among Native Hawaiians. For Filipinos, diabetes and age 65 years and older were both associated with an increased occurence for chronic kidney disease while lower ediucational attainment was associated with a reduced occurence of chronic kidney disease. Among Chinese, no factors were significantly associated with chronic kidney disease, although trends for all factors paralleled those of the overall study group. Conclusions The occurence of chronic kidney disease in the Hawai’i KEEP-2 study was nearly fourfold greater compared with the general US population. The clustering of susceptibility factors for chronic kidney disease occurence was found to differ for all five ethnic groups.
9. Prevalence and characteristics of a family history of end-stage renal disease among adults in the United States population: Reasons for Geographic and Racial Differences in Stroke (REGARDS) renal Cohort Study.
McClellan W, Speckman R, McClure L et al.
J Am Soc Nephrol. 2007 18 (4): 1344-52.
This reports desscribes the prevalence and characteristics of people with a family history of ESRD in a first-degree relative (FH-ESRD). This is a cross-sectional study of individuals in the Reason for Geographic and Racial Difference in Stroke (REGARDS) cohort, a population-based sample of US residents who are 45 yr and older. FH-ESRD was ascertained at baseline among 12.030 participants of the cohort, and multivariate logistic regression was used to identify characteristics that were independently associated with FH-ESRD. FH-ESRD was reported by 9.5% of participants. Individual characteristics that were independently associated with FH-ESRD included black race (odds ratio [OR] 2.14; 95% confidence interval [CI] 1.82 to 2.53); female gender (OR 1.28, 95% CI 1.08 to 1.51);a history of diabetes (OR 1.22; 95% CI 1.02 to 1.47); a 1-SD change in the log of the C-reactive protein level (OR 1.10; 95% CI 1.01 to 1.19); and World Health Organization body mass index weight categories normal (OR 2.11; 95% CI 0.66 to 6.79), overweight (OR 2.64, 95% CI 0.82 to 8.42), and obese (OR 3.48 95% CI 1.09 to 11.1) compared with underweight. Black but not white individuals with FH-ESRD were more likely to have an estimated GFR < 60 ml/min per 1.73 m (2). There is a high prevalence of FH-ESRD among US adults, and the prevalence of FH-ESRD was higher among black individuals. Individuals with a positive family history were more likely to have diabetes and to be obese. If confirmed, then these findings suggest that individuals with FH-ESRD may benefit from interventions to improve the detection and treatment of chronic kidney disease risk factors such as diabetes and obesity.
10. Kidney disease mortality - - Michigan, 1989-2005.
Centers for Disease Control and Prevention (CDC).
MMWR Morb Mortal Wkly Rep. 2007 56 (10): 225-7.
Kidney disease was the ninth leading cause of death in Michigan in 2005 and in the United States in 2004. In 2004, the incidence rate for kidney failure (i.e., end-stage renal disease) was higher in Michigan than in the United States (365 versus 353 per 1 million population). A total of 3.695 Michigan residents started treatment (i.e., dialysis or transplant) for kidney failure in 2004; by the end of that year, 11.002 Michigan resident were receiving dialysis, and 614 had received a transplant. Many of these persons had a diagnosis of diabetes (40%) or hypertension (30%) as the primary cause of kidney failure. To examine recent trends in kidney disease mortality, the Michigan Department of Community Health (MDCH) analyzed vital statistics data from the period 1989 - - 2005. This report describes the results of that analysis, which indictaed that kidney disease mortality is growing public health problem in Michigan and that blacks were more likely than whites to die from kidney disease. Continued disease-prevention and health-promotion activities, including targeted interventions among populations at greatest risk, are needed by MDCH and other organizations to reduce the burden of kidney disease in Michigan.
11. Cause and consequences of chronic kidney disease: Implications for managed health care.
Weiner DE.
J Manag Care Pharm. 2007 13 (3): 1-9.
Background Chronic kidney disease (CKD) is a major public health problem that often goes unrecognized until late-stage disease. In the United States, nearly 20 million people have CKD, and this number is likely to grow as the population ages and the prevalence of diabetes and hypertension rises. With $28 billion currently spent on end-stage renal disease care in the United States and with the rapidly expanding dialysis population, it is essential to actively address this epidemic, both by reducing the number of patients who reach kidney failure and by decreasing morbidity and mortality among those with early-stage CKD. Objective To review the burden of CKD and its comorbidities on patients, physicians, and payers and discuss the potential benefits to individual patients and society of identifying and treating earlier stages of CKD. Conclusion Major steps in dealing with the CKD epidemic are (1) identifying at risk for and with earlier stages of CKD, (2) initiating therapies to slow progression of kidney disease, and (3) treating comorbid conditions associated with CKD, including cardiovascular disease and anemia.
12. Wgener’s granulomatosis in New Zealand: Evidence for a latitude-dependent incidence gradient.
O’Donnell JL, Stevanovic VR, Frampton C et al.
Intern Med J. 2007 37 (4): 242-6.
Background The aim of the study was to determine whether there was evidence for a geographic gradient in the incidence of Wegener’s granulomatosis (WG) and WG-like disease in New Zealand (NZ). Methods The National Minimum Dataset of the Ministry of Health, NZ was searched for individual patient discharges coded by the International Classification of Disease 10th Revision, Australian Modification as either M301 (polyarteritis with lung involvement, including Churg Strauss and allergic granulomatous angiitis) or M313 (WG, necrotizing respiratory grnulomatosis) for the period 1 January 1999 to 31 December 2003. Data were standardized using the 2001 NZ census. Results One hundred and ninety-five patients (95) men) were given a first-time discharge code of either M301 (40 patients) or M313 (155 patients). No gender bias was seen. The rate among Europeans was twice that of NZ Maoris or Asians. The rate of disease peaked in the age band 70-79 years and during winter months. A significant positive north-south geographic gradient was present for M313. No difference in the rate of readmission or time to relapse between geographic regions was found for M313. Conclusion A north-south gradient in the rate of patients discharges given a diagnostic code of M313 (WG, necrotizing respiratory granulomatosis) was present in NZ. This finding supports the hypothesis that there is a latitude-dependent risk factor (s) for WG possibly common to both global hemispheres.
13. Community-based screening for chronic kidney disease among populations older than 40 years in Beijing.
Zhang L, Zuo L, Xu G et al.
Nephrol Dial Transplant. 2007 22 (4): 1093-9.
Background Chronic kidney disease (CKD) is a public health problem, while data from developing countries are limited. We sought to investigate the epidemiological features of kidney damage in metropolis-residing Chinese adults (> 40 years old), an to determine the associated factors of CKD. Methods Two thousand three hundred and fifty-three residents in on district of Beijing were interviewed and tested for albuminuria, reduced renal function, haematuria and pyuria. The associations between demographic characteristics, health characteristics and indicators of kidney damage were examined. Results Albuminuria was detected in 6.2% of subjects; reduced renal function was found in 5.2% of subjects; haematuria was found in 0.8% and non-infective pyuria was found in 0.09%. Approximately, 11,3% (95% confidence interval: 10.0 - 12.8%) of subjects had at least one indicator of kidney damage. The awareness rate of CKD was only 7.2%. systolic blood pressure and diabetes were independently associated with albuminuria. Age, diastolic blood pressure, hypercholesteraemia, hypertriglyceridaemia and hyperuricaemia were independently associated with reduced renal function. Conclusions This is the first report on the prevalence of CKD in a community-based population within a developing country, determined using protocols recommended by kidney disease improving global outcomes (KDIGO). The prevalence of CKD in our population was close to the levels observed in developed countries, and the spectrum of CKD and associated factors were similar to developed countries. Results from this study suggest that strategies aimed at an intervention of hypertension and other metabolic disorders might prove effective in controlling the pandemic of CKD in China, as well as other developing countries.
14. Prevalence of Balkan endemic nephropathy has not changed since 1971 in the Kolubara region in Serbia.
Bukvic D, Maric I, Arsenovic A et al.
Kidney Bood Press Res. 2007 30 (2): 117-23.
Background/Aims Thirty-one years after the first cross-sectional study, the population of Vreoci, a Balkan endemic nephropathy (BEN) village, was reinvestigated in order to determine the current prevalence of BEN and the clinical and laboratory characteristics of BEN family members with detected signs of kidney disease. Methods A total of 2.009 inhabitans (82% of the adult population) of the village were examined. Danilovic’s criteria were used for diagnosis and classification of BEN. Results The prevalence of BEN (1.70%) was similar to that in 1971 (1.67%). Diagnosis was established in 19 BEN family membres, suspected BEN in 23, proteinuria in 29, while 16 healthy members were examined as controls. Urine protein, alpha1-microglobulin levels and frequency of glucosuria were significantly higher and kidney lenght significantly smaller in the three patients groups than in healthy persons. Serum urea and creatinine levels were significantly higher, but creatinine clearence was lower in BEN and BEN suspected patients than in the other two groups. Conclusion The prevalence of BEN remains stable over time in Vreoci village. Manifested disease was found in both BEN and BEN suspected patients. In persons with proteinuria but not enough criteria for BEN, tubular disorders and hypertension were frequently found.
15. Country as the primary risk factor for renal amyloidosis in familial mediterranean fever.
Touitou I, Sarkisian T, Medlej-Hashim M et al.; International Study Group for Phenotype-Genotype Correlation in Familial Mediterranean Fever Members of the International Study Group for Phenotype-Genotype Correlation in FMF are shown in Appendix A.
Arthritis Rheum. 2007 56 (5): 1706-12.
Objective Familial mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibilty in FMF by determining the relative contributions of MEFV and numerous epiemiologic factors to the risk of renal amyloidosis. Methods Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2.482 cases, including 260 patients who developed renal amyloidosis). Results Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. Conclusion Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient’s country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous.
16. Genome-wide scans for diabetic nephropathy and albuminuria in multi-ethnic populations: The Family Investigation of Nephropathy and Diabetes.
Iyengar SK, Abboud HE, Goddard KA et al.
Diabetes. 2007 Mar 15; [Epub ahead of print].
The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy (DN). Eleven centers participated under a single collection protocol to recruit large number of diabetic sib pairs concordant and discordant for DN. We report the findings from the first phase genetic analyses in 1.227 participants from 378 pedigrees of European American, African American, Mexican American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for DN in 397 sib pairs, as well as the quantitative trait urine albumin:creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the trait DN was chromosomes 7q21.3, 10p15.3, 14q23.1 and 18q22.3. In ACR (883 diabetic sibpairs), the strongest linkage signals were on chromosome 2q14.1, 7q21.1 and 15q26.3. These results confirm regions of linkage to DN on chromosomes 7q, 10p, and 18q from prior reports, marking it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likey to accelerate the identification of genes causing DN, a life-threatening complications of diabetes mellitus.
17. Racial differences in trends of end-stage renal disease, by primary diagnosis - - United States, 1994 - 2004.
Centers for Disease Control and Prevention.
MMWR Morb Mortal Wkly Rep. 2007 56 (11): 253-6.
The leading cause of end-stage renal disease (ESRD) (i.e. kidney failure requiring dialysis or transplantation) in the United States is diabetes, followed by hypertension and glomerulonephritis. These three conditions accounted for approximatelly 80% of new cases of ESRD treated during 2004. This report presents an analysis of data from United States Renal Data System (USRDS) to examine trends in the primary diagnosis of ESRD in the United States. The findings of that analysis indicated that, during 1994-2004, ESRD incidence attributed to glomerulonephritis decreased among all races analyzed. During 1999-2004, ESRD incidence attributed to diabetes or hypertension also decreased for American Indians/Alaska Natives (AI/Ans) and Asians/Pacific Islanders (A/PIs) but not for whites or blacks. Continued interventions, such as those addressing blood-glucose and blood-pressure control, are needed to reduce the prevalence of these risk factors for kidney failure and to improve care among persons with these conditions.
18. SCreening for Occult REnal Disease (SCORED): A simple prediction model for chronic kidney disease.
Bang H, Vuppurti S, Shoham DA et al.
Arch Intern Med. 2007 167 (4): 374-81.
Background Despite the wide availability and low cost of serum creatinine measurement, at-risk populations are not routinely tested for chronic kidney disease (CKD). Methods We used a cross-sectional analysis of a nationally representative, population-based survey to develop a system, SCORED (Screening for Occult Renal Disease), that uses routinely available demographic and medical information to identify individuals with an increased likelihood of CKD. The analysis included 8530 adult participants in the National Health and Nutrition Examination Surveys conducted from 1999 to 2002 in the United States. Chronic kidney disease was defined as a glomerular filtration rate less than 60 mL/min per 1.73 m (2). Univariate and multivariate associations between a comprehensive set of risk factors and CKD were examined to develop a prediction model. The optimal characteristics of the model were examined with internal measures. External validation was performed using the Atherosclerosis Risk in Communities study. A model-based numeric scoring system was developed. Results Age (P < .001), female sex (P = .02), and various health conditions (hypertension [P = .03], diabetes [P = .03], and peripheral vascular disease [P = .008]; history of cardiovascular disease [P = .001] and congestiv heart failure [P = .04]; and proteinuria [P < .001] and anemia [P = .003]) were associated with CKD. The multivariate model was well validated in the internal and external data sets (area under the receiver operating characteristic curve of 0.88 and 0.71, respectively). A score of 4 greater was chosen by internal validation as a cutoff point for screening based on the diagnostic characteristics (sensitivity, 92%; specificity, 68%; positive predictive value, 18%; and negative predictive value, 99%). Conclusion This scoring system, weighted toward common variables associated with CKD, may be a useful tool to identify individuals with a high likelihood of occult kidney disease.
19. Use of albumin creatinine ratio and urine albumin concentration as a screening test for albuminuria in an Indo-Asian population.
Jafar TH, Chaturvedi N, Hatcher J et al.
Nephrol Dial Transplant. 2007 Apr 3; [Epubahead of print].
Background Albuminuria (> 30 mg/day) based on 24 h urine albumin excretion is one of the criteria for chronic kidney disease (CKD) and a predictor of cardiovascular disease (CVD). Differences in urine albumin concentration and creatinine excretion rates between Indo-Asians and other populations may require different threshold values for detection of albuminuria. We compared the use of spot urine albumin concentration and urine albumin to creatinine excretion ratio for detection of albuminuria in this population. Methods A total of 577 subjects aged >/= 40 years, 54% of whom were women, were recruited from the general population in Karachi, Pakistan. Albumin concentration (mg/l) and albumin to creatinine ratio (mg/g of creatinine) were determined in a spot morning urine sample, and albuminuria (30 mg/day or greater) measured in a 24 h urine collected on subsequent day. Results The median (25-75 parcentile) of urine albumin excretion was 4.8 (3.6-10.3) mg/day> 5.4 (3.7-12.5) mg/day in men and 4.5 (3.8-8.9) mg/day in women. The overall prevalence (95% CI) of albuminuria was 11.8% (7.2-12.0%): 14.8% in men and 9.2% in women (P = 0.04). The areas under the receiver operator characteristic (ROC) curves for urine albumin concentration were 0.86 (0.82-0.90) and 0.88 (0.84-0.92), respectively, in women and men). The areas under the ROC curves for albumin to creatinine ratio were 0.86 (0.82-0.89) and 0.90 (0.86-0.93), respectively, in women and men. For urine albumin concentration, the sensitivity and specificity were 37 and 97%, respectively, in women and 69 and 94%, respectively, in men at the conventionally recommended value of 2 mg/dl. The discriminator value of urine albumin concentration identified in the analysis was 0.5 mg/dl in women (sensitivity of 87% and specificity of 75%) and 1.7 mg/dl in men (sensitivity of 74% and specificity of 93%). For the albumin to creatinine ratio, the sensitivity and specificity were 46% and 95%, respectively, in women and 60% and 97%, respectively, in men at cut-off value of 30 mg/g. Conclusion Both urine albumin concentration and albumin to creatinine ratio are acceptable tests for population screening for albuminuria in Indo-Asians. While sensitivities may be suboptimal, particularly in women, lowering the existing thresholds would compromise specificity. Those who screen positive need evaluation and management of CKD and prevention of CVD.
20. A population-based, prospective study of blood pressure and risk for end-stage renal disease in China.
Reynolds K, Gu D, Muntner P et al.
J Am Soc Nephrol. 2007 May 2; [Epub ahead of print].
The association between BP and risk for ESRD has not been well characterized in Asian populations. This study examined the relationship between level of BP and incidence of ESRD in a prospective cohort study of 158.365 Chinese men and women who were 40 yr and older. Measurement of BP and covariables were made in 1991 following a standard protocol. Follow-up evaluations were conducted in 1999 to 2000 and included interviewing participants or proxies and obtaining medical records and death certificates for ESRD cases. During 1.236.422 person-years of follow-up, 380 participants iniciated renal replacement therapy or died from renal failure (30.7 cases per 100.000 person-years). Compared those with normal BP, the multivariate adjusted hazard ratios (95% confidence interval) of all-cause ESRD for prehypertension and stage 1 and stage 2 hypertension were 1.30 (0.98 to 1.74), 1.47 (1.06 to 2.06), and 2.60 (1.89 to 3.57), respectively (P < 0.001 for trend). The corresponding hazard ratios (95% confidence interval) of glomerulonephritis-related ESRD were 1.32 (0.82 to 2.11), 1.48 (0.83 to 2.61), and 3.40 (2.02 to 5.74), respectively (P < 0.001 for trend). Systolic BP was stronger predictor of ESRD than diastolic BP or pulse pressure. This study provides novel data on the incidence of ESRD and on the association between BP and glomerulonephritis-related ESRD from a nationally representative sample of adult in China. These results document the importance of high BP as a modifiable risk factor for ESRD in China. Strategies to prevent ESRD should incorporate the prevention, treatment, and control of BP.
21. Risk factors for mortality among patients with diabetes: The Translating Research Into Action for Diabetes (TRIAD) Study.
McEwen LN, Kim C, Karter AJ et al.
Diabetes Care. 2007 Apr 27; [Epub ahead or print].
Objective To examine demographic, socioeconomic, and biological predictors of all-cause, cardiovascular, and noncardiovascular mortality in patients with diabetes. Research Design and Methods Survey, medical record, and administrative data were obtained from 8.733 participants in Translating Research Into Action for Diabetes (TRIAD), a multicenter prospective observational study of diabetes care in managed care. Data on deaths (n = 791) and cause of death were obtained from the National Death Index (NDI) after 4 years. Predictors examined included age, sex, race, education, income, duration and treatment of diabetes, body mass index (BMI), smoking, microvascular and macrovascular complications, and comorbidities. Results Predictors of adjusted all-cause mortality included older age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.05), male sex (HR 1.57, CI 1.35-1.83) lower income ($75.000 HR 1.82, CI 1.30-2.54; $15.000-$40.000 vs. >$75.000 HR 1.58, CI 1.15-2.17), longer duration of diabetes (/= 2-3 vs. < 1 HR 2.01, CI 1.04-3.90; >/= 3 vs. < 1 HR 4.38, CI 2.26-8.47). The predictors of cardiovascular and noncardiovascular mortality were different. Macrovascular disease predicted cardiovascular but not noncardiovascular mortality. Conclusions Among people with diabetes and access to medical care, older age, male gender, smoking, and renal disease are important predictors of mortality. Even within an insured population, socioeconomic circumstances are an important independent predictor of health.
22. The metabolic syndrome and chronic kidney disease in a Southeast Asian cohort.
Kitiyakara C, Yamwong S, Cheepudomwit S et al.
Kidney Int. 2007 71 (7): 693-700.
US adults with metabolic syndrome, as defined by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, ahve been shown to be at increased risk of chronic kidney disease (CKD), but there is limited information in other populations. The relationship between metabolic syndrome and CKD (defined as estimated glomerular filtration rate < 60 ml/min/1.73 m (2)) was examined in a Southeast Asian cohort. This relationship was examined when the subjects (n = 3195) were initially recruited in a cross-sectional analysis. The risks of developing new CKD associated with metabolic syndrome were also examined prospectively in a subgroup (n = 2067) without CKD at entry after 12 years follow-up. Metabolic syndrome was defined according to both NCEP ATP III and the new International Diabetes Federation (IDF) criteria. The prevalence of CKD was 1.6%, and the incidence of new CKD was 6.3%. Metabolic syndrome by NCEP ATP III definition was associated with the increased risk of CKD at baseline (adjusted odds ratio (OR) 2.48 and 95% confidence interval 1.33-4.62), and of developing new CKD at follow-up (adjusted OR 1.62 and 95% confidence interval 1.00-2.61). There was a significant graded relationship between the number of metabolic syndrome components present and risk of CKD. By contrast, metabolic syndrome by IDF definition was not associated with increased risk of CKD. These results suggest the relationship between CKD and metabolic syndrome in a Southeast Asian population is highly dependent on the criteria used to define metabolic syndrome.
23. Chronic kidney disease and mortality and morbidity among patients with established cardiovascular disease: A West of Ireland community-based cohort study.
Glynn LG, Reddan D, Newell J et al.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
Background The importance of chronic kidney disease as an independent risk factor for morbidity and mortality in patients with cardiovascular disease in the community is not widely recognized. Methods A retrospective cohort study based in the West of Ireland followed a randomized practice-based sample of patients with cardiovascular disease. A database of 1609 patients with established cardiovascular disease was established in 2000. This was generated from a randomized sample of 35 general practice in the West of Ireland. The primary endpoint was a cardiovascular composite endpoint, which included death from a cardiovascular cause or any of the cardiovascular events of myocardial infarction (MI), heart failure, peripheral vascular disease and stroke. The secondary endpoint was death from any cause. Results Of the original community-based cohort of 1609 patients with cardiovascular disease, 1272 (79%) had one or more serum creatinine measurements during the study period and 31 (1.9%) patients were lost to follow-up. Median follow-up was 2.90 years (SD 1.47) and the risk of the cardiovascular composite endpoint (total of 219 events) was significantly increase in those patients with reduced estimated glomerular filtration rate (GFR) [log rank (Mantel-Cox) 26.74, P < 0.001] as was the risk of death from any cause (total of 214 deaths) [log rank (Mantel-Cox) 56.97, P < 0.001]. On the basis of the proportional hazards model, while adjusting for other significant covarities, reduced estimated GFR was associated with a significant increase in risk of the primary and secondary outcomes (P < 0.01). For every 10 ml decrement in estimated GFR there was a corresponding 20% increase in hazard of the cardiovascular composite endpoint and a 33% increase in hazard of death from any cause. Conclusions Estimated GFR appears to discriminate prognosis between patients with established cardiovascular disease. These results emphasize the importance of recognising chronic kidney disease as a significant risk factor in patients with cardiovascular disease in the community.
II. ETIOPATHOGENESIS
1. Congenital cytomegalovirus infection: A cause of renal dysplasia?
Chan M, Hecht J, Boyd T et al.
Pediatr Dev Pathol. 2007 Mar 22; [Epub ahead of print].
Cytomegalovirus (CMV) infection is one of the most frequently encountered viral infections of the fetus and induces a wide range of histological and clinical manifestations. Congenital abnormalities are typically restricted to the central nervous system despite evidence of CMV inclusion occuring in most epithelial cells. Although tissue injury and even glomerulonephritis have been observed in congenital CMV infections, renal multicystic dysplasia has not been reported. Herein we describe a case of unilateral renal dysplasia in a nineteen-week fetus with concurrent CMV infection. We belive the present case to be the first description of a virus apparently inducing renal multicystic dysplasia.
2. Cryoglobulinemia related to hepatitis C virus infection.
Dore MP, Fattovich G, Sepulveda AR et al.
Dig Dis Sci. 2007 52 (4): 897-907.
A causal link among hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia, cryoglobulinemic glomerulonephrits, and vasculitis is strongly supported. HCV triggers autoimmune response in predisposed individuals that manifests as organ-specific and non-organ-specific autoantibodies and as polyclonal/monoclonal rheumatoid factor, which has a central role in causing damaging cryoglobulin and immune complex tissue levels. Immunologic events are mainly induced by HCV infection persistence, with excessive immune stimulation. Humoral immune dysfunction leads to autoantibodies and rheaumatoid factor production with cryoglubulinemia, glomerulonephritis, vasculitis, neuropathy, and probably thyroiditis, and arthritis in rare cases. Cellular immune dysfuction leads to lymphocytic infiltration, proliferation, and cytokine production. Pegylated (or not) interferon-alpha in combination with ribavirin appears to be the treatment of choice for patients with symptomatic essential mixed cryoglobulinemia with or without glomerulonephritis. Novel treatment with rituximab is promosing.
3. Autosomal dominant polycystic kidney disease.
Torres VE, Harris PC, Pirson Y.
Lancet. 2007 369 (9569): 1287-301.
Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogenity and modifier genes. An increased understanding of the disorder’s underlying genetic, molecular, and cellular mechanisms and a better apprecitation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
4. Correlation between mRNA expression level of mutant COL4A5 gene and phenotypes of XLAS females.
Wang Y, Zhang H, Ding J et al.
Exp Biol Med (Maywood). 2007 232 (5): 638-42.
Alport syndrome (AS) is a progressive hereditary glomerulonephritis presented with hematuria, progressive renal failure, sensorineural deafness, and ocular lesions. Females with X-linked Alport syndrome (XLAS) have variable phenotypes, from asymptomatic hematuria to renal failure. In order to understand the possible mechanism of different phenotypes in female XLAS, we analyzed mRNA expression level of the mutant COL4A5 gene in fibroblasts, the X-inactivation pattern in peripheral blood DNA, and the phenotype variability of XLAS females. Total RNA isolated from cultured skin fibroblasts in five females with XLAS and confirmed deletion mutations of COL4A5 mRNA. Reverse transcription-polymerase chain reaction (PCR) was performed to amplify the fragment, including the mutation sequences of the COL4A5 gene. The PCR products were electrophoresed with 8% polyacrylamide gel. Messenger RNA expression level of the mutant COL4A5 gene was analyzed with the optical density of PCR product revealed under polyacrylamide gel. The X-inctivation analysis was performed using HpaII predigestion of peripheral blood DNA followed by PCR of the highly polymorphic CAG repeat of the androgen receptor (AR) gene. All patients in the study had persistent microscopic hematuria. Two of the had gross hematuria. Three cases had persistent and severe proteinuria of 2+ ~ 3+, and the others had discontinous and milder proteinuria of - ~ +. The patients whose mRNA expression level of the mutant COL4A5 gene was higher had persistent and more severe proteinuria (r = 0.975, P = 0.005). None of them had skewed X inactivation. Our preliminary results demonstrate that the quantity of mRNA expression level of the mutant COL4A5 gene was correlated with the phenotypic severity of females with XLAS, and this could not be explained by X-inctivation pattern in peripheral blood leukocytes.
5. Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases.
Rana K, Tonna S, Wang YY et al.
Pediatr Nephrol. 2007 22 (5): 652-7.
Both thin basement membrane nephropathy (TBMN) and autosomal recessive Alport syndrome result from mutations in the COL4A3 and COL4A4 genes, and this study documents further mutations and polymorphisms in these genes. Thirteen unrelated children with TBMN and five individuals with autosomal recessive Alport syndrome were examined for mutations in the 52 exons of COL4A3 and the 47 coding exons of COL4A4 using single-stranded conformation polymorphism (SSCP) analysis. Amplicons producing different electrophoretic patterns were sequenced, and mutations were defined as variants that changed an amino acid but were not present in 50 non-hematuric normals. Three further novel mutations were identified. These were IVS 22-5 T>A in the COL4A3 gene in a consanguineous family with autosomal recessive Alport syndrome, and R1677C and R1682Q in the COL4A4 gene. In addition, six novel polymorphisms (G455G, I462I, G736G and IVS 38-8 G>A in COL4A3, and L658L and A1577A in COL4A4 were demonstrated. Many different COL4A3 and COL4A4 mutations cause TBMN and autosomal recessive Alport syndrome. The identification of polymorphisms in these genes is particularly important to enable diagnostic laboratories to distinguish mutations from uncommon normal variants.
6. Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?
Zhang KW, Tonna S, Wang YY et al.
Pediatr Nephrol. 2007 22 (5): 645-51.
Thin basement membrane nephropathy (TBMN) is the commest cause of persistent glomerular haematuria and often presents in childhood. Only 70% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n = 23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4/2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haemauria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymoprphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.
7. Toll-like receptors: Emerging concepts in kidney disease.
Anders HJ, Schlondorff D.
Curr Opin Nephrol Hypertens. 2007 16 (3): 177-83.
Purpose of review To summarize the recent advances in the role of Toll-like receptors (TLRs) in innate immunity, with a special focus on recent studies addressing the expression and function of TLRs in kidney disease. Recent findings Pathogen-recognition including TLRs mediate immune activation upon pathogen recognition in different extracellular and intracellular compartments. In contrast to professional antigen-presenting cells, renal cells express a limited pattern of TLR (i.e. express TLR1-TLR6 but lack expression of the endosomal TLR7-TLR9). TLRs on renal cell contribute to the innate immune response in renal infection. Furthermore, recent studies provide experimental evidence for the functional role of TLRs in immune complex disease and autoimmunity. Furthermore, the recognition of endogenous molecules released from injured cells such as biglycan or heat-shock proteins may contribute to acute tubular injury and seem to provide adjuvant activity for renal inflammation. Furthermore, TLR7 and TLR9 are involved in the pathogenesis of lupus nephritis. Summary The field of TLR research elucidates the molecular mechanisms of infection-associated kidney diseases but may also further support the concept that innate immunity significantly contributes to the so-called types of nonimmune kidney disease.
8. BMP in the kidney: Signaling, function and pathophysiological significance.
Hanai J.
Clin Calcium. 2007 15 (5): 704-10.
Bone morphogenetic proteins (BMPs) are multipotent signaling molecules that belong to the transforming growth factor-beta (TGF-beta) superfamily. Developmentally these proteins promote endochondrial bone formation and are involved in the cascade of body pattering and morphogenesis. Moreoevr, BMPs play an important role in the pathophysiology of several diseases, including osteoporosis, arthritis, pulmonary hypertension, cerebrovascular diseases, cancer and kidney diseases. In this review, BMP signaling and regulation, the pathophysiological role of BMP in kidney diseases and potential therapeutic applications have been discussed.
9. Mast cells and inflammatory kidney disease.
Blank U, Essig M, Scandiuzzi L et al.
Immunol Rev. 2007 217 (1): 79-95.
Inflammatory kidney disease involves a complex network of interactions between resident kidney and infiltrating hematopoietic cells. Mast cells (MCs) are constitutively found in kidneys in small numbers but increase considerably in various renal diseases. While this increase is usually interpreted as a sign of pathological involvement, recent data using MC-deficient animals show their ability to restore kidney homeostasis. In anti-glomerular basement membrane antibody-induced glomerulonephritis, MCs are protective by initiating repair and remodeling functions counteracting the devastating effects of glomerular injury. Protection may also include immunoregulatory capacities to limit autoreactive T-cell responses. MCs also control tubulointerstitial fibrosis by activating tissue remodeling and neutralizing fibrotic factors. Release of mediators by MCs during inflammation, however, could also promote unwanted response that ultimately lead to destruction of kidney structure, as examplified by data showing either protection or aggravation in related disease models. Similarly, while the action of proteases may initially be beneficial, the generation of fibrosis-promoting angiotensin II by chymase also shows the limits of adaptive responses to achieve homeostasis. Thus, it is likely the physiological context involving the intercation with other cells and inflammatory mediators that determines the final action of MCs in the development of kidney disease.
10. The mast cell IgG receptors and their roles in tissue inflammation.
Malbec O, Daeron M.
Immunol Rev. 2007 217 (1): 206-221.
Mast cells are effector cells of the innate immune system, but because they express Fc receptors (FcRs), they can be enganged in adaptive immunity by antibodies. Mast cell FcRs include immunoglobulin E (IgE) and IgG receptors and, among these, activating and inhibitory recptors. The engagement of mast cell IgG receptors by immune complexes may or may not trigger cell activation, depending on the type of mast cell. The coengagement of IgG and IgE receptors results in inhibition of mast cell activation. The Src homology-2 domain-containing inositol 5-phosphatase-1 is a major effector of negative regulation. Biological responses of mast cells depend on the balance between positive and negative signals that are generated in FcR complexes. He contribution of human mast cell IgG receptors in allergies remains to be clarified. Increasing evidence indicates that mast cells play critical roles in IgG-dependent tissue-specific autoimmune diseases. Convincing evidence was obtained in murine models of multiple sclerosis, rheumatoid arthritis, bullous pemphigoid, and glomerulonephritis. In these models, the intensity of lesions depend on the relative engagement of activating and inhibitory IgG receptors. In vitro models of mature tissue-specific murine mast cells are needed to investigate the roles of mast cells in these diseases. One such model unraveled unique differentiation/maturation-dependent biological responses of serosal-type mast cells.
11. Mechanisms of disease: The complement system in renal injury - - new ways of looking at an old foe.
Brown KM, Sacks SH, Sheerin NS.
Nat Clin Pract Nephrol. 2007 3 (5): 277-86.
The fact that the complement system is activated during immune-complex glomerular disease has been known for nearly 50 years. Detection of complement deposition in the glomerulus using immunohistochemistry has become an important element of the histological analysis of renal biopsies, and is key to the diagnosis of many types of glomerulonephritis. In recent years it has become evident that complement activation is involved in the pathogenesis of other types of renal disease; complement activation is implicated in transplant injury, atypical hemolytic uremic syndrome and progressive tubulointerstitial fibrosis. Emergence of this evidence has provided insight into how these diseases develop, and has yielded useful diagnostic tools and potential targets for therapeutic intervention. Clinicians have, by using plasma-based therapies, unknowingly treated abnormalities of the complement system in renal patients for many years: advances in antibody and protein technologies have lead to the development of complement inhibitors that have been used in phase III clinical studies. More-specific agents and applications are likely to be developed over the coming years and are discussed in this Review.
12. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions.
Woltman AM, de Fijter JW, Zuidwijk K et al.
Kidney Int. 2007 Mar 14; [Epub ahead of print].
Dendritic cells (DCs) play critical roles in immune responses and can be distinguished in two major subsets, myeloid and plasmocytoid DCs. Although the presence of DC in all peripheral organs, including kidney, has been well documented, no accurate estimates of DC subset in human kidneys have been reported. This study shows a detailed analysis of DC subsets in cryosection of human renal tissue. The cortex of normal kidneys contains at least two different HLA-DR (+) myeloid DC subtypes characterized by BDCA-1 (+) DC-SIGN (+) and BDCA-1 (+) DC-SIGN (-). The staining for DC-SIGN completely overlapped with CD68 in the renal interstitium. Unexpectedly, BDCA-2 (+) DC-SIGN (-) plasmocytoid DCs are also abundantly present. Both subsets are located in the tubulo-interstitium often with a high frequency around, but rarely observed within glomeruli. Qwuantification of BDCA-1 (+), DC-SIGN (+), and BDCA-2 (+) cells in normal human renal tissue (pretransplant biopsy living donors; N = 21) revealed BDCA-1 is about four times as frequently present as BDCA-2. A preliminary cross-sectional analysis of DC in diseased kidneys, including rejection and immunoglobulin A nephropathy, revealed that the number of DC as well as their anatomical distribution might change under pathophysiological conditions. In conclusion, we show that human kidneys contain a dense network of myeloid and plasmocytoid DCs and provide the tools for phenotyping and enumeration of these cells to better understand interindividual differences in immune responses.
13. Physiologic and pathophysiologic roles of lipid mediators in the kidney.
Hao CM, Breyer MD.
Kidney Int. 2007 Mar 14; [Epub ahead of print].
Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) and PGE2 critical role in maintaining blood pressure and renal function in volume concentrated states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFbeta induced mesangial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, andd toxic insults. Those pathways shold provide fruitful targets for intervention in the pharmacologic treatment of renal disease.
14. Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes.
Asanuma K, Campbell KN, Kim K et al.
Proc Natl Acad Sci U S A. 2007 May 30; [Epub ahead of print].
Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeleton dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-beta signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-beta1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine- and TGF-beta1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions.
15. Kidney growth during catabolic illness: What it does not destroy makes it grow stronger.
Franch HA.
J Ren Nutr. 2007 17 (3): 167-72.
The kidney undergoes hypertrophy under conditions that paradoxically cause a loss of lean body mass, such as diabetes, acidosis, and chronic kidney disease. What unique mechanisms account for kideny growth during negative nitrogen balance? One adaptation is that renal tubular cells substantially decrease protein breakdown during kidney cell growth. In this review, we discuss how acidosis and diabetes reduce protein breakdown within the kidney and the intracellular signaling pathways that may regulate protein metabolism. Our results suggest that in cell culture models and in acute diabetes, kidney cells specifically reduce protein breakdown by the lysosomal pathway of chaperone-mediated autophagy. This differs from the activation of proteolysis by the ubiquitin-proteasome system in muscle in acute diabetes and uremia. A shared signaling pathway regulates protein breakdown in both kidney and skeletal muscle, namely, phosphatidylinositol-3 kinase signaling. Diabetes mellitus activates signaling through this pathway in the kidney while down-regulating it in skeletal muscle. We conclude that similar signaling pathways may regulate distinct proteolytic pathways in different tissues.
16. Kidney growth, hypertrophy and the unifying mechanism of diabetic complications.
Satriano J.
Amino Acids. 2007 Apr 19; [Epub ahead of print].
Michael Brownlee has proposed a ’Unifying Mechanism’ of hyperglycemia-induced damage in diabetes mellitus. At the crux of this hypothesis is the generation of reactive oxygen species (ROS), and their impact on glycolytic pathways. Diabetes is the leading cause of chronic kidney failure. In the early phase of diabetes, prior to establishment of proteinuria or fibrosis, comes kidney growth and hyperfiltration. This early growth phase consists of an early period of hyperplasia followed by hypertrophy. Hypertrophy also contributes to cellular oxidative stress, and may precede the ROS perturbation of glycolytic pathways described in the Brownlee proposal. This increase in growth promotes hyperfiltration, and along with the hypertrophic phenotype appears required for hyperglycemia-induced cell damage and the progression of downstream diabetic complications. Here we will evaluate this growth phenomenon in the context of diabetes mellitus.
17. Fibrillogenic amylin evokes the apoptosis of human mesangial cells.
Peng A, Liu ZH, Zhou H et al.
Diabetes Res Clin Pract. 2007 Apr 5; [Epub ahead or print].
Objective To explore the apoptotic role of amylin on human mesangial cell (MC). Materials and Methods Primarily cultured human MCs were applied and treated with fresh amylin preparation. Human Mcs were identified by the morphology and immunofluorescence staining. The apoptotic cells were determined by ultrastructure changes, TUNEL, and DNA fragmentation analysis. Propidium iodide staining and flow cytometry was employed for quantitative measurement of apoptosis. Results Under the light and transmission electronic microscopy (TEM), the human MCs with condensed chromatin, plasma shrinkage, marginated nuclear chromatin or apoptotic body were observed in amylin-treated MCs. Positive TUNEL staining, hypolipoid DNA peak, and atypical DNA ’’ladder’’ pattern were also detected in amylin-treated MCs. Quantitative analysis of the apoptotic MCs showed that human amylin induced an increase of the percentage of apoptotic cells in a dose-dependent manner. Amylin nano-scale fibrils (5-18 nm) in diameter were detected in the cultured solution using negative staining under the TEM.
18. Role of matrix metalloproteinases in renal pathophysiologies.
Catania JM, Chen G, Parrish AR.
Am J Physiol Renal Physiol. 2007 292 (3): F905-11.
Matrix metalloproteinases (MMPs) are a large family of proteinases that remodel extracellular matrix (ECM) components and cleave a number of cell surface proteins. MMP activity is regulated via a number of mechanisms, including inhibition by tissue inhibitors of metalloproteinases (TIMPs), Originally thought to cleave only ECM proteins, MMP substrates are 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.
19. The (pro) renin receptor: Pathophysiological roles in cardiovascular and renal pathology.
Nguyen G.
Curr Opin Nephrol Hypertens. 2007 16 (2): 129-33.
Purpose of review The pathophysiological role of the (pro) renin receptor is yet to be estabilished. The present review summarizes the findings, suggesting that it may play pathological role in cardiac and renal fibrosis, and in hypertensive and diabetic nephropathy. Recent findings In-vitro and animal studies have shown that increased receptor expression could be linked to high blood pressure and to cardiac and glomerular fibrosis by activating mitogen-activated protein kinases and by upregulated gene expression of profibrotic molecules. Studies also suggest that the receptor is involved in diabetic nephropathy by activating receptor-bound prorenin, thereby increasing angiotensin II tissue generation. Moreover, in diabetic mice, a peptide able to block prorenin binding to the receptor was claimed to be more effective for renal protection than angiotensin-converting enzyme inhibitor. Summary The experimental data confirmed the pivotal role of the receptor in cell surface generation of angiotensin and suggested its potential role in tissue fibrosis via receptor activation and intracellular signaling. The data also questioned the ability of soon available renin inhibitors to inhibit the activity of receptor-bound renin and prorenin, and the benefit of a new class of drug - - (pro) renin receptor blockers - - to prevent tissue damage.
20. Human T and natural killer cells possess a functional renin-angiotensin system: Further mechanisms of angiotensin II-induced inflammation.
Jurewitz M, McDermott DH, Sechler JM et al.
J Am Soc Nephrol. 2007 18 (4): 1093-102.
The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, littlle is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angitensin-converting enzyme by mRNA analysis. Flow cytometryc analysis and Western blot revealed angiotensin receptor 2 (AT (2)) expression in T and NK cells, whereas AT (1) was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT (1) and AT (2) antagonists alone or in combination were unable abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system.
21. The emerging role of angiotensin-converting enzyme-2 in the kidney.
Burns KD.
Curr Opin Nephrol Hypertens. 2007 16 (2): 116-21.
Purpose of review The intrarenal renin-angiotensin system contributes to the progression of chronic kidney disease. Angitensin-converting enzyme-2 is a recently identified protein that is highly expressed in the kidney and results in formation of angiotensin-(1-7). This manuscript highlights current information on the localization and function of angiotensin-converting enzyme-2 in the kidney, along with recent studies on the role of enzyme in hypertension, glomerulosclerosis, and diabetic nephropathy. Recent findings Angiotensin-converting enzyme-2 is expressed in relative abundance in the proximal tubule and metabolizes angiotensin II to angiotensin-(1-7). Angiotensin-converting enzyme-2 also catalyzes conversion of angiotensin I to angiotensin-(1-9), which is cleaved to angiotensin-(1-7) by angiotensin-converting enzyme. In mice, gene deletion of angiotensin-converting enzyme-2 elevates blood pressure response to angiotensin II, and increases renal angiotensin II levels. Male angiotensin-converting enzyme-2-deficient mice exhibit accelerated glomerulosclerosis. In early diabetic nephropathy, proximal tubular angiotensin-converting enzyme-2 expression and activity are increased, suggesting that the enzyme may counterregulate the effects of local angiotensin II. Summary Angiotensin-converting enzyme-2 appears to be critical in determining the balance between the intrarenal effects of angiotensin II and angiotensin-(1-7). Angiotensin-converting enzyme-2 could thereby represent a target for novel therapeutic approaches in a variety of kidney disorders.
22. Vascular endothelium summary statement I: Health promotion and chronic disease prevention.
Hooper WC, Catravas JD, Heistad DD et al.
Vascul Pharmacol. 2007 46 (5): 315-7.
The endothelium can be considered a discrete organ with pathophysiologic implications and as such has both diagnostic and therapeutic possibilities. It is essential for the normal function of the cardiovascular, cerebrovascular, renovascular, and pulmonary vascular system. The endothelium is directly involved in the development and progression of heart disease, stroke, peripheral vascular disease, venous thrombosis, insulin resistance, diabetes, chronic kidney failure, tumor growth, metastases and adverse reproductive outcomes for both the mother and her newborn child. Consequently the endothelium represents an objective biological determinant on which to base new multidisciplinary prevention and health promotion strategies. This summary statement suggest some possible avenues for clinical and public health research.
23. Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease.
Bellini MH, Figueira MN, Piccoli MF et al.
Nephrology (Carlton). 2007 12 (3): 289-93.
Background Nitric oxide (NO) released from endothelial cells is related to the maintenance of physiological vascular tone. The impairment of endothelial NO generation brought about by gene polymorphism is considered one of the deterioration factors in progressive renal disease. In the endothelial nitric oxide synthase (eNOS) intron 4 polymorphism, the presence of the aa genotype has been associated with cardiovascular and renal disease. The aim of this study was to investigate the presence of eNOS gene intron 4 polymorphism in patients with end-satge renal disease (ESRD). Methods A total of 114 patients and 94 controls were studied. DNA specimens were extracted from blood and amplified by polymerase chain reaction. The alleles were separated by agarose gel electrophoresis: genotype distribution and allele frequencies were compared between groups using the chi-squared test. Results Statistical analysis revealed that the frequency of the eNOS4 genotype aa was significantly different in ESRD patients and in controls. (P = 0.016; OR = 2.07; CI 95%: 1.14-3.74). There was also a statistically significant difference between ESRD patients and controls regarding allele carriers (P = 0.004; OR = 2.26; CI 95%: 1.29-3.96). When the frequencies of allele carriers in the diabetic nephropathy group and in the control group were compared, a significant difference was found (P = 0.034; OR = 2.28; CI 95%: 1.04-5.00). Conclusion This study showed a strong correlation between eNOS4a polymorphism and end-stage renal disease.
24. Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?
Stenvinkel P, Karimi M, Johansson S et al.
J Intern Med. 2007 261 (5): 488-99.
Objective The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes. Design DNA methylation was analysed in peripheral blood leukocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty-six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n = 98) starting dialysis treatment were followed for a period of 36 +/- 2 months. Results Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio < median) was significantly associated with both all-cause (RR 5.0; 95% CI: 1.7-14.8; < 0.01) and cardiovascular (RR 13.9; 95% CI: 1.8-109.3; P < 0.05) mortality, even following the adjusment for age, CVD, diabetes mellitus and inflammation. Conclusion The present study demonstrates that global DNA methylation is associated with inflammation and increased mortality in CKD.
25. The past, presence and future of ADMA in nephrology.
Kielstein JT, Fliser D.
Nephrol Ther. 2007 3 (2): 47-54.
Kakimoto and Akazawa, first isolated and identified asymmetric dimethylarginine (ADMA) from urine in 1970. They speculated that ADMA, and its structural isomer symmetric dimethylarginine (SDMA), ’’may be important for the study of various pathological states’’. It took 22 years this hypothesis materialized in form of the seminal paper by Vallance et al. who advanced the idea that ADMA accumulation may be a cardiovascular risk factor in chronic kidney disease (CKD). In the last 15 years the relationship between ADMA and adverse cardiovascular outcomes has been thoroughly investigated in more than 600 published reports. These studies have shown that ADMA does not only correlate with traditional and non-traditional risk factors but also, independently of other risk factors, is strongly associated with clinical measures of cardiovascular burden such as intima-media thickness (IMT) of the carotid artery and left ventricular mass. Furthermore, cohort studies in both the general population and the dialysis population demonstrated a strong and independent link between ADMA, all-cause mortality and cardiovascular events. Last but not least, ADMA predicts the progression of CKD. This burgeoning body experimental and clinical studies form a fairly coherent framework indicating that ADMA is not only a marker but also a potent mediator of endothelial dysfunction and atherosclerosis as well as a solid predictor of mortality in selected patients populations. This article reviews the role of ADMA as a marker and mediator in cardiovascular disease in the setting of CKD and summarizes the effect of different renal replacement therapies as well as the effect on ADMA levels of commonly used drugs in nephrology. We conclude with remarks on the usefulness of ADMA as a marker in the clinical setting as well as emerging therapeutic strategies.
26. Vascular calcifiaction and fetuin-A deficiency in chronic kidney disease.
Westenfeld R, Jahnen-Dechent W, Ketteler M.
Trends Cardiovasc Med. 2007 17 (4): 124-8.
In past decades, extraosseous (including cardiovascular) calcification was predominantly regarded as passive process of limited pathohysiological significance. It was thought that a calcium (Ca)×phosphate (P) product in excess of Ca and P solubility was the key trigger of progressive hydroxyapatite precipitation and deposition in vessels and soft tissues. Recently, however, it became apparent that calcification is a complex and highly regulated proces involving inhibitors, inducers, and cell differentiation processes. It further became evident that cardiovascular manifestations of calcification predict patient outcomes in general populations, but in particular, in patients with chronic kidney disease. This review discusses the role of fetuin-A in the regulation of extraosseus and especially cardiovascular calcification processes. Fetuin-A is an inflammation-related Ca-regulatory glycoprotein and the prototype of a systemically acting calcification inhibitor. The emerging role of fetuin-A deficiency as a risk factor in dialysis patients was documented in cross-sectional studies demonstrating a significant correlation with all-cause and cardiovascular mortality.
27. Transthyretin amyloidoses.
Magy-Bertrand N.
Rev Med Interne. 2007 28 (5): 306-13.
Purpose Transthyretin amyloidoses are the most common form of amyloidosis. Two different types of transthyretin amyloidosis are described, one is rare, familial, its precusor is the mutated transthyretin, this type is called transthyretin amyloid, the other is more common, its precusor is wild transthyretin, this second type is called senile amyloid. The review describes the molecular, clinical and evolutives features of both types. Current knowledge and key points Transthyretin is a naturally beta-pleated protein. Reported mutations increase its proteolysis resistance and its abilty to form amyloid deposits. While transthyretin amyloid is clinically agressive (neuropathy, cardiomyopathy, nephropathy, and vitreous deposits), senile amylod is slightly symptomatic (rarely heart failure). The differenctial diagnosis is essentially based on molecular biology. Future prospects and projects Liver transplantation is an effective treatment of transthyretin amyloid because it switches the mutated protein synthesis to the protein synthesis. Liver transplantation is sometimes associated with cardiac or kidney transplantation depending of the clinical presentation. Concerning a specific treatment, P component analogous are developed for inhibiting amyloid deposits formation. Tetrameric transthyretin structure stabilisators are in development.
28. Mechanism of beta (2)-microglobulin-related amyloid fibril formation in CKD.
Yamamoto S, Kazama JJ.
Clin Calcium. 2007 17 (5): 740-4.
Dialysis-related amyloidosis is a serious complication in patients on long-term dialysis. Amylod fibrils, that major component is beta (2)-microglobulin (beta (2)-m), deposit mainly in osteoarticulat joint tissues and cause varous complications such as carpal tunnel syndrome, destructive spondyloarthropathy, bone cyst, and various organ dysfunction. The retention of beta (2)-m in chronic kidney disease (CKD) induces the amyloid fibril formation according to a nucleation-dependent polymerization model. Specific molecules such as glycosaminoglycans and proteolglycans that affect the conformation and stability of beta (2)-m and amyloid fibrils are considered to have significant effects on the formation and deposition of amylod fibrils.
29. Phenylalanine and tyrosine metabolism in chronic kidney disease.
Kopple JD.
J Nutr. 2007 137 (6): 1586S-90S.
In chronic kidney failure, there is impairment in the conversion of phenylalanine to tyrosin. As a result, tyrosine and the tyrosine/phenylalalnine ratio are reduced in plasma and many tissue, and phenylalanine concentrations tend to be normal and slightly increased. Although animal studies indicate that the kidney is not a major contributor to the conversion of phenylalanine to tyrosine, human studies conducted in the postabsorptive state suggest that the kidney plays a major role in the uptake phenylalanine and its hydroxylation and release as tyrosine. The human splanchnic bed in the postabsorptive state also displays net uptake of both phenylalanine and tyrosine and hydroxylation of substantial amounts of phenylalanine to form tyrosine. In chronic renal failure (CRF) patients, splanchnic uptake of tyrosine appears to be reduced in the postabsorptive state. After an amino acid meal, there is net release of phenylalanine from the splanchnic bed in normal subjects and to an even greater degree in CRF patients; tyrosine is released postprandially in both normal subjects and CRF patients. In the postabsoptive state, tyrosine release from the kidney is largely derived from the hydroxylation of phenylalanine. In CRF, the release of tyrosine from the kidney is reduced and this reduction may be marked with advanced CRF. These observations, as well as isotope studies indicating normal phenylalanine flux, reduced tyrosine flux and impaired conversion of phenylalanine to tyrosine in CRF patients, raise the possibility that tyrosine may be an essential amino acid in this condition. Further research will be necessary to answer this question. Oxidative stress, which often increases in CRF patients, may lead to increased formation of chlorothyrosine and nitrotyrosine in plasma proteins and of nitrotyrosine in the brain. Increased nytrotyrosine is also found in kidneys of patients with diabetic nephropathy or allograft nephropathy. Increased serum concentrations of oxidation products of phenylalanine have also been observed in patients with CRF. Impaired urinary excretion also may lead to accumulation of metabolic products of both phenylalanine and tyrosine in CRF. It is not known whether the elevated protein chlorotyrosine or nitrotyrosine or increased oxidative products of phenylalanine cause adverse metabolic or toxic effects in patients with CRF.
30. Disorders of bone and mineral metabolism in CKD: CKD-MBD as a new entity.
Tsukamoto Y.
Clin Calcium. 2007 17 (5): 660-4.
Since vascular calcification due to mineral disorder has been revealed a chief cause of decreasing life expectancy of chronic kidney disease (CKD) patients in recent years, the term ’’renal osteopdystrophy’’ can no longer express the pathophysiology of entire bone and mineral disorder in CKD. This is the reason why new disease entity ’’CKD-bone mineral disorder (MBD)’’ was introduced by the GBMI (Global Bone Mineral Initiative) (one of the workgroups of KDIGO [Kidney Disease Improving Global Outcome]). GBMI has also produced new pathological classification of renal osteodystrophy (ROD) as TMV (turnover, mineralization, volume) classification and LBC (laboratory abnormalities, bone abnormalities, extra osseous calcification) classification for CKD-MBD.
31. Streptococcal exotoxin B increases interleukin-6, tumor necrosis factor alpha, interleukin-8 and transforming growth factor beta-1 in leukocytes.
Viera N, Pedreanez A, Rincon J et al.
Pediatr Nephrol. 2007 May 25; [Epub ahead of print].
Previeous reports have shown the presence of streptococcal erythrogenic exotoxin type B (ETB), leukocyte infiltration, interleukin-8 (IL-8), transforming growth factor-beta (TGF-beta) and glomerular proliferation in renal biopsies from patients with acute post-streptococcal glomerulonephritis (APSGN). In addition, increased levels of plasma interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha), urinary IL-6, have also been reported in this disease. To determine the effect of streptococcal proteins on leukocyte proliferation and leukocyte production of IL-6, TNFalpha, IL-8 and TGF-beta1, we cultured human mononuclear leukocytes with ETB or ETB precursor (ETBP). After 24 h, 48 h and 96 h, culture supernatans were assessed for cytokines by enzyme-linked immunosorbent assay (ELISA), and for leukocyte proliferation by a monoclonal antibody anti-proliferating cellular nuclear antigen (PCNA). A significant increase in all cytokines was found in ETB- or ETBP-treated cultures when compared with controls. A polyclonal anti-ETB antibody dimineshed the cytokine stimulatory effect of ETB. An increased number of PCNA-positive cells was observed in ETB or ETBP treated cultures at 48 h and 96 h. Cytokine production and proliferation were not correlated. The stimulatory effect of streptococcal exotoxin B on leukocyte cytokine production may be relevant in renal tissue during the course of APSGN.
32. Activation of the lectin complement pathway in post-streptococcal acute glomerulonephritis.
Hisano S, Matsushita M, Fujita T et al.
Pathol Int. 2007 57 (6): 351-7.
The aim of the present study was to elucidate the correletion between complement pathways and clinicopathological findings in post-streptococcal acute glomerulonephritis (PSAGN). Immunohistological staining was performed on renal specimens obtained from 18 patients with PSAGN and 20 controls, using antibodies against IgG, IgA, IgM, C1q, C3c, C4, fibrinogen, factor B, C4-binding protein (C4-bp), C5b-9, CD59, mannose-binding lectin (MBL) and MBL-associated serine protease-1 (MASP-1). Controls showed no deposition of any antibody. In seven patients, glomerular deposits of C3c, C4, factor B, C4-bp, C5b-9, CD59, MBL and MASP-1 were found. In the remaining 11 patients glomerular deposits of neither C4 nor MBL/MASP-1 were found, and glomerular deposits of C3c, factor B, C5b-9 and CD59 were evident. C4-bp was detected in seven of these 11 patients. Glomerular deposits of fibrinogen were detected in five of seven patients with MBL/MASP-1 deposits and in only two of 11 patients without MBL/MASP-1 deposits. Hematuria was prolonged in three of seven patients with MBL/MASP-1 deposits through follow-up, whereas urinanalysis was normal in all patients without MBL/MASP-1 deposits. However, the histological indicators were not different between the two groups. To the authors’ knowledge this is the first report to show that complement activation through both the alternative and lectin pathways is evident in some patients with PSAGN. Complement activation is promoted in situ in the glomerulus.
33. Collapsing glomerulopathy: An inflammatory podocytopathy?
Barisoni L, Nelson PJ.
Curr Opin Nephrol Hypertens. 2007 16 (3): 192-5.
Purpose of review Collapsing glomerulopathy is a relatively new and debated podocytopathy. Among several conjectures, inflammatory injury orchestrated by podocytes is emerging to explain the pathogenesis of collapsing glomerulopathy. Here, we briefly summarize recent studies in support of this novel and intriguing hypothesis. Recent findings Immunohistochemical analyses of markers conventionally used to demarcate podocytes apart from parietal epithelium identified the parietal podocyte. MafB-deficient mice exhibited abnormal podocyte and macrophage differentiation, suggesting ancestral and functional overlap. These apparent developmental anomalies were detected in studies showing an admixture of hyperplastic podocytes with macrophage epitopes and hyperplastic parietal epithelium in pseudocrescents and in true crescents. Experimental antibody-mediated injury of podocytes could trigger capillary collapse and pseudocrescent formation marked by recruitment of epithelial cells from Bowman’s capsule. In contrast, experimental stabilization of hypoxia-inducible factors within podocytes – a known inflammatory response by macrophages – could trigger podocyte proliferation and the formation of true necrotizing crescents. Summary Preliminary evidence suggest that visceral and parietal podocytes may become macrophage-like inflammatory mediators of proliferative epithelial injury within the glomerulus. This may manifest as collapsing glomerulopathy or crescentic glomerulonephritis - lesions that appear to be anatomically and pathogenetically linked.
34. Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescent of pauci-immune glomerulonephritis.
Mezzano S, Droguett A, Burgos ME et al.
Nephrol Dial Transplant. 2007 Apr 1; [Epub ahead of print].
Background Recent evidence in vitro and in vivo suggest that gremlin, a bone morphogenetic protein antagonist, is participating in tubular epithelial mesenchymal transition (EMT) in diabetic nephropathy as a downstream mediator of TGF-beta. Since EMT also occurs in parietal epithelial glomerular cells (PECs) leading to crescent formation, we hypothesized taht gremlin could participate in this process. With this aim we studied in 30 renal biopsies of patients with pauci-immune crescentic nephritis. Methods Gremlin was detected by in situ hybridization (ISH) and immunohistochemistry (IMH) and TGF-beta by ISH and Smads by southwestern histochemistry (SWH). Phosphorylated Smad2, CTGF BMP-7, PCNA, alpha-SMA, synaptopodin,CD-68, and phenotypic markers of PECs (cytokeratin, E-cadherin), were detected by IMH. In cultured human monocytes, gremlin and CTGF induction by TGF-beta was studied by western blot. Results We observed strong expression of gremlin mRNA and protein in cellular and fibrocellular crescents corresponding to proliferating PECs and monocytes, in co-localization with TGF-beta. A marked over-expression of gremlin was also observed in tubular and infiltrating interstitial cells, correlating with tubulointerstitial fibrosis (r = 0.59; P < 0.01). A nuclear Smad activation in the same tubular cells, that are expressing TGF-beta and gremlin, was detected. In human cultured monocytes, TGF-beta induced gremlin production while CTGF expression was not detected. Conclusion We postulate that gremlin may play a role in the fibrous process in crescentic nephritis, both glomerular crescentic and tubular epithelial cells. The co-localization of gremlin and TGF-beta expression found in glomeruli and tubular cells suggest that gremlin may be important in mediating some of the pathological effects of TGF-beta.
35. Ault and paediatric patients with minimal change nephrotic syndrome show no major alterations in glomerular expression of sulphated heparan sulphate domains.
Wijnhoven TJ, Geelen JM, Bakker M et al.
Nephrol Dial Transplant. 2007 May 25; [Epub ahead or print].
Background Minimal change nephrotic syndrome (MCNS) is the most frequent form of nephrotic syndrome in childhood. In the glomerular basement membrane (GBM) of adult patients with MCNS, a reduced expression of a specific heparan sulphate (HS) domain has been reported. In children with MCNS, urinary activity of the HS-degrading enzyme heparanase was increased. It is, therefore, possible that a decreased GBM HS expression is associated with the pathogenesis of proteinuria in patients with MCNS. Methods In this study, HS in glomeruli of five adult and six paediatric patients with MCNS were analysed by immunofluorescence staining using four different antibodies, each defining a specific sulphated HS domain. The paediatric patients were subdivided into three groups depending on the presence or absence of podocyte foot process effacement, the level of proteinuria and prednisone administration at the time of the biopsy. In addition of rats with adriamycin nephropathy (ADRN), a model for MCNS, were included in the study. Results Expression of sulphated HS domains was not aberrant in adult or paediatric patients compared with control subjects. Children with and without proteinuria had the same HS content. In contrast, rats with ADRN showed a decreased glomerular expression of sulphated HS domains. Conclusions These results suggest that in patients with MCNS proteinuria is not associated with major changes in glomerular expression of sulphated HS domains.
36. TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurence of idiopathic membranous nephropathy.
Thibaudin D, Thibaudin L, Berthoux P et al.
Kidney Int. 2007 71 (5): 431-7.
Idiopathy membranous nephropathy (IMN) has a strong association with the major histocompability complex HLA B8DR3 (17) DQ2 haplotype. The tumor necrosis factor (TNF) A gene is located within the major histocompability complex region on chromosome 6. We have studied the influence of two functional polymorphisms; the -308 (promoter region) and the TNFd microsatellites on initiation and/or progression of IMN. This was a case-control study comparing data from 100 Caucasians patients (67 male subjects; 67%) with IMN to 232 Caucasian local controls (171 male subjects; 74%). We have analyzed genotypes and alleles distributions and the role of these polymorphisms in disease progression towards end-stage renal failure or patient death. For -308 TNFA polymorphism, distribution of genotypes was significantly different between IMN and controls (chi (2) = 16.25; P = 0.0003): the A2 allele frequency was 28.0% in IMN vs 15.3% in controls (chi (2) = 14.57, P = 0.0001). For TNFd polymorphism, alleles distribution (from d1 to d7) was also significantly different between IMN and controls (chi (2) = 56.74; P < 0.0001) with both diminished d3 allele frequency (chi (2) = 27.30; P < 0.0001; Pc = 0.001) and increased d2 allele frequency (chi (2) = 29.95; P < 0.0001; Pc = 0.001) in IMN. We could not isolate any significant and independent influence of these different genotypes on IMN disease progression. The TNFA2 and TNFd2 alleles were strongly associated with occurence/initiation of IMN and should be considered as susceptibility genes for this disease.
37. Membranous nephropathy is developed under Th2 environment in chronic graft-versus-host disease.
Nakashima H.
Med Hypotheses. 2007 Mar 28; [Epub ahead of print].
Clinical data from case reports of nephrotic syndrome including allogenetic hematopoietic stem cell transplantation (HSCT) suggest that there may be some relationship between chronic graft-versus-host disease (GVHD) and membranous nephropathy (MN). It is widely recognized T cells are crucial for the development of GVHD, and that T helper (Th) cells differentiate into at least two subsets, Th1 and Th2. The polarized situation between Th1 and Th2 cells is estabilished to be important in animal models and human autoimmune disease. In a chronic GVHD murine model a Th2 cell plays a pivotal role for the pathogenesis. In MRL/1pr mice, which is particularly valuable model for systemic lupus erythematosus, developed diffuse proliferative glomerulonephritis (DPGN) in Th1 environment and MN in Th2 environment. Similarly, Th2 cells may be predominantly activated in chronic GVHD, production and deposition of IgG4 in the glomeruli may develop MN. A hypothesis is: when the patient in period of chronic GVHD developed immune complex-mediated disease, IgG4 might be mainly produced in Th2 environment, and the deposition of IgG4 in the glomeruli may result in the formation of MN.
38. Dense deposit disease is not a membranoproliferative glomerulonephritis.
Walker PD, Ferrario F, Joh K et al.
Mod Pathol. 2007 20 (6): 605-16.
Dense deposit disease (first reported in 1962) was classified as subtype II of membranoproliferative glomerulonephritis in the early 1970s. Over the last 30 years, marked differences in etiology and pathogenesis between type I membranoproliferative glomerulonephritis and dense deposit disease have become apparent. The sporadic observation that dense deposit disease can be seen with markedly different light microscopy appearances prompted this study. The goal was to examine a large number of renal biopsies from around the world to characterize the histopathologic features of dense deposit disease. Eighty-one cases of dense deposit disease were received from centers across North America, Europe and Japan. Biopsy reports, light microscopy materials and electron photomicropgraphs were reviewed and histopathologic features scored. Sixty-nine cases were acceptable for review. Five patterns were seen: (1) membranoproliferative n = 17; (2) mesangial proliferative n = 30; (3) crescentic n = 12, (4) acute proliferative and exudative n = 8 and (5) unclassified n = 2. The age range was 3-67 years, with 74% in the range of 3-20 years; 15% 21-30 years and 11% over 30 years. Males accounted for 54% and females 46%. All patients with either crescentic dense deposit disease or acute proliferative dense deposit disease were between the ages of 3 and 18 years. The essential diagnostic feature of dense deposit disease is not the membranoproliferative pattern but the presence of electron dense transformation of the glomerular basement membranes. Based upon this study and the extensive data developed over the past 30 years, dense deposit disease is clinically distinct from membranoproliferative glomerulonephritis and is morphologically heterogenous with only a minority of cases having a membranoproliferative pattern. Therefore, dense deposit disease should no longer be regarded as a subtype of membranoproliferative glomerulonephritis.
39. The genetics of IgA nephropathy.
Beerman I, Novak J, Wyatt RJ et al.
Nat Clin Pract Nephrol. 2007 3 (6): 325-38.
IgA nephropathy is the most common form of primary glomerulonephritis. Variations in clinical manifestations indicate that a diagnosis of IgA nephropathy encompasses multiple disease subsets that cannot be distinguished on the basis of renal pathology or clinical variables alone. Familial forms of the disease have been reported throughout the world, but are probably under-recognized because associated urinary abnormalities are often intermittent in affected family members. IgA nephropathy has complex determination, with different genes probably causing disease in different patients subgroups. Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently implicated. Here, we present the evidence for genetic contributions to the disease, review clinical patterns of familial disease, and summarize some of the most promising genetic studies conducted to date. Linkage-based approaches to the study of familial forms of the disease have identified significant or suggestive loci on chromosome 6q22-23, 2q36, 4q26-31, 17q12-22 and 3p24-23, but no causal gene has yet been identified. Many interesting, but poorly replicated, genetic association studied have also been reported. We discuss recent developments in analytic tools that should enable genetic studies of sporadic forms of disease by the genome-wide association approach.
40. Variants of the ST6GALNAC2 promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy.
Li GS, Zhu L, Zhang H et al.
Hum Mutat. 2007 May 4; [Epub ahead of print].
IgA nephropathy (IgAN) is a polygenic disorder. Increasing evidence has implicated that aberrant glycosilation of IgA1 molecules, including alpha2,6 sialic acid defects, are involved in the pathogenesis of IgAN. In the present study, we designed an association study to investigate polymorphisms of two important genes, ST6GALNAC2 and NEU1, which are involved in the sialylation of the IgA1 molecule, in the susceptibility to IgAN. A total of 670 patients with histologically proven IgAN and 494 healthy controls were enrolled. Screening of SNPs in the coding and promoter regions of the ST6GALNAC2 and NEU1 genes was performed by sequencing. ST6-SNP1 (c. -988A>G), ST6-SNP2 [rs3840858:D>I (CGGC), c.-450 -449insCGGC], ST6-SNP3 (rs1867561: C>G, c.-135C>G), and ST6-SNP7 (rs2304921:G>A, c.186+12G>A) in the ST6GALNAC2 gene were selected as tagging SNPs. Functional evaluation of targets were assayed by luciferase activity. The alpha2,6 sialic acid contents of serum IgA1 in 497 patients were analyzed. Our results demonstrated that the frequency of haplotype ADG in the promoter region of ST6GALNAC2 was significantly higher in IgAN patients than that in controls p=0.069; odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.08-1.72). Furthermore, the ADG haplotype was associated with the deficient degrees of alpha2,6 sialic acid of IgA1 molecules in IgAN patients (r=0.408, p=0.0035). The ADG haplotype conferred significantly reduced promoter activity compared with the most common haplotype GDG in vitro (196.43 +/- 21.55 vs. 258.41 +/- 46.25; p=0.002). In the present study, we identified for the first time the ADG haplotype in the ST6GALNAC2 gene as a functional regulatory variant that may contribute to the genetic susceptibility in a subset of patients whom the desialylation of IgA1 molecules was main causative pathogenesis of IgAN.
41. Identification and characterization of CMP-NeuAc:GalNAc-IgA1 alpha2, 6-sialyltransferase in IgA1-producing cells.
Raska M, Moldoveanu Z, Suzuki H et al.
J Mol Biol. 2007 369 (1): 69-78.
Glycosylation defects occur in several human diseases. In IgA nephropathy, IgA1 contains O-glycans that are galactose-deficient and consist mostly of core 1 alpha2,6 sialylated N-acetylgalactosamine, a configuration suspected to prevent beta1,3 galactosylation. We confirmed the same aberrancy in IgA1 secreted by the human DAKIKI B cell line. Biochemical assays indicated CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase activity in this cell line. However, a candidate enzyme, ST6-GalNAc, was not transcribed in DAKIKI cells, B cells isolated from blood, or Epstein-Barr virus (EBV)-immortalized IgA1-producing cells from the blood of IgAN patients and healthy controls. Instead, ST6-GalNAcII transcription was detected at a high level. Expression of the ST6-GalNAcII gene and activity of the CMP-NeuAc:GalNAc.IgA1 alpha2, 6-sialyltransferase were higher in IgA1-producing cell lines from IgAN patients than in such cells from healthy controls. These data are the first evidence that human cells that lack ST6-GalNAcI can sialylate core 1 GalNAc-Ser/Thr.
42. The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy (Review Article).
Barratt J, Smith AC, Feehally J.
Nephrology (Carlton). 2007 12 (3): 275-84.
Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galatosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggest that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylationmay be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggest undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.
43. Differential binding characteristics of native monomeric and polymeric immunoglobulin A1 (IgA1) on human mesangial cells and the influence of in vitro deglycosylation of IgA1 molecule.
Gao YH, Xu LX, Zhang JJ et al.
Clin Exp Immunol. 2007 148 (3): 507-14.
Recent studies had demonstrated that serum and mesangial immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) were polymeric and deglycosylated. The current study was to investigate the binding characteristics of monomeric and polymeric normal IgA1 on mesangial cell and the influence of in vitro deglycosylation of IgA1 molecules. The normal human IgA1 was desialylated and degalactosylated with specifi enzymes, respectively. The monomeric IgA1 (mIgA1) and polymeric IgA1 (pIgA1) were separated by SephacrylS-300 chromatography. The binding capacities of the mIgA1 and pIgA1 to primary human mesangial cells (HMC) were evaluated by classical radioligand assay. Both the native mIgA1 and pIgA1 could bind to HMC in a dose-dependent and saturable manner. The maximal binding capacity of the native pIgA1 were significantly higher than that of the native mIgA1 (P < 0.05). However, the affinity of the native mIgA1 was almost 100 times higher than that of the native pIgA1. After deglycosylation, binding of the two deglycosylated mIgA1 to HMC could not be detected. However, the maximal binding capacities of the two deglycosylated pIgA1 to HMC were increased significantly compared with that of native pIgA1. The affinity of the two deglycosylated pIgA1 was similar to that of native pIgA1 (P > 0.05). The current study suggest differential binding characteristics of native monomeric and polymeric IgA1 on mesangial cells. Glycosylation of IgA1 molecules could significantly affect the binding of IgA1 on HMC.
44. Underglycosylation of IgA in IgA nephropathy: More than a diagnostic marker?
Roos A, van Kooten C.
Kidney Int. 2007 71 (11): 1089-91.
Moldoveanu et al. present a diagnostic test for IgA nephropathy based on the presence undergalactosylated IgA in serum. This undergaltosylated IgA appears to be overrepresented in serum of IgA nephropathy patients and is most likely related to mesangial IgA deposition. Further studies on the nature, production, regulation, and cellular and molecular interactions of this undergalactosylated IgA may facilitate disease diagnosis and provide further insight into the pathogenesis of this iportant disease.
45. T-cell homing receptor expression in IgA nephropathy.
Batra A, Smith AC, Feehally J et al.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
Background IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). In IgAN, mucosal pIgA production is reduced while systemic production is increased, making latter the likely source of mesangial pIgA, and suggesting a displacement of pIgA-producing cells from mucosal to systemic sites. Upon activation, lymphocytes migrate through the circulation up-regulating homing receptors (HR) which direct their return to appropriate effector locations. We investigated the HR expression of T-cell subset in IgAN, healthy adults and membraneous nephropathy (MN). Methods Peripheral blood cells were labelled for CD3, CD4, and CD8, and for 1-selectin (naive cells), integrin alpha (4) beta (1) (systematically homing cells) and integrin alpha (4) beta (7) (mucosally homing cells) and analysed by flow immunocytometry. Results In IgAN, CD3 T cells displayed reduced 1-selectin and increased alpha (4) beta (1) (hi) expression, with no difference in alpha (4) beta (7). No abnormality of T-cell HR expression was found in MN. Both IgAN and healthy adults maintained their patterns of T-cell HR expression when studied again at a later time point, and the changes in IgAN were entirely accounted for by the CD4 T-cell subset with CD8 HR espression being normal. Conclusion The consistently reduced 1-selectin expression by CD T cells indicates increased activation of this subset in IgAN. These activated cells express alpha (4) beta (1) rather than alpha (4) beta (7), and therefore home to systemic effector sites. CD4 T cells regulate antibody production, including IgA. As pIgA is overproduced in systemic sites in IgAN, we hypothesize that these activated systemic homing CD4 T cells may direct the aberrant systemic pIgA production observed in IgAN.
46. Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients.
Kobori H, Katsurada A, Ozawa Y et al.
Biochem Biophys Res Commun. 2007 Apr 26; [Epub ahead of print].
This study was performed to determine whether immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen are increased in IgA nephropathy (IgAN) patients. Hemeoxygenase-1 and angiotensinogen immunoreactivity were determined by immunohistochemistry robot system from 39 patients with IgAN. Normal portions of surgically resected kidney served as controls. IgAN patients showed moderate proteinuria (1.1 +/- 0.2 g/day); however, the control group did not show any proteinuria. Immunoreactivity of intrarenal hemeoxygenase-1 and angiotensinogen in IgAN were significantly increased compared to normal kidneys (2.42 +/- 0.42 vs 1.00 +/- 0.26 for hemeoxygenase-1 and 4.05 +/- 0.40 vs 1.00 +/- 0.21 for angiotensinogen, arbitrary unit). Even though these IgAN patients did not show massive renal damage, hemeoxgenase-1 and angiotensinogen immunoreactivity were increased in thse patients at this time point. These data suggest that activated intrarenal reactive oxygen species-angiotensinogen axis plays some roles in development of IgAN at the early stage and will provide supportive foundation of effectiveness of the renin-angiotensin system blockade in IgAN.
47. Soluble fibrin formation in the mesangial area of IgA nephropathy.
Liu N, Mori N, Iehara N et al.
Clin Exp Nephrol. 2007 11 (1): 71-6.
Background Fibrin monomer and its derivates in blood are found in early stage of thrombosis. When they are produced in blood, the form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanims of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted. Methods Nineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated. Results XFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P < 0.05). Furthermore, factor V, and SF depositions were markedly correlated with disease activity (P < 0.001 in each case). Conclusions These findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompained by mesangial proliferation, in particular, in its early stage.
48. Hypothesis - - haptoglobin genotype and diabetic nephropathy.
Nakhoul FM, Miller-Lotan R, Awaad H et al.
Nat Clin Pract Nephrol. 2007 3 (6): 339-44.
Vascular complications cause serious morbidity in patients with diabetes mellitus. Three such complications are nephropathy, retinopathy and accelerated atherosclerotic cardiovascular disease. There is currently scant evidence of a genetic marker that predicts which patients will have vascular complications. Oxidative stress has an important role in the development of diabetic vascular complications. Haptoglobin (Hp) is a hemoglobin-binding protein that has a major role in protecting against heme-driven oxidative stress. There are two common alleles for Hp (1 and 2) and, three common Hp genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. The antioxidant protection provided by Hp is genotype-dependent; the protein encoded by Hp 1-1 provides superior antioxidant protection compared with that encoded by Hp 2-2. We have shown that diabetic individuals with Hp 2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease than those with the Hp 2-1 or Hp 1-1 genotypes.
49. Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via upregulation of MAP kinase phosphatase-1 (MKP-1).
Wahab NA, Cox DJ, Witherden AS et al.
Biochem J. 2007 May 10; [Epub ahead of print].
Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis in chronic pathological conditions, including diabetic nephropathy (DN). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins (ECM). CTGF is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to human mesangial cells (HCM) rapidly activates ERK 1/2 MAPK and JNK MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6. The aim of this study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMC. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MAPK phosphatase-1 (MPK-1), a dual specificity phosphatase which dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.
50. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
Lindenmeyer MT, Kretzler M, Boucherot A et al.
J Am Soc Nephrol. 2007 18 (6): 1765-76.
Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidney were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decreased in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1alpha mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.
51. Pathogenesis of extra efferent vessel development in diabetic glomeruli.
Stout LC, Whorton EB.
Hum Pathol. 2007 May 7; [Epub ahead of print].
The development of extra efferent vessels (EEV) is a little-known feature of diabetic glomerulopathy. The only previous large study [Min W, Yamanaka N. Three-dimensional analysis of increased vasculature around the glomerular vascular pole in diabetic nephropathy. Virchows Archiv A Pathol Anat 1993; 423: 201-7] known to us found that up to 5 EEV per glomerulus (glom) each drained a separate lobule. Most EEV connected to the second- and third-order branches of the afferent arteriole (AA), and drained into peritubular capillaries. Although not so stated, the illustrations suggested that some EEV could be shunts, and thus detrimental to glom function, and possibly glom health. There was no correlation between the unquantitated presence of increased EEV at the vascular pole (VP) and severity of the major diabetic glomerular (glom) lesions. The authors opined that efferent arteriole (EA) stenosis by insudative lesions (IL) stimulated the formation of EEV. To confirm and extend these findings, we have repeated the study in 18 diabetic cases with mild to severe, but not end-stage diffuse and nodular lesions (DL and NL), 8 controls, and the 2 normal traumatic nephrectomy cases. Up to 18 EEV per glom were found in diabetic cases along with occasional EEV in controls. EEV contained muscle and were almost identical to the EA in structure. Nearly all EEV connected with efferent glom capillaries at the VP, where they exited the glom through apparently preexisting gaps in the Bowman’s capsule and/or glomerular capillary basement membranes (BCBM/GCBM). The EA exited through a similar gap, so the exit of EEV was accomplished without altering the anatomical relationships between the exiting vessels and the components of the VP thought to be important in the control of glom outflow. The largest number of EEV occured in long-standing T2DM cases with mild to moderate DL and NL. Complete photographic glom reconstructions revealed numerous anastomoses among efferent glom capillaries in normal and diabetic gloms with mild to moderate DL and NL. No disproportionately dilated EEV were seen. The findings just cited confirm that EEV are common and surprisingly numerous in diabetic gloms. They suggest that EEV formation served to preserve glom function, and that EEV could neither shunt nor restrict glom outflow locally. In our opinion, the formation of EEV represents a significant, possibly hemodinamically induced, remodeling of the glom that should be added to the list of changes that occur in diabetes. It si hypothesized that EEV develop because of increased glom inflow, and that the latter may be attributable to AA mucle damage that impairs its contractile ability.
52. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy.
Toyoda M, Najafian B, Kim Y et al.
Diabetes. 2007 May 29; [Epub ahead of print].
Objective To study the structural characteristics of podocytes and endothelial cells (EC) in diabetic nephropathy (DN). Research Design and Methods We studied 18 patients with type 1 diabetes (T1DM) [7 normoalbuminuric (NA), 6 microalbuminuric (MA), 5 proteinuric (P)] and 6 normal controls (C). Groups were not different for age. T1DM groups were not different for diabetic duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact non-detached foot process (IFP), fraction of glomerular capillary lumen surface covered by fenestrated endothelium [S (S) (Fenestrated/cap)] and classic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. Results GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r = -0.71, p = 0.001) and directly with AER (r = 0.66, p = 0.003), GBM and mesangial parameters. The GBM fraction covered by IFP was decreased in P vs. C (p = 0.001), NA (p = 0.0002) and MA (p = 0.04) patients and correlated with renal structural and functional parameters, including AER (r = -0.52, p = 0.03). Only 78% of GBM was covered by IFP in P patients. S (S) (fenestrated/cap) was reduced in NA (p = 0.03), MA (p = 0.03) and P (p = 0.002) vs. C. S (S) (Fenestration/cap) correlated with Vv (Mes/glom) (r = -0.57, p = 0.01), IFP (r = 0.61, p = 0.007) and FPW (r = -0.58, p = 0.01). Conclusions These novel studies document that podocyte detachment and diminished EC fenestration are related to classical DN lesions and renal function in T1DM and support a need for further studies of podocyte/GBM adherence and podocyte/EC functional interaction in DN.
53. Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach.
Kankova K, Stejskalova A, Pacal L et al.
Diabetologia. 2007 Mar 8; [Epub ahead of print].
Aims/Hypothesis In the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methological approaches suitable for analysing susceptibility to complex traits: single- and multi-locus analyses. Materials and Methods The study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCR-based methodology (PCR only, PCR plus RFLP, or allele-specific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis. Results After collection for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p = 0.0006) in single-locus analysis. In multi-locus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER -429T/C) and two SNPs on chromosome 7q (NOS3 774C/t and NOS3 E298D), omnibus p = 0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p = 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184 and NOS3 774C/T, together with diabetes duration and HbA (1c), as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction. Conclusion/Interpretation Using the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single- and multi-locus analyses represent complementary methods.
54. The relationship of the methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish type 2 diabetic patients with and without nephropathy.
Eroglu Z, Erdogan M, Tetik A et al.
Diabetes Metab Res Rev. 2007 Mar 12; [Epub ahead of print].
Background Poor glycaemic control, hypertension and duration of diabetes are risk factors for the development of diabetic nephropathy, but there may be genetic factors. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677C > T) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. We aim to investigate Turkish type 2 diabetic patients with/without diabetic nephropathy and healthy group and examine the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy. Methods DNA was extracted from peripheral leukocytes of the subjects. Genotyping of the MTHFR C677T polymorphism for all individuals was performed by melting curve analysis of the generated amplicons after real-time online PCR. Results This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 6.8% were TT, 43.7% were CT and 49.5% were CC (chi (2) = 0.201, p > 0.05). The frequency of the mutant T allele was 23.4% in diabetic patients with nephropathy versus 33.0% in those without nephropathy. The genotype frequencies were TT, 2.1%, CT, 46.6%; CC, 55.3% in diabetic patients with nephropathy versus TT, 10.7%, CT, 44.6%; CC, 44.6% in those without nephropathy. Conclusions The MTHFR genotype and allele frequencies were not different between diabetic patients with and without nephropathy (chi (2) = 3, 386, p > 0.005; chi (2) = 2.320, p > 0.005, respectively). Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Turkish type 2 diabetic patients.
55. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.
Lindenmeyer MT, Kretzler M, Boucherot A et al.
J Am Soc Nephrol. 2007 May 2; [Epub ahead of print].
Diabetic nephropathy (DN) is a frequent complications in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and kontrol kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGFand proteinuria, and positive correaltion between VEGF-A and hypoxia-inducible factor-1alpha mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the question about roden models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.
56. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy.
Wong CK, Ho AW, Tong PC et al.
Clin Exp Immunol. 2007 Apr 11; [Epub ahead of print].
Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signaling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2, and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the undelying immunopathological mechanisms of type 2 DM patients with DN.
57. Elevated circulating transforming growth factor beta-1 may explain poorer renal survival in type II diabetics with chronic hepatitis C.
Peterson MC.
Med Sci Monit. 2007 13 (5): RA50-4.
Hepatitis C is reported to be associated with poorer renal survival in patients with diabetes. The mechanism for this observation has not been elucidated. Transforming growth factor beta-1 is involved in signaling for human disease involving fibrosis and excess matrix deposition including diabetic nephropathy. Hepatitis C virus core protein is known to upregulate transcription of TGF beta-1 in the liver and HCV patients have elevated levels of circulating TGF beta-1 versus controls. There is evidence that elevated circulating TGF beta-1 levels results in more rapid progression of nephropathy and that lowering circulating TGF beta-1 levels with an angiotensin converting enzyme inhibitor correlates with treatment efficacy in diabetic nephropathy. This paper outlines a hypothesis that the elevated level of circulating TGF beta-1 which is associated with HCV is a mediator of more rapid progression of diabetic renal disease in persons with HCV.
58. Physiologic and pathophysiologic roles of lipid mediators in the kidney.
Hao CM, Breyer MD.
Kidney Int. 2007 71 (11): 1105-15.
Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney disease. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) play critical roles in maintaining blood pressure and renal function in volume contracted states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-Lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraeonic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFbeta induced mesangial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease.
59. Involvement of the fractalkine in the pathogenesis of childhood hemolytic uremic syndrome.
Ramos MV, Fernandez GC, Patey N et al.
Blood. 2007 109 (6): 2438-45.
Thrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by senzitizing cells to Stx fractalkine (FKN), a CX (3) C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX (3) CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX (3) CR1, down-modulated CD62L, and increased CD16. In addition, the CD56 (dim) natual killer (NK) subpopulation was decreased, leading to an altered peripheral CD56 (dim) / CD56 (bright) ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX (3) CR1 (+) leukocytes and the severity of renal failure. Finally, CX (3) CR1 (+) leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX (3) CR1 (+) cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.
III. CLINICAL PRESENTATION
1. Useful indicators for performing renal biopsy in adult patients with isolated microscopic haematuria.
Shen P, He L, Jiang Y et al.
Int J Clin Pract. 2007 Mar 16; [Epub ahead of print].
Among adult patients with isolated microscopic haematuria (IMH) which is defined as persistent microscopic haematuria but wihout proteinuria, hypertension, renal insufficiency, urinary tract infection or structural abnormality of the urinary tract, some patients have chronic glomerulonephritis (CGN), in whom early diagnosis by renal biopsy is beneficial to timely intervention. Nevertheless, a considerable number of patients with optimistic prognosis [e.g. thin basement membrane nephropathy (TBMN)] undergo invasive and needless renal biopsy. Indicators for weighing the necessity of renal biopsy would be clinically significant. To investigate the value of urinary albumin/creatinine ratio (UACR), serum IgA level, serum C3 level and serum IgA to C3 ratio in predicting the necessity of renal biopsy for adult patients with IMH, 216 patients were studied retrospectively. Patients were divided into: (CGN group, n = 137), (TBMN group, n = 56) and normal biopsy (normal group, n = 23). Of all patients, 131 (61%) evidenced microalbuminuria (UACR = 30-299 mg/g) and 85 (39%) had normoalbuminuria (UACR < 30 mg/g). The mean value of UACR in CGN group was higher (96 +/- 17 mg/g) compared with that in TBMN (20 +/- 4 mg/g, P < 0.01) or normal (18 +/- 3 mg/g, p < 0.01) group. The mean values of serum IgA and serum IgA/C3 ratio in patients with IgA nephropathy (IgAN) were significantly higher than those with non-IgAN (380 +/- 103 : 217 +/- 99 mg/dl, p < 0.01; 4.5 +/- 1.2 : 2.4 +/- 0.9, p < 0.01). The oddsd ratio for distinguishing IgAN from non-IgAN was significantly correlated with seum IgA level and serum IgA to C3 ratio. For adult patients with IHM, UACR, serum IgA level and serum IgA to C3 ratio are non-invasive markers for predicting the necessity of renal biopsy.
2. Can cystatin C replace creatinine to estimate glomerular filtration rate? A lierature review.
Zahran A, El-Husseini A, Shoker A.
Am J Nephrol. 2007 27 (2): 197-205.
Background With the increasing knowledge that estimation of glomerular filtration rate (GFR) from serum creatinine (Scr) has limited value, researchers have developed new equations based on serum cystatin C (Cys C). Aim To compare the performance of serum Cys C and Cys C-based GFR equations to Scr and Scr-based GFR equations. Methods A Medline literature search for studies in English. Results Fourteen studies in kidney transplant patients and 29 in patients with native kidney disease were identified. 70% of studies on transplants favored Cys C over Scr while 60% favored serum Cys C over Scr in patients with native kidney disease. Three studies in transplant patients and 6 in patients with native kidney disease compared the performance of Cys C- and Scr-based equations. 70% of the studies performed on transplantation Cys C, while 85% the studies performed in native kidney diseases showed superiority of Cys C-based equation. Conclusion A large number of studies favor Cys C over Scr for the estimation of GFR. Still, many reports show not superior of Cys C over Scr. Consistent with this, more studies are needed to study the performance of Cys-based GFR equations.
3. Anemia as a risk factor for kidney function decline in individuals with heart failure.
Bansal N, Tighiouart H, Weiner D et al.
Am J Cardiol. 2007 99 (8): 1137-42.
Chronic kidney disease (CKD), anemia, and declining kidney function are recognized as risk factors for adverse outcomes in patients with heart failure. This analysis was conducted whether anemia is a risk factor for kidney function decrease in patients with heart failure. Data from the Studies of Left Ventricular Dysfunction (SOLVD), a randomized trial of enalapril versus placebo in patients with ejecetion fractions < / = 35%, were analyzed. After randomization, creatinine measurements were taken at 2 weeks, 6 weeks, 4 months, and every 4 months thereafter. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study (MDRD) equation, and GFR slope was calculated. ’’Rapid decrease’’ was defined as a decrease in the GFR of > / = 6 ml/min/1.73 m (2) / year. Anemia was defined as baseline hematocrit < 36%. Multivariate logistic regression weighted by the number of GFR assessment was used to test the relation between anemia and rapid decrease. We also evaluated whether CKD (baseline < / = 60 ml/min/1.73 m (2) modified the relation between anemia and rapid decrease. In the 6.360 subjects, the mean age was 59 years, 31% had CKD, and 6% had anemia. Median follow-up was 2 years. In multivariate analysis, anemia was associated with a 1.30 increased odds (95% confidence interval 1.18 to 1.45) of rapid decrease in GFR. In subjects with CKD, anemia was associated with a 1.71 increased odds (95% confidence interval 1.43 to 2.05) of rapid decrease, while in subjects without CKD, anemia was associated with a 1.16 increased odds (95% confidence interval 1.03 to 1.31) of rapid decrease (p for interaction < 0.001). In conclusion, anemia is associated with a rapid decrease in kidney function in patients with heart failure, particularly in those with underlying CKD.
4. Validation of a predictive risk score for radiocontrast-induced nephropathy following percutaneous coronary intervention.
Skelding KA, Best PJ, Bartholomew BA et al.
J Invasive Cardiol. 2007 19 (5): 229-33.
Objective We sought to externally validate the William Beaumont Hospital (WBH) risk score for radiocontrast-induced nephropathy (RCIN) following percutaneous coronary intervention (PCI). Background RCIN is associated with increased mortality and morbidity following PCI and accounts for increased hospital costs and lenght of stay. Methods A total of 4.814 PCI procedures were used for validation of the WBH risk score, using a > 1.0 mg/dl increase in serum creatinine (Cr) as the definition of RCIN. Clinical and procedural details were identified within the Mayo Clinic PCI registry. Multiple imputation was used to impute values where missing. Five imputation sets were created and averaged to compute the final estimate. Results Follow-up Cr was available in 3.213 (67%) of procedures and RCIN occured in 1.9% of cases. Baseline Cr clearence was missing in 13%. All other risk factors used to calculate the risk score were missing in 25% of the procedures. The risk score has the ability to discriminate well between patients at low and high risk of post-PCI RCIN; c-statistic = 0.86. In-hospital mortality occured in 6.6% (4/61) with RCIN vs. 1.2% (37/3152) without RCIN. The odds ratio for in-hospital mortality is 5.3 (95% CI, 1.9, 15.0; p = 0.002) for those with RCIN vs. those without. Conclusions The WBH risk score can identify patients at high and low risk of RCIN following PCI. Use of this risk score can identify patients at high risk of RCIN development and direct the use of preventive measures to the highest-risk population, improving patients outcome and prognosis.
5. Paradoxical association between body mass index and mortality in men with CKD not yet on dialysis.
Kovesdy CP, Anderson JE, Kalantar-Zadeh K.
Am J Kidney Dis. 2007 49 (5): 581-91.
Background Low body mass index (BMI) is associated with greater mortality in patients on dialysis therapy. This relationship is less well characterized in patients with chronic kidney disease (CKD) who are not yet on dialysis therapy. Study design Historic prospective cohort. Setting & Participants 521 male US veterans with CKD (age, 68.8 +/- 10.4 years; 21.3% black; estimated glomerular filtration rate, 37.5 +/- 16.8 mL/min/173 m (2) [0.62 +/- 0.28 mL/s/1.73 m (2)]) at single medical center. Predictor BMI. Outcomes & Measurements Associations with all-cause mortality were explored in fixed-covariate and time-dependent Cox models and sequentially adjusted for demographic characteristics (age and race), case-mix (comorbidity index, smoking, blood pressure, estimated glomerular filtration rate, and medication use), and surrogates of malnutrition and inflammation (serum albumin, cholesterol, and bicarbonate levels; white blood cell count; percentage of lymphocytes; and hemoglobin level). Results Patients were followed up for up to 5.5 years, and the mortality rate was 128.3 deaths/1.000 patient-years (95% confidence interval [CI], 110.5 to 149.0). Higher BMI was associated with lower mortality in the fixed-covariate Cox models, including the fully adjusted model (adjusted hazard ratios for mortality in the group with BMI in 10th to 50th, 50th to 90th, and > 90th versus < 10th percentiles, 0.75 [95% CI, 0.46 to 1.22], 0.56 [95% CI, 0.33 to 0.94], and 0.39 [95% CI, 0.17 to 0.87]; P (trend) = 0.005). Associations were similar in a time-dependent Cox model (P (trend) = 0.008 in the fully adjusted model). Limitations Results may not be generalizable. Conclusions Lower BMI is associated with greater mortality in patients with CKD not yet on dialysis therapy. Adjusment for case-mix and surrogate markers of malnutrition and inflammation attenuated, but did not reverse, this relationship.
6. Impact of haemoglobin concentration and chronic kidney disease in patients with coronary heart disease undergoing percutaneous coronary interventions.
Husemann W, Fobker M, Pohlen M et al.
Nephrol Dial Transplant. 2007 Apr 23; [Epub ahead of print].
Background A few recent studies suggested that anaemia has a marked impact on the survival of patients with coronary heart disease (CHD). However, all of these analyses did not take into consideration that chronic kidney disease (CKD) plays an important role in erythropoiesis and anaemia. Therefore, we assessed in this study whether anaemia is an independent predictor of mortality or if its impact was confounded by CKD, which is known to have itself a marked impact on outcomes of patients with CKD. Methods In a retrospective cohort study, we analysed 709 patients with symptomatic and significant CHD who underwent percutaneous coronary interventions. Patients were classified as anaemic using the WHO definition; renal function was classified by the estimated glomerular filtration rate (eGFR). Results In comparison with non-anaemic patients, anaemic patients had a significantly higher in-hospital mortality (4.9 vs 0.5%, P < 0.001). moreover, 1-year mortality rates of anaemic patients were significantly higher regardless of whether they had a normal eGFR (22 vs 2.8%, P = 0.029), an eGFR of 60-89 ml/min (14 vs 4.2%, P < 0.001), an eGFR of 30-59 ml/min (21 vs 3.7%, p < 0.001) or an eGFR < 30 ml/min (26 vs 0%, NS). When cumulative mortality was analysed by haemoglobin concentrations in steps of 1 g/dl from < 11.0 g/dl to > 16.9 g/dl, 1-year mortality rates were 28, 18, 15, 5.5, 3.8, 5.7, 1.5 and 0%, respectively (P < 0.001, log rank). Even after adjusment for comorbidities by multivariable Cox regression models, haemoglobin remained a significant predictor of long-term mortality (hazard rate ratio 0.77, 95% confidence interval (CI): 0.62-0.82, P < 0.001) while eGFR was not (hazard rate ratio 1.0, 95% CI: 0.99-1.01). Conclusions Anaemia was found to be a strong and independent predictor of acute and long-term mortality in patients with symptomatic CHD, regardless of the presence of CKD.
7. An introduction to biomarkers: Applications to chronic kidney disease.
Lemley KV.
Pediatr Nephrol. 2007 Mar 30; [Epub ahead of print].
Diagnosis and management of chronic kidney disease (CKD) will be characterized in the future by an increasing use of biomarkers-quantitative indicators of biologic or pathologic processes that vary continuously with progression of the process. ’’Classical’’ biomarkers of CKD progression include quantitative proteinuria, the percentage of sclerotic glomeruli or fractional interstitial fibrosis. New candidate biomarkers (e.g., urinary proteomic patterns) are being developed based on both mechanistic and ’’shotgun’’ approaches. Validation of potential biomarkers in prospective studies as surrogate endpoints for hard clinical outcomes is often complicated by the long lag time to the ultimate clinical outcome (e.g., end-stage rena disease). The very dense data sets that result from shotgun approaches on small numbers of patients carry a significant risk of model overfitting, leading to spurious associations. New analytic methods can help to decrease this risk. It is likely that clinical practice will come to depend increasingly on multiplex (vector) biomarkers used in conjunction with risk markers in early diagnosis as well as to guide therapy.
8. Urinary proteome profiling using microfluidic technology on a chip.
Thongboonkerd V, Songtawee N, Sritippayawan S.
J Proteome Res. 2007 6 (5): 2011-8.
Clinical diagnostics and biomarker discovery are the major focuses of current clinical proteomics. In the present study, we applied microfluidic technology on a chip for proteome profiling of human urine from 31 normal healthy individuals (15 males and 16 females), 6 patients with diabetic nephropathy (DN), and 4 patients with IgA nephropathy (IgAN). Using only 4 muL of untreated urine, automated separation of proteins/peptides was achieved, and 1-7 (3.8 +/- 0.3) spectra/bands of urinary proteins/peptides were observed in the normal urine, whereas 8-16 (11.3 +/- 1.2) and 9-14 (10.8 +/- 1.2) spectra were observed in urine samples of DN and IgAN, respectively. Coefficient of variations of amplitudes of lower marker (1.2 kDa), system spectra (6-8 kDa), and upper marker (260.0 kDa) were 22.84, 24.92, and 32.65%, respectively. ANOVA with Tukey post-hoc multiple comparison revealed 9 spectra of which amplitudes sinificantly differed between normal and DN urine (DN/normal amplitude ratios ranged from 2.9 to 3102.7). Moreover, the results also showed that 3 spectra (with molecular masses of 12-15, 27-28, and 34-35 kDa) were significantly different between DN and IgAN urine (DN/IgAN amplitude ratios ranged from 3.9 to 7.4). In addition to the spectral amplitudes, frequencies of some spectra could differentiate the normal from the disease urine but could not distinguish between DN and IgAN. There was no significant difference, regarding the spectral amplitude frequency, observed between males and females. These data indicate that the microfluidic chip technology is applicable for urinary proteome profiling with potential uses in clinical diagnostics and biomarker discovery.
Keywords: proteomics * proteome * urine* microfluidics * chip * arrays * diagnostics * biomarker discovery.
9. Plasma and urine levels of resistin and adiponectin in chronic kidney disease.
Yaturu S, Reddy RD, Rains J et al.
Cytokine. 2007 Mar 23; [Epub ahead of print].
Background Subjects with chronic kidney disease (CKD) have an increased risk of developing coronary atherosclerosis. Adipocyte hormones, resistin and adiponectin are implicated in insulin resistance and atherosclerosis. However, few studies in the literature address the role of adipocyte hormones in CKD. The aim of this study was to compare the levels of resistin, adiponectin and other inflammatory markers in subjects with CKD with those of the control subjects. Material and Methods In a cross-sectional study, we measured basal metabolic panel, fasting lipid panel and levels of glucose, resistin, adiponectin, insulin, C-reactive protein (CRP) and TNF-alpha in 43 subjects with CKD compared with those of 34 control subjects. We also measured the resistin and adiponectin levels in urine samples (16). Results Subjects with CKD have increased insulin levels and insulin resistance index (IRI). Compared with controls, subjects with CKD had increased levels of resistin (5.12 +/- 3.2 vs. 7.5 +/- 5.9, p < 0.05), CRP (1.7 +/- 2.2 vs. 5.97 +/- 6.0, p < 0.0005), and TNF-alpha (3,4 +/- 2.0 vs. 5.2 +/- 3.5, p < 0.005). Resistin levels correlated with CRP and TNF-alpha, even with BMI as a covariate. Although 60% of subjects with CKD have CAD, the plasma levels of adiponectin were not decreased in subjects with CKD compared with controls (17.02 +/- 9.8 vs. 16.40 +/- 9.0 with p value 0.78). Urinary adiponectin levels correlate inversely with GFR (r = -0.4; p < 0.05) and plasma adiponectin levels (r = 0.9; p < 0.0001). Conclusions Subjects had normal levels of plasma adiponectin despite the adverse metabolic environment for CAD. In addition, this study demonstrates the relationship between resistin and TNF-alpha in subjects with CKD and suggests that resistin may play a role in the sub-clinical inflammation associated with CKD, suggesting that adiponectin clearence may be decreased as shown by the inverse correlaton of urinary adiponectin with GFR.
10. Low fat adiponectin expression is associated with oxidative stress in non-diabetic humans with chronic kidney disease - impact on plasma adiponectin concentration.
Barazzoni R, Bernardi A, Biasia F et al.
Am J Physiol Regul Integr Comp Physiol. 2007 Mar 15; [Epub ahead of print].
In spite of association between high plasma adiponectin and high metabolic and cardiovascular (CV) risk, highest adiponectin increments retain CV and metabolic protective effects in advanced chronic kidney disease (CKD). Passive accumulation can favor CKD-associated hyperadiponectinemia but potential additional regulation by adipose tissue remains undefined. Oxidative stress (OS) is associated with metabolic and CV disease and with CKD [increasing from conservative treatment (CT) to maintenance hemodialysis (MHD)], and OS can reduce adiponectin expression in experimental models. OS (plasma thio-barbituric acid-reactive substances: TBARS), subcutaneous adipose adiponectin mRNA, and plasma adiponectin were studied in CKD patients (stage 4-5) on CT (n = 7) or MHD (n = 11). Compared to CT and controls (C: n = 6) MHD had highest TBARS and lowest adiponectin mRNA (P < 0.05) with lower adipose adiponectin protein (P < 0.05 vs CT). MHD also had lower plasma adiponectin than CT although both had higher adiponectin than C (P < 0.05). In renal transplant recipients (RT: CKD stage 3; n = 5) normal TBARS were in turn associated with normal adiponectin mRNA (P < 0.05 vs MHD). In all CKD (n = 23) adiponectin mRNA was associated positively with adiponectin plasma concentartion (P < 0.01). In all subjects (n = 29) adiponectin mRNA was related (P < 0.05) negatively with TBARS after adjusting for plasma C-reactive protein (CRP) or CRP and creatinine. Thus altered OS, adiponectin expression and plasma concentration represent a novel cluster of metabolic and CV risk factors in MHD that are normalized in RT. The data suggest novel roles of: a) MHD-associated OS in modulating adiponectin expression; b) adipose tissue in contributing to circulating adiponectin in advanced CKD.
Key words: adiponectin, oxidative stress, kidney disease.
11. Gender-specific association of adiponectin as a predictor of progression of chronic kidney disease: The Mild to Moderate Kidney Disease Study.
Kollerits B, Fliser D, Heid IM et al.
Kidney Int. 2007 Apr 25; [Epub ahead of print].
Progressive renal vascular sclerosis is a key feature of chronic kidney disease (CKD). Adiponectin, and adipokine with potent anti-inflammatory and antiatherosclerotic properties, is associated with insulin resistance, type II diabetes and cardiovascular disease. In this study, we evaluated the predictive value of adiponectin for the progression of CKD in patients enrolled in the Mild to Moderate Kidney Disease Study. The primary endpoint was defined as a doubling of the baseline serum creatinine and/or terminal renal failure in 177 patients who completed a prospective follow-up of 7 years. Patients who reached a progression endpoint (n = 65) were significantly older, had higher baseline serum creatinine, proteinuria and adiponectin concentrations and more components of the metabolic syndrome. A gender-stratified Cox model revealed adiponectin in men as a significant predictor of progression after adjusment for age, glomerular filtration rate, and proteinuria. Male patients with adiponectin levels above their ROC analysis-derived optimal cutoff of 4 mug/ml had a significantly faster progression than patients below this point. This prospective long-term study in patients with CKD indicates high adiponectin as a novel independent predictor of disease progression in men but not in women. Our observation may be relevant for the other conditions of progressive vascular sclerosis and diabetic nephropathy.
12. B-type natriuretic peptide concentrations predict the progression of nondiabetic chronic kidney disease: The-Mild-to-Moderate Kidney Disease Study.
Spanaus KS, Kronenberg F, Ritz E et al.
Clin Chem. 2007 May 3; [Epub ahead of print].
Background Plasma concentrations of B-type natriuretic peptide (BNP) and N-terminal proBNP are diagnostic and prognostic biomarkers of heart failure and are also increased in patients with chronic kidney disease (CKD). WE examined the relevance of BNP and NT-proPNP as predictors of CKD progression. Methods Of 227 nondiabetic patients with mild-to-moderate renal insufficiency, 177 patients ages 18-65 years were followed in a prospective multicenter cohort study for a period of 2.5 ml/min per yr) during a mean follow-up period of 23 mo (maximum 43 mo) was associated with urinary angiotensinogen of > 3.0 nmol Ang I equivalent per 1 g of urinary creatinine (AngI Eq/g Cre) at enrollment (hazard ratio 3.52). The event-free survival for deterioration of renal function was better in patients with urinary angiotensinogen < 3.0 nmol AngI Eq/g Cre than those > 3.0 nmol AngI Eq/g Cre. Losartan reduced urinary and plasma angiotensinogen, urinary protein and type IV collagen, and systolic BP, despite concomitant increase in plasma renin and AngII. These data suggest that urinary angiotensinogen is a potentially suitable marker of intrarenal AngII activity associated with increased risk for deterioration of renal function in patients with CKD.
14. Chronic glomerulonephritis associated with IgG subclass deficiency.
Kamei K, Nakagawa A, Otsuka Y et al.
Pediatr Nephrol. 2007 Apr 17; [Epub ahead of print].
We experienced two patients with IgG subclass deficiency who suffered from chronic glomerulonephritis (GN). Patient 1 was a 17-year-old girl with IgG subclass deficiency (combined deficiency of IgG2 and IgG4). Renal biopsy was performed when she was aged 16 years, and she was diagnosed with membranoproliferative GN. Patient 2 was a 16-year-old girl with IgG subclass deficiency of IgG2, IgG3 and IgG4). Renal biosy was performed when she was aged 15 years, and she was diagnosed with membranous nephropathy. We examined the glomerular deposition patterns of their IgG subclasses. Furthermore, we compared their clinical and laboratory findings with those of three patients with IgG subclass deficiency without GN. Patients with GN suffered infections more frequently than those without GN. The serum levels of IgG (especially IgG1) and IgM were higher in patients with GN than in those without GN. In patient 1 IgG1 and IgG3 were deposited in mesangiocapillary pattern, but, in patient 2, only IgG1 was deposited in a capillary pattern. Thus, the different patterns of IgG subclass deficiency between the two patients may be responsible for their different glomerular pathologies. To the best of our knowledge, this is the first report of chronic GN in patients with IgG subclass deficiency.
15. Hepatitis C infection with false negative serology in a patient with mixed cryoglobulinemic vasculitis.
Tini GM, Wuscher V, Jeker R.
Dtsch Med Wochenschr. 2007 132 (12): 616-8.
History and Admission findings A 72-year-old man with nausea, fever and elevated inflammatory parameters was transferred for further diagnostic assessment and treatment. On examination a palpable purpura was obvious without any signs of infection. Investigations Creatinine kinase was 350 mmol/l with a proteinuria of 20 g per day. Histological examination revealed hypersensitivity vasculitis in the cutis and a membranoproliferative glomerulonephritis. In addition there was a mixed cryoglobulinemia with a negative test for hepatitis C virus. Further investigation revealed hepatitis C virus RNA genotype 1 b in the cryoprecipitate. Diagnosis and Treatment The patient was succesfully treated with interferon alpha for 12 month. The nephrotic syndrome improved and the proteinuria ceased. Conclusion Mixed cryoglobulinemias are associated with hepatitis C infection in over 80% of cases. Normally it is easy to make the diagnosis serologically with an ELISA test. But in a few cases the virus RNA is only detectable in the cryoprecipitate. If there is a high suspicion of an hepatitis C infection with cryoglobulinemia but HCV serolgy is negative, it is essential that virus antigen and antibodies are searched for in the cryoprecipitate.
16. Chronic lead poisoning: A ’’forgotten’’ cause of renal disease.
Benjelloun M, Tarrass F, Hachim K et al.
Saudi J Kidney Dis Transpl. 2007 18 (1): 83-6.
Chronic lead nephropathy occurs as a results of years of lead exposure. Nowadays, with the induction of high standards for industrial hygiene, symptomatic lead intoxication has become extremely rare. We report a case of chronic lead nephropathy in a 59-year-old man who worked in a battery-recycling unit and was diagnosed with plumbism during a regular screening few years ago. The diagnosis was suspected by the following findings: serum creatinine 160 microg/L, creatinine clearence 46 ml/min, daily urine protein excretion 0.1 g, uric acid 9.7 mg/dl, blood lead 9.2 microg/dl, and a urinary excretion of 850 microg lead/72h after a moblisation test by a Na (2)-Ca-EDTA chelating agent. Renal ultrasound showed bilateral boderline small kidneys. The kidney biopsy revealed moderate focal atrophy, loss of proximal tubules, and prominent interstitial fibrosis. The patients was prescribed angiotensin-converting enzyme inhibitors to slow the progression of renal insufficiency and control the blood pressure. Hyperuricemia was also treated and controlled. During the regular follow-up, renal function remained stable with no proteinuria. A high index of suspicion for lead intoxication in chronic kidney disease patients should be practiced, especially in patients with hyperuricemia. Chelation of lead urinary excretion is helpful in the diagnosis of this disease.
17. Case-control study of gadodiamide-related nephrogenic systemic fibrosis.
Marckmann P, Skov L, Rossen K et al.
Nephrol Dial Transplant. 2007 May 4; [Epub ahead of print].
Background Nephrogenic systemic fibrosis may be caused by gadolinium (gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients exposed to gadodiamide develop nephrogenic systemic fibrosis. Methods We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were retrieved from medical records. Results Cases had been exposed to a mean gadodiamide dose of 0.29 mmol/kg (range 0.18-0.50) shortly before first signs of nephrogenic systemic fibrosis. Controls had been exposed to 0.28 mmol/kg (0.13-0.49). Cumulative gadodiamide exposure while in chronic kidney disease stage 5 was significantly higher among cases compared with controls (0.41 vs 0.31 mmol/kg, P = 0.05) and among severe cases (n = 9) compared with non-severe cases (0.49 vs 0.33 mmol/kg, P = 0.02). Severe cases developed primarily among patients in regular haemodialysis therapy at exposure. Cases had higher serum concentrations of ionized calcium and phosphate than controls and tended to receive higher doses of epoietin-beta than controls at time of exposure. Severe cases were treated with higher doses of epoietin-beta than non-severe cases at exposure (10.8 vs 4.4 10(3) IU/week, P = 0.02). Conclusions Increasing cumulative gadodiamine exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamine-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.
18. Enforcement of the ban on aristolochic acids in Chinese traditional herbal preparations on the Dutch market.
Martena MJ, van der Wielen JC, van de Laak LF et al.
Anal Bioanal Chem. 2007 May 8; [Epub ahead of print].
In traditional chinese medicine several Aristolochia species are used. Aristolochia spp. Contain a mixture of aristolochic acids (AAs), mainly AA I and AA II which are nephrotoxicants and carcinogens. After AA-related nephropathy (AAN) and urothelial cancer were described in female patients in Belgium following intake of AA-contamined herbal preparations, herbs with AAs were prohibited worlwide. Confusing nomenclature can cause AA contamination of certain Chinese traditional herbal preparations (THPs). Here we report the results of investigations by the Dutch Food and Consumer Product Safety Authority (VWA) into the presence of AAs in THPs sampled on the Dutch market using a liquid-chromatography - - mass spectrometry method. Between 2002 and 2006 we sampled 190 Chinese THPs using recent information on Chinese THPs potentially containing AAs. AA I was found in 25 samples up to a concentration of 1.676 mg/kg. AA II was also found in 13 of these samples up to 444 mg/kg. All 25 positive samples including Mu Tong, Fang Ji, Tian Xian Teng and Xi Xin were part of a group of 68 THPs identified as possibly conatining AAs. In a worst-case scenario, use of a sample of Mu Tong with the highest AA content over a 7-day period would result in the same intake levels of AAs which significantly raised the cancer risk in the Belgian AAN cases. Our results show that contaminated THPs still can be found on the marker following worlwide publicity. Therefore, it can be concluded that testing of possibly AA-contaminated THPs is still essential. [Figure Various Chinese Herbs].
19. Nephrogenic fibrosing dermopathy associated with exposure to gadolium-containing contrast agents - - St. Louis, Missouri, 2002-2006.
Centers for Disease Control and Prevention (CDC).
MMWR Morb Mortal Wkly Rep. 2007 56 (7): 137-41.
Nephrogenic fibrosing dermopathy (NFD) causes thickening and hardening of the skin, often in the extremities, and occurs in patients with underlying renal disease. The skin lesions can progress rapidly, sometimes leading to joint immobility and the inability to walk. In May 2006, nephrologists at hospital A in St. Louis, Missouri, reported to CDC and the Missouri Department of Health and Senior Services (MoDHSS) a cluster of NFD among patients treated in their dialysis units. CDC and MoDHSS conducted an investigation to determine the number of affected patients and identify risk factors for NFD. Thirthy-three patients with NFD were identified in St. Louis, 28 of whom had been treated at hospital A. A matched case-control study was conducted at the hospital. This report summarizes the preliminary results of that study, which indicated that exposure to gadolium-containing contrast agents during magnetic resonance imaging (MRI) studies was independently associated with NFD. Clincians should be aware of the potential for NFD, and when possible, should avoid use of gadolium-containing contrast agents in patients with advanced renal disease.
20. Carbonated beverages and chronic kidney disease.
Saldana TM, Basso O, Darden R et al.
Epidemiology. 2007 May 25; [Epub ahead of print].
Background Carbonated beverage consumption has been linked with diabetes, hypertension, and kidney stones, all risk factor for chronic kidney disease. Cola beverages, in particular, contain phosphoric acid and have been associated with urinary changes that promote kidney stones. Methods We examined the relationship between carbonated beverages (including cola) and chronic kidney disease, using data from 465 patients with newly diagnosed chronic kidney disease and 467 community controls recruited in North Carolina between 1980 and 1982. Results Drinking 2 or more colas per day was associated with increased risk for chronic kidney disease (adjusted odds ratio = 2.3, 95% confidence interval = 1.4-3.7). Results were for regular colas (2.1; 1.3-3.4) and artifically sweetened colas (2.1; 0.7-2.5). Noncola carbonated beverages were not associated with chronic kidney disease (0.94; 0.4-2.2). Conclusions These preliminary results suggest that cola consumption may increase the risk of chronic kidney disease.
21. High incidence of autoantibodies in Fabry disease patients.
Martinez P, Aggio M, Rozenfeld P.
J Inherit Metab Dis. 2007 Apr 24; [Epub ahead of print].
Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism that results from a deficiency of the lysosomal enzyme alpha-galactosidase A. This defect leads to the accumulation of its substrates, mainly globotriaosylceramide, in lysosomes of cells of different tissues. Different studies have shown the involvement of immunopathologies in different sphingolipidoses. The coexistence of FD and immune disorders such as systemic lupus erythematosus, rheumatoid arthritis and IgA nephropathy, has been described in the literature. The aim of this study was to evaluate the prevalence of a group of autoantibodies in a series of Argentine FD patients. Autoantibodies against extractable nuclear antigens (ENAs), double-stranded DNA, anticardiolipin and phosphatidylserine were assayed by ELISA. Lupus anticoagulants were also tested. Fifty-seven percent of the samples showed reactivity with at least one autoantigen. Such reactivities were more frequent among males than among females. Antiphospholipid autoantibodies were detected in 45% of our patients. The high rate of thrombosis associated with FD could be related, at least in part, to the presence of antiphospholipid autoantibodies in Fabry patients. We found the presence of ENAs, which are a characteristic finding of rheumatological diseases, previous a frequent misdiagnosis of FD, in around 39% of the cases. The detection of a high level of autoantibodies must be correlated clinically to determine the existence of an underlying autoimmune disease. With the recent development of therapy, the life expectancy in FD will increase and autoimmune disease might play an important role in the morbidity of FD.
22. Historical perspective of pregnancy in chronic kidney disease.
Hou S.
Adv Chronic Kidney Dis. 2007 14 (2): 116-8.
Preeclampsia was first recognized as a cause of proteinuria unique to pregnancy in 1843 and the risk of pregnancy in women with preexisting renal disease was noted in the 1930s. Since then, we have recognized that the majority of women with kidney disease who become pregnant have surviving infants. The exception is women on dialysis whose pregnancy results in only 50% to 75% of infant survival. All women with renal disease are at increased risk for hypertension during pregnancy, but the risk of more rapid than expected progression of renal disease generally occurs in women serum creatinine greater than 1.4 mg/dL, with an even higher risk in women with serum creatinines greater than 2 mg/dL. Dialysis patients conceive infrequently and have a high frequency of fetal loss and neonatal death. Fertility is restored by renal transplant and guidelines are being developed regarding the ideal timing of pregnancy, the kidney function required for a safe pregnancy, and the use of immunosuppressive drugs in pregnancy.
23. Chronic kidney disease and pregnancy: Maternal and fetal outcomes.
Fischer MJ.
Adv Chronic Kidney Dis. 2007 14 (2): 132-45.
Chronic kidney disease complicates an increasing number of pregnancies, and at least 4% of childbearing-aged women are afflicted by this condition. Although diabetic nephropathy is the most common type of chronic kidney disease found in pregnant women, a variety of other primary and systemic kidney disease also commonly occur. In the setting of mild maternal primary chronic kidney disease (serum creatinine < 1.3 mg/dL) without poorly controlled hypertension, most pregnancies result in live births and maternal kidney function is unaffected. In caes of more moderate and severe maternal primary chronic kidney disease, the incidence of fetal prematurity, low birth weight, and death increase substantially, and the risk of accelerated irreversible decline in maternal kidney function, proteinuria, and hypertensive complications rise dramatically. In addition to kidney function, maternal hypertension and proteinuria portend negative outcomes and are important factors to consider when risk stratifying for fetal and maternal complications. In the setting of diabetic nephropathy and lupus nephropathy, other systemic disease features such as disease activity, the presence of antiphospholipid antibodies, and glycemic control play important roles in determining pregnancy outcomes. Concomitant with advances in obstetrical management and kidney disease treatments, it appears that the historically dismal maternal and fetal outcomes have greatly improved.
24. Outcome of infants born to women with chronic kidney disease.
Blowey DL, Warady BA.
Adv Chronic Kidney Dis. 2007 14 (2): 199-205.
Pregnancy in women with chronic kidney disease is not uncommon and is not without risk to the mother and child. This article reviews the literatue on the outcome of infants from pregnancies in women with chronic kidney disease (CKD), including those receiving dialysis and those living with a fuctional kidney transplant. Pregnancy in women with CKD and end-stage renal disease (ESRD) is associated with a higher rate of premature birth and small-for-gestational-age (SGA) infants, with resultant increase in neonatal mortality. Although congenital anomalies or long-term developmental issues do not appear to be a significant risk, these areas deserve further study, especially as newer immunosuppressive mediactions are employed in kidney transplant recipients.
25. Nutritional management of pregnancy in chronic kidney disease.
Stover J.
Adv Chronic Kidney Dis. 2007 14 (2): 212-4.
The nutritional management of pregnant adults with chronic kidney disease (CKD) presents the challenge of combining necessary modifications in nutrient requirements for both pregnancy and kidney impairment. The dietitian must follow these women closely to ensure adequate intakes of kilocalories, protein, and specific vitamins and minerals. Combining the suggested energy and protein needs for CKD recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines with those for the general population seems feasible during pregnancy. Vitamin and mineral requirements are also a combination of those for CKD and pregnancy. Although diets may need to be restricted because of CKD, golas are to have good communication among members of the health-care team to allow the patient optimal nutrition combined with quality medical care.
26. Pregnancy and contraceptive counseling of women with chronic kidney disease and kidney transplants.
Watnick S.
Adv Chronic Kidney Dis. 2007 14 (2): 126-31.
Women with kidney disease of childbearing age should expect proactive counseling regarding pregnancy and contraception. Discussions should include the impact of pregnancy on their kidney disease and the impact of kidney disease on maternal and fetal outcomes. However, nephrologists rarely discuss sexual dysfunction, infertility, menstrual irregularities, and contraception with their premenopausal women patients. This review will consider pregnancy-related issues to discuss when counseling women with all stages of chronic kidney disease. Issues related to contraception in women on dialysis, women with functioning kidney transplants, and those with chronic kidney disease will also be reviewed.
27. Ethical considerations regarding pregnancy in chronic kidney disease.
Davison SN.
Adv Chronic Kidney Dis. 2007 14 (2): 206-11.
Pregnancy in the context of chronic kidney disease (CKD) is a daunting clinical scenario for both health-care providers and patients and raises ethical and social questions that have important implications for health policy and funding. Despite potential problems, women with CKD will continue to conceive and deliver babies, and nephrologists will be faced with the challenge of caring for them. This paper discusses ethical issues regarding pregnancy in CKD and highlights the controversies surrounding parental, fetal, and societal rights.
28. How have the past 5 years of research changed clinical practice in paediatric nephrology?
Marks SD.
Arch Dis Child. 2007 92 (4): 357-61.
Clinical practice in paediatric nephropathy is continously evolving to mirror the research output of the 21st century. The management of antenatally diagnosed renal anomalies, urinary tract infections, nephrotic syndrome and hypertension is becoming more evidence based. Obesity and related hypertension is being targeted at primary and secondary care. The evolving field of molecular and cytogenetics is discovering genes that are facilitating clinicians and families with prenatal diagnoses and understanding of disease processes. The progression of chronic kidney disease in childhood to end-stage renal failure (ESRF) can be delayed using medical treatment to reduce proteinuria and treat hypertension. Pre-emptive living-related renal transplantation has become the treatment of choice for children with ESRF, thereby reducing the morbidity and mortality associated with peritoneal and haemodialysis. Although peritoneal dialysis, which is performed in the patient’s home, is the preferred modality for children for whom there is not living or deceased donor for transplantation, home nocturnal haemodialysis is becoming a feasible option. Imaging modalities with the use of magnetic resonance and computerised tomography are continously improving. As mortality for renal and vasculitic disease improves, the gauntlet is now thrown down to reduce morbidity with secondary prevention of longer-term complications such as atherosclerosis and hyperlipidemia. Clinical and drug trials in the fields of hypertension, nephrotic syndrome, systemic lupus erythematosus, vasculitis and transplantation are producing more effective treatments, thereby reducing the morbidity results from the disease processes and the side effects of drugs.
29. Bone mass, biochemical markers and growth in children with chronic kidney disease: A 1-year prospective study.
Swolin-Eide D, Magnusson P, Hansson S.
Acta Pediatr. 2007 Mar 23; [Epub ahead of print].
Aim This study was designed to investigate bone mineral density (BMD), growth parameters and biochemical markers in children with chronic kidney disease (CKD). Methods Sixteen patients, 4-18 years, with CKD were prospectively followed for 1 year. Auxological data, body composition, BMD by dual-energy X-ray absorptiometry, bone age, bone turnover markers, vitamin D, parathyroid hormone (PTH), leptin, osteoprotegerin, insulin-like growth factor-I (IGF-I) and IGF binding protein-3 were measured. A questionnaire regarding bone health and diet was also performed. Results Delayed bone age was observed (n = 11) and the BMD Z-score for total body were below zero in seven patients. However, total body BMD (TBBMD) increased in 12 patients. Most patients had increased osteocalcin and carboxy-terminal telopeptide of type I collagen, but normal alkaline phosphatase, type I procollagen intact amino-terminal propeptide and tartrate-resistant acid phosphatase 5b. Ten patients had increased PTH. Most children had normal levels of leptin, osteoprotegerin, IGF-I and IGFBP-3. Leptin, at baseline, correlated with differences in TBBMD over 1 year. Conclusions Only seven (44%) had negative Z-scores and TBBMD increased over 1-year. Bone markers at baseline did not predict the longitudinal changes in BMD.
30. Sexual function in chronic kidney disease.
Anantharaman P, Schmidt RJ.
Adv Chronic Kidney Dis. 2007 14 (2): 119-25.
Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and fertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.
31. Therapy insight: Sexual dysfunction in patients with chronic kidney disease.
Finkelstein FO, Shirani S, Wuerth D et al.
Nat Clin Pract Nephrol. 2007 3 (4): 200-7.
Sexual dysfunction is common in people with chronic kidney disease (CKD). Sexual dysfunction in these patients should be thought of as a multifactorial problem that is affected by a variety of physiological and psychological factors, as well as by comorbid conditions. Assessment of sexual difficulties in patients with CKD, therefore, involves a careful investigation of a variety of domains. The development of treatment strategies presents challanges as it is often difficult to determine the primary factor (s) responsible for the sexual dysfuction. It is important to think of the treatment in the overall context of the management of various medical problems presented by patients with CKD. It must be remembered that the design of therapeutic approaches for each patients is dependent on the systematic evaluation of the functional and psychosocial problems presented, and assessment of the cause (s) of sexual dysfunction.
32. Progression of coronary artery calcification in predialysis patients.
Russo D, Corrao S, Miranda I et al.
Am J Nephrol. 2007 27 (2): 152-8.
Background In patients on dialysis coronary artery calcification (CAC) rapidly proceeds due to impaired mineral metabolism and/or exogenous calcium load. Progression has not been assessed in patients with chronic kidney disease not yet requiring dialysis (CKD patients). In this study, rate and determinants of CAC progression have been evaluated in CKD patients who are exposed to minor derangement of mineral metabolism and calcium load. Methods Consecutive patients enrolled. Exclusion criteria were: symptomatic coronary disease, arrhythmia, myocardial infarction, and diabetes. Serum calcium, phosphorus, parathyroid hormone, homocysteine, C-reactive protein, triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol were serially measured. Fetuin-A was assessed at entry into the study. CAC progression was detected by measuring total calcium score (TCS) with computed tomography. Initial and final scans were obtained. Predictive factors of progression were investigated. Results Fifty-three patients had CKD (stage 3-5 CKD; K-DOQI classification) not yet requiring dialysis, and 60 patients had normal renal function (NRF patients). Follow-up lasted 24 +/- 4.2 months (mean +/- SE). Patients with CAC were older with lower serum fetuin-A. TCS increased from 73 +/- 17 to 80 +/- 20 (mean +/- SE; p = NS) in NRF patients, and from 384 +/- 116 to 602 +/- 140 (mean +/- SE; p < 0.01) in CKD patients. Serum phosphorus [OR = 1.97 (1.14-3.41, 95% CI); p = 0.015] was the only variable that was associated with CAC progression. Cardiovascular events occured in CKD patients with CAC. Conclusion CAC progression was prominent in CKD patients and correlated with serum phosphorus. Fatal and nonfatal cardiovascular events were more frquent in CKD patients. Studies are required to ascertain whether the attainment of serum phosphorus concentration lower than that suggested by current guidelines may reduce CAC progression and ultimately mortality.
33. Differential impact of age on verbal memory and executive functioning in chronic kidney disease.
Thornton WL, Shapiro RJ, Deria S et al.
J Int Neuropsychol Soc. 2007 13 (2): 344-53.
We compared aspects of verbal memory and executive functioning in 51 community-dwelling persons with chronic kidney disease (CKD) and 55 healthy controls matched on age and education. Depressive symptoms were assessed with the Centre for Epidemiological Studies-Depression Scale (CES-D), and illness variables included glomerular filtration rate (GFR) and hemaoglobin. Findings indicate that persons with CKD exhibited poorer performance on measures of memory (CVLT-II) and executive functioning (DKEFS Trailmaking Test B and Color-Word Interference Tests) in comparison with healthy controls. Furthermore, performance decrements were magnified in older CKD participants on measures of verbal memory and inhibition. Nearly half of CKD participants aged 61 and older exhibited significant impairments in verbal memory and inhibition in comparison to matched controls. Cognitive performance in CKD was not associated with measures of illness severity. The differences observed were not accounted for by depressive symptoms, which were only weakly associated with cognitive performance, and negatively associated with age. Findings highlight the need for further exploration of the etiologies and functional consequences of the neuropsychological presentation of CKD.
34. Association between multidisciplinary care and survival for elderly patients with chronic kidney disease.
Hemmelgarn BR, Manns BJ, Zhang J et al.
J Am Soc Nephrol. 2007 18 (3): 993-9.
The effectiveness of multidisciplinary care (MDC) in improving health outcomes for patients with chronic kidney disease (CKD) is uncertain. This study sought to determine the association among MDC, survival, and risk for hospitalization among elderly outpatients with CKD. A total of 6978 patients who were 66 yr and older and had CKD were identified between July 1 and December 31, 2001, and followed to December 31, 2004; 187 (2.7%) were followed in an MDC clinic. Logistic regression was used to determine the propensity score (probability of MDC) for each patient, and MDC and non-MDC patients then were matched 1:1 on the basis of their score. A Cox model was used to determine the association between MDC and risk for death and hospitalization. After adjusment for age, gender, baseline GFR, diabetes, and comorbidity score, there was a 50% reduction in the risk for death for the MDC compared with the non-MDC group (hazard ratio [HR] 0.50; 95% confidence interval [CI] 0.35 to 0.71). There was no difference in the risk for all-cause (HR 0.83; CI 0.64 to 1.06) or cardiovascular-specific hospitalization (HR 0.76; 95% CI 0.54 to 1.06) for the MDC compared with the non-MDC group. In conclusion, it was found that MDC was associated with a significant reduction in the risk for all-cause mortality and, although not statistically significant, a trend toward a reduction in risk for all-cause and cardiovascular specific hospitalizations. The benefits of MDC and an assessment of their economic impact should be tested in randomized, controlled trial.
35. Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage 5.
Murtagh FE, Marsh JE, Donohoe P et al.
Nephrol Dial Transplant. 2007 Apr 4; [Epub ahead of print].
Background The number of elderly patients with chronic kidney disease (CKD) stage 5 is steadily increasing. Evidence is needed to inform decision-making for or against dialysis, especially in those patients with multiple comorbid conditions for whom dialysis may not increase survival. We therefore compared survival of elderly patients with CKD stage 5, managed either with dialysis or conservatively (without dialysis), after the manegement decision had been made, and explored which of several key variables were independently associated with survival. Methods A retrospective analysis of the survival of all over 75 years with CKD stage 5 attending dedicated multidisciplinary pre-dialysis care clinics (n = 129) was performed. Demographic and comorbidity data were collected on all patients. Survival was defined as the time from estimated GFR < 15 ml/min to either death or study endpoint. Results One- and two-year survival rates were 84% and 76% in the dialysis group (n = 52) and 68% and 47% in the conservative group (n = 77), respectively, with significantly different cumulative survival (log rank 13.6, P < 0.001). However, this survival advantage was lost in those patients with high comorbidity scores, especially when the comorbidity included ischaemic heart disease. Conclusions In CKD stage 5 patients over 75 years, who receive specialist nephrological care early, and who follow a planned management pathway, the survival advantage of dialysis is substantially reduced by comorbidity and ischaemic heart disease in particular. Comorbidity should be a major consideration when elderly patients for or against dialysis.
36. Urine biomarkers predict the cause of glomerular disease.
Varghese SA, Powell TB, Budisavljevic MN et al.
J Am Soc Nephrol. 2007 18 (3): 913-22.
Diagnosis of the type of glomerular disease that causes the nephrotic syndrome is necessary for appropriate treatment and typically requires a renal biopsy. The goal of this study was to identify candidate protein biomarkers to diagnose glomerular diseases. Proteomic methods and informatic analysis were used to identify patterns of urine proteins that are characteristic of the diseases. Urine proteins were separated by two-dimensional electrophoresis in 32 patients with FSGS, lupus nephritis, membranous nephropathy, or diabetic nephropathy. Protein abundances from 16 patients were used to train an artificial neural network to create a prediction algorithm. The remaining 16 patients were used as an external validation set to test the accuracy of the prediction algorithm. In the validation set, the model predicted the presence of the diseases with sensitivities between 75 and 86% and specificities from 92 to 67%. The probability of obtaining these results in the novel set by chance is 5× 10 (-8). Twenty-one gel spots were most important for the differentiation of the disease. The spots were cut from the gel, and 20 were identified by mass spectrometry as chargde forms of 11 plasma proteins: Orosomucoid, transferrin, alpha-1 microglobulin, zinc alpha-2 glycoprotein, alpha-1 antitrypsin, complement factor B, haptoglobin, transthyretin, plasma retinol binding protein, albumin, and hemopexin. These data show that disease that cause nephrotic syndrome change glomerular protein permeability in characteristic patterns. The fingerprint of urine protein charge forms identifies the glomerular disease. The identified proteins are candidate biomarkers that can be tested in assays that are more amenable to clinical testing.
37. NOx (nitrite/nitrate) in patients with pediatric nephrotic syndrome.
Kawashima H, Kashiwagi Y, Watanabe C et al.
Pediatr Nephrol. 2007 Feb 8; [Epub ahead of print].
To better understand the role of nitric oxide (NO) in pediatric nephrotic syndrome, we measured nitrite/nitrate (NOx) [Formula: see text] in serum obtained from patients with several pediatric kidney diseases and investigated the locations of endothelail nitric oxide synthase (eNOS) and inducible nitric oxyde synthase (iNOS). Nox in serum showed significantly higher levels than those in healthy controls (mean +/- SE: 297 +/- 55.7 vs. 158 +/- 13.1 pmol/10 mul). There was no significant difference between six patients with frequent relapse and five patients with nonfrequent relapse. The studies with immunostaining of iNOS and nitrotyrosine were negative for glomerulus in patients with nephrotic syndrome. Those findings suggest that NOx might indirectly influence disease progression in nephrotic syndrome.
38. Immunotactoid glomerulonephritis in a child with HIV infection: A case report.
van Biljon G, Louw M, Dreyer L.
Pediatr Nephrol. 2007 Apr 25; [Epub ahead of print].
Renal disease is a common complication of human immunodeficiency virus (HIV) infection in adults. In children, however, HIV pathology of the gastrointestinal and respiratory tracts predominates, whereas renal disease is often an incidental finding. In this report, we describe a child with stage III HIV infection associated with immunotactoid glomerulonephritis (IT). The patient was referred for investigation of idiopathic nephrotic syndrome. Electron microscopy of his renal biopsy specimen revealed numerous electron-dense microtubular deposits, arranged in parallel fashion, consistent with a diagnosis of IT. He received highly antiretroviral therapy (HAART) as well as corticosteroids and is currently in remission. To our knowledge, this is the first report of IT in a child.
39. Nephrotic syndrome preceding psoriasis in children.
Bagga A, Menon S, Hari P et al.
Pediatr Nephrol. 2007 Apr 25; [Epub ahead of print].
Nephrotic syndrome is considered to be a late complication of psoriasis, reported usually in adults and characterized by IgA nephropathy or focal segmental glomerulosclerosis. We report on four children in whom steroid-resistant nephrotic syndrome either preceded (n = 3), by 41-120 months, or occured simultaneously (n = 1) with psoriasis; renal histology showed minimal change disease. Therapy with corticosteroid and cyclosporine resulted in remission of renal and cutaneous symptoms. Minimal change nephrotic syndrome and psoriasis might share similar mechanisms of pathogenesis involving cell-mediated immunity.
40. Polymyosistis associated with focal mesangial proliferative glomerulonephritis with depositions of immune complexes.
Takizawa Y, Kanda H, Sato K et al.
Clin Rheumatol. 2007 26 (5): 792-6.
A 58-year-old man concurrently developed polymyosistis (PM), interstitial lung disease, and nephrotic-range proteinuria. Renal biopsy revealed focal mesangial proliferative glomerulonephritis (mesPGN) with deposition of immunoglobulin and complements. A combination therapy of corticosteroid, intravenous immunoglobulin, and cyclosporine was found very effective for the patient. Glomerulonephritis associated with PM/dermatomyositis (DM) is rare. In our review of related literature, mesPGN was exclusively observed in polymyositis while membranous nephropathy in DM. The mechanism underlying the association between myositis and glomerulonephritis remains to be elucidated.
41. Meningococcal disease associated with an acute-streptococcal complement deficiency.
Daskas N, Farmer K, Coward R et al.
Pediatr Nephrol. 2007 22 (5): 747-9.
Chronic deficiencies in the complement pathway proteins are associated an increased risk of meningococcal disease. Such deficiencies are caused by primary congenital immunodeficiency of a complement protein, properdin or mannose binding lectin, or are secondary to consumption of complement by systemic lupus erythematosus (SLE) or membranoproliferative glomerulonephritis (MPGN). Whatever the cause, the complement deficiency is always chronic. Here we report a case of meningococcal disease (MCD) in a child with a transient complement deficiency (CD), caused by post-steptococcal glomerulonephritis (PSGN).
42. Glomerulonephritis induced by methicillin-resistant Staphylococcus aureus infection that progressed during puerperal period.
Hashimoto M, Nogaki F, Oida E et al.
Clin Exp Nephrol. 2007 11 (1): 92-6.
A 28-year-old Japanese woman developed fever, leg edema, purpura, and abdominal pain during the puerperal period, showing nephrotic syndrome with microscopic hematuria. At first she was thought to have Henoch-Schonlein purpura nephritis and was given steroids at another hospital. Because anasarca and massive urinary protein excretion developed, she was referred to our hospital. Renal biopsy specimens showed endocapillary proliferative glomerulonephritis with massive IgA and C3d deposition along the capillary loops and the mesangium. A bacteriological study detected methicillin-resistant Staphylococcus aureus (MRSA) in cultures of vaginal secretions, urine, stool, and pharyngeal mucus samples. based on the diagnosis of MRSA nephritis, anti-MRSA therapy with antibiotics was tarted, and MRSA became negative for each culture, and urinary protein decreased. Two months after the first renal biopsy, a second renal biopsy was performed, which revealed feeble endocapillry proliferation with mild IgA and C3d deposition in the mesangium. This case showed that the delivery procedura can cause MRSA nephritis after MRSA infection, and that steroid therapy should be avoided in the early phase of this type of nephritis.
43. A 59-kd renal antigen as a new target for rapidly progressive glomerulonephritis.
Audard V, Hellmark T, El Karoui K et al.
Am J Kidney Dis. 2007 49 (5): 710-6.
Anti-glomerular basement membrane (anti-GBM) antibodies are the hallmark of anti-GBM disease, which is characterized by rapidly progressive glomerulonephritis. We describe the case of a 58-year-old woman who presented with rapidly progressive glomerulonephritis with typical anti-GBM staining found by means of direct immunofluorescence microscopy, associated with linear immunoglobulin G deposits on tubules. Serum analysis showed circulating anti-tubular basement membrane antibodies, but failed to detect anti-GBM antibodies. Immunoblotting showed that serum antibodies reacted with a 59-kd antigen found along both GBM and tubular basement membrane.
44. Systemic lupus erythematosus and pregnancy.
Skomsvoll JF, Aasarod K, Salvesen KA et al.
Tidsskr Nor Laegeforen. 2007 127 (6): 725-9.
Background Systemic lupus erythematosus (SLE) often starts in women of fertile age. Due to the unpredictable nature of the disease and the increased risk of the disease flaring up during pregnancy, women with SLE have previously often been advised to avoid pregnancy. This summary reviews current insights in pregnancy management of women with SLE. Method Search in the Medline database (period 1980-2005) using keywords: SLE, lupus nephritis, antiphospholipid antibody, neonatal lupus and pregnancy. Results Previous studies of pregnant women with SLE hav had different designs, sample sizes, selections of patients, definitions and measures of outcome. Women with previous pregnancy losses, an ongoing active diease with nephritis or hypertension and positive antiphospholipid antibodies, have an increased risk of pregnancy loss. The most favourable pregnancy outcomes are achieved when conception takes place during a remission of the disease. Interpretation There are few absolute contraindications for pregnancies in women with SLE. Women with SLE may experience uncomplicated pregnancies, but they need to plan their pregnancies as the risk for complications is increased. Best results are achieved through the cooperation of rheumatologists, gynecologists and nephrologists.
45. Recurrent major infections in juvenile-onset systemic lupus erythematosus - - a close link with long-term disease damage.
Lee PP, Lee TL, Ho MH et al.
Rheumatology (Oxford). 2007 May 23; [Epub ahead of print].
Objectives We postulate that patients with systemic lupus erythematosus (SLE) having recurrent infections are more likely have poorer disease outcome. The aim of this study is to describe the pattern of infections and disease damage that occured in a cohort of patients with juvenile-onset SLE, and to find out whether cumulative disease damage was associated with recurrent infections in these patients. Methods We retrospectively reviewed (1988-2004) the clinical characteristics, infective complications, and disease damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage INDEX (SDI) in 47 juvenile-onset SLE patients. Potential risk factors for disease damage were evaluated by univariate analysis and logistic regression. The correlation between of major infections and disease damage was determined. Results Thirty-two (68.1%) patients had lupus nephropathy and 16 patients (34%) had neuropsychiatric lupus. Sixty-one episodes of major infections, defined as infections requring more than 1 week of antimicrobial agents, occured in 27 patients (57.4%), and 18 patients (31.4%) had recurrent major infections (>/= 2 episodes). Organ damage (SDI >/= 1) was documented in 21 subjects (44.7%). By logistic regression, occurence of major infections (P < 0.001) was the only significant risk factor for disease damage. There was a positive correlation between SDI score with the number of recurrent major infections (Spearman’s correlation coefficient = 0.50, P < 0.001). Conclusion Infections and disease damage are common co-morbidities in juvenile-onset SLE. Recurrent infections could predict poorer disease outcome and associated organ damage in SLE.
46. Diffuse alveolar hemorrhage in Colombian patients with systemic lupus erythematosus.
Canas C, Tobon GJ, Granados M et al.
Clin Rheumatol. 2007 Mar 22; [Epub ahead of print].
Diffuse alveolar hemorrhage (DAH) is a rare life-threatening complication seen in patients with systemic lupus erythematosus (SLE). This paper describes the clinical features and outcome of seven SLE patients with DAH admitted to a medical intensive care unit (ICU) in a referral center. Of a total of 122 SLE patients, seven patients presented this complication (5.7%). Five patients were women (71.4%). Mean age was 24.3 (range 4-51 years). Mean duration of SLE before clincal DAH was 15.7 months (range 0-48 months). DAH was the initial manifestation of SLE in two patients (29%). DAH recurrence was seen in two patients (29%). Active lupus was present in all seven patients. Fever, glomerulonephritis, arthritis, myositis, and peripheral neuropathy were observed in six, four, four, three, and two patients, respectively. Five patients who underwent to bronchoscopy had positive findings of DAH (71.4%; i.e., bloody return of bronchoalveolar lavage with hemosiderin-laden macrophages). Treatment options included intravenous methylprednisolone (10 mg kg (-1) –3 days) following by prednisolone 1 mg kg (-1) and pulse cyclophosphamide (750 mg/m (2)). Plasmapheresis was added in four patients (57.1%) because of the persistence of DAH. All patients were treated in an ICU, six of them requring mechanical respiratory support (85.1%). Mortality rate during ICU stay was 12% (one patient). Our results show that DAH is an incommon complication in SLE patients, requiring a prompt and agressive recognition and treatment with high-dose steroid, intravenous cyclophosphamide, and plasmapheresis. With all of these treatment, there is a trend to a low mortality rate in patients with SLE presenting DAH.
47. Oral 9, Hypocomplementaemic urticarial vasculitis: A rare but important cause of urticaria and angio-oedema.
Roberts C, Rangaraj A, Murphy R.
Br J Dermatol. 2007 Apr 17; [Epub ahead of print].
A 12-year-old girl presented initially with arthritis, back and abdominal pain, weight loss and lethargy. Preliminary blood test showed a positive antinuclear factor, and low C3 and C4. Serum creatinine was normal repeat urinanalysis demonstrated a persistent proteinuria. A diagnosis of systemic lupus erythematosus was made and immunosuppressive treatment was commenced with hydroxychloroquine and prednisolone orally and methotrexate by intramuscular injection. Initially her joint symptoms slightly improved but after 3 months she was still complaining of lethargy with abdominal pains. She also complained of facial swelling and was noted to have urticaria on her face and limbs. Because of the urticaria and angio-oedema, low complement levels and abdominal pain, a diagnosis of hypocomplementaemic urticarial vasculitis (HUVS) was considered and serum C1q and C1q antibody titres were determined showing the presence of C1q antibodies and low C1q titre. A diagnosis was made the immunosuppressive treatment was increased with pulse methylprednisolone, with improvement of her symptoms. HUVS is rare condition. Diagnosis depends on the presentation of hypocomplementaemia, urticaria and at least two of the following: vasculitis from dermal biopsies, arthralgia and arthritis, glomerulonephritis, uveitis or episcleritis, recurrent abdominal pain and the presence of C1q precipitating factor in the plasma. This disorder can present in isolation or in association with other diseases. Treatment of HUVS is notoriously dificult and affected individuals are a particular risk of end-stage renal disease.
48. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: Follow-up of a population-based study.
Karstila K, Korpela M. Sihvonen S et al.
Clin Rheumatol. 2007 May 10; [Epub ahead of print].
The objective is study was to assess the long-term prognosis of nephropathy findings and the incidence of new abnormal clinical renal findings in patients with rheumatoid arthritis (RA). The original population-based cross-sectional study of 604 RA patients was carried out in 1988, 103 nephropathy patients being found. Controls matched for age, sex, and duration of RA were selected from among RA patients with normal renal function and urinanalysis in 1988. In 2003, a follow-up study was made of the 103 nephropathy patients and 102 controls, and the median follow-up time was 13 years. In the original nephropathy group, serum creatinine exceeded 200 mumol/l in 8% of the original isolated hematuria patients, in 30% of the isolated proteinuria patients, in 57% of the combined hematuria and proteinuria patients, but in none of the isolated chronic renal failure (CRF) patients (p = 0.001 for the difference). Probale or definitive renal amyloidosis was diagnosed in 19% of the nephropathy patients. Dialysis therapy was given to 10 out of the 103 nephropathy patients, nine of them belonging to the original isolated proteinuria or combined hematuria and proteinuria groups. There were six renal deaths among the nephropathy patients, and none in the controls. In the control group, new abnormal renal findings, in most cases mild, were detected in 28%. Serum creatinine exceeded 200 mumol/l in 4% of the controls, and dialysis therapy was given to 2% of the controls. Probable or definitive renal amyloidosis was diagnosed in 4% of this group. With regards to the development or progression of chronic renal failure, the long-term clinical prognosis is isolated hematuria and isolated CRF was found to be favorable. Proteinuria alone or combined with hematuria or CRF was related to evidently poorer prognosis.
49. Clustering of inflammatory bowel disease with immune mediated diseases among members of a Northern California-Managed Care Organization.
Weng X, Liu L, Barcellos LF et al.
Am J Gastroeneterol. 2007 Apr 16; [Epub ahed of print].
Background and Aims Previous studies provide evidence that some immun-mediated disease occur at greater frequency among inflammatory bowel disease (IBD) patients than in the general population. The present study examined the co-occurence of IBD with common immune-mediated disorders including asthma, psoriasis, type 1 diabetes, rheumatoid arthritis, multiple slerosis, systemic lupus erythematosus, vitiligo, autoimmune thyroiditis (Grave’s and Hashimoto’s), and chronic glomerulonephritis. Methods We conducted a cross-sectional study among members of the Kaiser Permanente Medical Care Program for the period 1996-2005. A total of 12.601 patients with at least two IBD diagnoses in computerized visit data were asceratined. Four persons without IBD were matched to each IBD patients on age, gender, and lenght of enrollment. Information on co-occuring diseases was obtained from computerized visit data for 1996-2005. Conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the associatation of IBD with immune-mediated disorders after adjusting for smoking. Results Seventeen percent of the IBD patients and 10% of the perons without IBD had a diagnosis for least one immune-mediated disease. IBD patients were more likely to have asthma (1.5. 95% CI 1.4-1.6), psoriasis (1.7, 95% CI 1.5-2.0), rheumatoid arthritis (1.9. 95% CI 1.5-2.3), and multiple slerosis (2.3, 95% CI 1.6-3.3). Conclusions Among the immune-mediated disease we studied, most were more common in IBD patients than in persons without IBD, suggesting that IBD shares common etiologic factors with other immun-mediated diseases.
50. Anti-glomerular basement membrane antibody disease with granulomatous lesions on renal biopsy.
Takahashi M, Otsubo S, Takei T et al.
Intern Med. 2007 46 (6): 295-301.
We present the case of a 56-year-old woman with anti-glomerular basement membrane (anti-GBM) antibody disease accompained by granulomatous reaction in the kidney. Three months prior to admission to our kidney center, she had suffered from interstitial pneumonia and had a slightly elevated level of MPO-ANCA (13 EU). Her serum level of creatinine was normal (0.72 mg/dl) but proteinuria (1+) and hematuria (2+, 1-4/HF) were present. She was admitted to our hospital because of general fatigue, loss of appetite, high fever (over 38.5 degrees C) and a rapid decline in renal function (creatinine 8.50mg/dl). Hemodialysis therapy was started immediately after admission. The serological study was negative for MPO-ANCA but positive for anti-GBM antibody (139 EU). Renal biopsy demonstrated necrotizing glomeruli, cellular crescents and granuloma formation with multinucleated giant cells. Immunoflurescence microscopy revealed liner staining of IgG and C3. We diagnosed granulomatous, crescentic and necrotizing glomerulonephrits, pathologically. She was diagnosed as having anti-GBM antibody disease because alveolar hemorrhage was absent. Steroid therapy including methylprednisolone pulse therapy (500 mg/day, 3 days) and 2 courses of plasma exchange were effective in reducing the fever, anti-GBM antibody titer and C-reactive protein level. Her renal function recovered and she was able to quit hemodialysis therapy 68 days after the start of hemodialysis and she has shown no signs of pulmonary alveolar hemorrhage to date. The present case suggest that intensive therapy may restore renal function in anti-GBM disease even though renal function was sufficiently damaged and required hemodialysis therapy and active pathological changes were observed in renal biopsy specimens.
51. Fibrillary glomerulonephritis with small fibrils in a patients with the antiphospholipid antibody syndrome successfully treated with immunosuppressive therapy.
Javaid MM, Denley H, Tagboto S.
BMC Nephrol. 2007 May 9; [Epub ahead of print].
Background Fibrillary glomerulonephritis is a rare cause of progressive renal dysfunction often leading to the need for dialysis within a few years. The role of immunosuppressive treatment is still uncertain although this has been triad with variable success. Case presentation A 56 year old woman with the antiphospholipid antibody syndrome (IgM anticardiolipin antibodies) was seen in the nephrology clinic with haematuria, proteinuria, and worsening renal function. A renal biopsy demonstrated a mesangial proliferative glomerulonephritis on light microscopy and smaller fibrills (10.6-13.8 nm in diameter) than is usual for fibrillary glomerulonephritis (typically 18-22 nm) on electron microscopy. Amyloidosis was excluded following detailed evaluation. On account of rapidly worsening renal failure she was started on cyclophosphamide and prednisolone which led to the partial recovery and stabilization of her renal function. Conclusion This case highlights the need for routine electron microscopy in native renal biopsies, where the differential diagnosis is wide and varied and the light and immunofluorescence microscopic findings may be non specific.
52. Microscopic polyangiitis.
Pagnoux C, Guilpain P, Guillevin L.
Presse Med. 2007 36 (5P2): 895-901.
Microscopic polyangiitis was initially considered a ’’microscopic’’ form of polyarteritis nodosa and was not definitively distinguished from it until the Chapel Hill nomenclature (1994). Microscopic polyangiitis is a systemic necrotizing vasculitis of small vessels. Its typical clinical manfestations are rapidly progressive glomerulonephritis and alveolar hemorrhage. Other possible symptoms resemble those encountered in polyarteritis nodosa. Microscopic polyangiitis belongs to the group of ANCA-associated vasculitides, and 75-80% of patients have pANCA to myeloperoxidase (MPO). Anti-MPO ANCA pathogenicity has been estabilished in animal models, and a recent report describes transplacental transfer of these antibodies in humans, resulting in pulmonary hemorrhage and renal involvement in the newborn. Patients with no poor prognostic factors, as defined by a five-factor score, can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide, with plasma exchange as an adjuvant therapy for those with severe renal involvement. Once remission is achieved, maintenace therapy can replace cyclophosphamide by azathioprine or methotrexate. Biologiacal therapies are under evaluation. The remission rate is above 80% with these regimens, and the relapse rate is around 30% at 5 years, lower than for Wegener’s granulomatosis.
53. Microscopic polyangitis presenting with temporal arteritis and multiple cranial neuropathies.
Morinaga A, Ono K, Komai K et al.
J Neurol Sci. 2007 256 (1-2): 81-3.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis affects vessels of various diameters in various tissues or organs, sometimes associated with neurological complications. A 77-year-old man developed dysphagia, hoarseness, dysgeusia, gait unsteadiness, and right temporalgia; neurological examination revealed multiple cranial neuropathies. Laboratory studies demonstrated severe inflammatory responses, elevation of perinuclear ANCA, and mild proteinuria. Magnetic resonance imaging of the brain showed dural enhancement in the cerbellar tentorium. Biopsy revealed necrotizing glomerulonephritis in the kidney, and temporal arteritis giant cells in the temporal artery. The patient was diagnosed with microscopic polyangitis presenting with temporal arteritis and multiple cranial involvement, and was treated with prednisolone, after which the symptoms and laboratory data showed improvement. This is the first case of ANCA-associated vasculitis with pathologically verified lesions in the temporal artery as well as in the kidney. Thus, ANCA-associated vasculitis may simultaneously affect large vessels such as temporal artery, as well as microvessels in the kidney, nerves and other organs.
54. Wegener’s granulomatosis: Current trends in diagnosis and management.
Erickson VR, Hwang PH.
Curr Opin Otolaryngol Head Neck Surg. 2007 15 (3): 170-6.
Purpose of review To provide an update on diagnostic methods and treatment options for Wegener’s granulomatosis and to review common head and neck manifestations of the disease. Recent findings Recent advances have been made in the systemic treatment of Wegener’s granulomatosis, including the introduction of investigational immunosuppressive agents such as etanercept, leflunomide and deoxyspergualin. Surgical options remain indicated in selected complications of Wegener’s granulomatosis such as saddle nose deformity and subglottic stenosis. Summary Wegener’s granulomatosis is an idiopathic, systemic vasculitis characterized by the formation of necrotizing granulomas of the respiratory tract in addition to focal or proliferative glomerulonephritis. Diagnosis made by a combination of physical examination, laboratory studies and tissue biopsy. Head and neck manifestation are abundant and varied; common sites of involvement include the middle ear, nose and sinuses and subglottis. The mainstay of treatment remains systematic therapy using a combination of glucocorticoids and immunosuppressants. The otolaryngologist plays a key role in the diagnosis and treatment of head and neck complications of the disease. A surgical role exist for the management of nasal and sinus disease as well as laryngeal and tracheal disease.
55. Clinical features and outcome of pediatric Wegener’s granulomatosis.
Akikusa JD, Schneider R, Harvey EA et al.
Arthritis Rheum. 2007 57 (5): 837-44.
Objective Wegener’s granulomatosis (WG) is a predominantly small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). There are few report describing its clinical features and outcome in children. We report on the experience at a single tertiary referral center over 21 years. Methods We conducted a retrospective chart review of all patients diagnosed with WG at The Hospital for Sick Children between 1984 and 2005. Results Twenty-five patients were identified. Median age at diagnosis and median followup were 14.5 years and 32.7 months, respectively. Male-to-female ratio was 1:4. Median duration of symptoms before diagnosis was 2 months. Of 22 patients, 21 were ANCA positive during their disease course (classic ANCA 78.9%). Constitutional symptoms were the most common clinical feature at presentation (24 of 25). Glomerulonephritis was present in 22 patients at presentation. Only 1 of 11 patients who presented with or developed renal impairment had normalization of serum creatinine. Upper airway involvement occured in 21 patients at presentation and 24 over followup; only 1 had subglottic stenosis. Twenty patients had initial pulmonary involvement, most commonly nodules (44%) and pulmonary hemorrhage (44%). Five patients required ventilation for pulmonary hemorrhage. Four patients (16%) had venous thrombotic events (VTEs). Treatment included prednisone (100%), cyclophosphamide (76%), azathioprine (40%), and methotrexate (32%). Conclusion Pediatric WG typically presents in adolescence and has a female predominance. Glomerulonephritis and pulmonary disease are common at diagnosis and frequently present as a pulmonary-renal syndrome. Loss of renal function is common and rarely completely reversible. As in adults, children with WG are at risk of VTEs.
56. Wegener’s granulomatosis.
Pagnoux C, Teixeira L.
Press Med. 2007 36 (5P2): 860-74.
Wegener’s granulomatosis is described by the Chapel Hill nomenclature (1994) as a systemic necrotizing vasculits affecting small to medium-sized vessels. Cytoplasmic-labeling antineutrophil cytoplasmic autoantibodies (cANCA) directed against proteinase 3 (PR3) are deteceted the sera of approximately 90% of patients. Reported incidence varies from 2 to 12 cases/million inhabitants/year and prevalence from 24 to 157 cases/million inhabitants, depending on the series. While still rare, incidence seems to have increased slightly over the past few decades. Most new cases involve adults aged 45-60 years. Many of the immune mechanisms involved in its pathogenesis have been identified. These involve cANCA as well as neutrophils, various lymphocyte subtypes, activation molecules, and cytokines. Genetic and environmental factors have been observed in some cases. However, the precise causes of the disease and of the initial immune process leading to cANCA production remain unknown. The most characteristics clinical manifestations are involvement of the upper and lower respiratory tracts and glomerulonephritis. Diffuse/systemic forms may be clinically distinguished from localized/limited forms: the former are mainly associated with vasculitis, and the latter with granulomatous inflammation. Diagnosis relies largely on the combination of characteristic clinical symptoms and cANCA anti-PR3, but histological confirmation should always obtained when biopsy of affected organs is feasible and safe. Kidney biopsy is particularly useful in cases with renal manifestations, because it also provides some prognostic information. Current recommendations for treatment of systemic forms call first for an induction phase that combines corticosteroids and intravenous cyclophosphamide; the first three pulses are given every 2 weeks and then every 3 weeks until remission is achieved, followed by a maintenance phase with a less toxic immunosuppressant. The optimal duration of this regimen has not yet been determined, but it must certainly not be less than 18 months. Continuation of cotrimoxazole for two additional years is advised once immunosuppressants have been withdrawn. Remission is obtained in more than 85% of the cases to date, but the high relapse rate remains a matter of concern: approximately half of all patients will relapse within the five years following diagnosis. Promising new therapeutic agents, including rituximab, anti-TNF-alpha, and abatacept, are currently under evaluation and may substantially modify management of this disease in the years to come. Today, however, they reserved for refractory cases.
57. Clinical and pathological features of renal involvement in propylthiouracil-associated ANCA-positive vasculitis.
Yu F, Chen M, Gao Y et al.
Am J Kidney Dis. 2007 49 (5): 607-14.
Background The kidney is one of the organs affected in patients with propylthiouracil (PTU)-associated antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. We present a series of Chinese patients with renal involvement in PTU-associated ANCA-positive vasculits and describe their clinical and pathological characteristics. Methods Clinical and pathological data from patients with PTU-associated ANCA-positive vasculits with renal involvement, diagnosed in Peking University First Hospital, were collected and analyzed retrospectively. Results Nineteen patients with PTU-associated ANCA-positive vasculitis were treated at Peking University Fist Hospital between December 1999 and December 2005, and 15 of them had renal involvement. Of the 15 patients, 13 were female and 2 were male, with an average age 26.3 +/- 11.8 years. All 15 patients were perinuclear ANCA positive with specificities to myeloperoxidase (15 of 15), cathepsin G (9 of 15), human leukocyte elastase (8 of 15), lactoferrin (7 of 15), azurocidin (5 of 15), and proteinase 3 (4 of 15). Duration of PTU adminstration was 43.0 +/- 31.2 months. All patients had clinical markers of renal involvement, including hematuria (100%), proteinuria (100%), and renal function abnormality (47%). All 15 patients underwent percutaneous renal biopsy. Ten patients had necrotizing crescentic glomerulonephritis, and 7 of these 10 patients had immune complex deposition. Three patients had minimal involvement, 2 patients had immunoglobulin A nephropathy, and 2 patients had membranous nephropathy. PTU treatment was discontinued in all 15 patients. All except 2 patients with minimal renal involvement received immunosuppressive treatment. Eleven of 15 patients achieved complete clinical remission. Conclusion Renal involvement in our case series of patients with PTU-associated ANCA-positive vasculitis was heterogenous, and nearly half our patients had renal immune complex deposition.
58. Eye manifestations in patients with perinuclear antineutrophil cytoplasmic antibody-associated vasculitis: Case series and literature review.
Matsuo T.
Jpn J Ophtalmol. 2007 51 (2): 131-8.
Purpose To report and summarize eye manifestations of patients with perinuclear pattern antineutrophil cytoplasmic antibody [pANCA, myeloperoxidase (MPO)-ANCA]-associated vasculitis. Methods The medical records of four consecutive patients with pANCA (MPO-ANCA) vasculitis who showed eye manifestations were retrospectively reviewed. In addition, the medical literature databases, PubMed and Japana Centra Revuo Medicina for Japanese literature, were searched for pANCA vasculitis patients eye manifestations. Results Three of the four patients treated at the Okayama University Hospital showed unilateral or bilateral scleritis. In the literature review, eight of the 27 patients showed ocular surface manifestations such as scleritis and peripheral keratitis. Other frequent eye presentations were posterior segment manifestations such as central or branch retinal vein occlusion, optic neuropathy, and acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Systematically, the most frequent manifestations were glomerulonephritis in the present patients as well as in the patients reported in the past studies. Conclusions Ocular surface manifestations and posterior segment manifestations were major eye presentations in patients with pANCA-associated vasculitis. ANCA testing including both pANCA and cytoplasmic pattern antineutrophil cytoplasmic antibody would help establish a systemic diagnosis in patients with eye manifestation such as scleritis, retinal vein occlusion, optic neuropathy, or APMPPE.
59. Long-term outcome of 37 patients with Wegener’s granulomatosis with renal involvement.
Gottenberg JE, Mahr A, Pagnoux C et al.; for the French Vasculitis Study Group (FVSG).
Presse Med. 2007 36 (5P1): 771-8.
Objectives This prospective study sought to assess the long-term outcome and identify prognostic factors of patients with kidney disease related to Wegener’s granulomatosis (WG). Methods Of 50 patients with newly diagnosed WG who were enrolled between 1990 and 1993 in a trial comparing IV and oral cyclophosphamide (CYC), 37 had renal disease, either histologically proven or diagnosed based on laboratory findings. Their principal demographic, laboratory and therapeutic data, and progression to end-stage renal disease and/or death (ESRD) provided a basis for survival analysis, using Cox proportional hazards models. Results Of the 37 patients (M/F ratio, 23/14; mean age, 55.1 +/- 12.1 years; antineutrophil cytoplasmic antibody-positivity, 97%; ear-nose-throat involvement, 75%; pulmonary involvement, 78%; IV/oral CYC, 23/14), 36 had glomerulonephritis and one had a granulomatous renal tumor; 22 (59%) had initial serum creatinine levels > 150 mumol/L. During a mean follow-up of 6.4 +/- 4.7 years, 15 (41%) patients died and two developed ESRD (10-year dialysis-free survival: 51 +/- 17%). Only one of the nine patients with renal relapses was alive without ESRD at the end of the study. According to uni- and multivariate analyses, dialysis-free survival was significantly shorter for patients with initial serum creatinine > 150 mumol/L (10-year dialysis-free survival, 24 +/- 18% versus 89 +/- 21%) (hazard ratios = 20.2 and 21.7; P < 0.005), while the initial route of CYC administration did not influence outcome. Conclusion These observations confirm the poor survival and functional outcome associated with renal involvement of WG had highlight the strong prognostic impact of renal function at diagnosis and of renal relapses during follow-up. Conversely, the initial route of CYC administration appears to have no effect on survival.
60. Atypical p-ANCA is not a poor prognostic marker in postinfectious glomerulonephritis.
Waters A, Langlois V, Thorner P et al.
Pediatr Nephrol. 2007 May 4; [Epub ahead of print].
Postinfectious glomerulonephritis (PIGN) most commonly follows streptococcal infection. Antineutrophil cytoplasmic antibodies (ANCA) are characteristically negative in PIGN. We report on five cases who had positive atypical pANCA at presentation. The outcome was typical of other cases of PIGN with complete resolution of the glomerulonephritis in all five patients. Atypical pANCA occurs in a number of inflammatory conditions and antigenic targets may include proteins other than myeloperoxidase or proteinase 3. The presence of atypical p-ANCA does not indicate a poor prognosis.
61. Churg-Strauss syndrome.
Lhote F.
Presse Med. 2007 36 (5P2): 875-89.
Churg—Strauss syndrome is a systemic and pulmonary vasculitis, defined by its association with severe asthma and with hypereosinophilia of the blood and tissues. The systematic vasculitis is a small-vessel vasculitis frequently associated with purpura, mononeuritis multiplex, and, more rarely, with rapidly progressive glomerulonephritis or diffuse alveolar hemorrhage. Its prevalence of 7 to 13 per million population makes it one of the rarest of the systemic vasculitidies. Anti-MPO (antimyeloperoxidase) pANCA (ANCA with a perinuclear fluorescence pattern) is present in 35-40% of cases and appears to determine a subgroup of patients with a higher frequency of renal damage, alveolar hemorrhage, and central nervous system damage. Cardiac involvement is an important cause of morbidity and the leading cause of mortality in Churg-Strauss syndrome. Treatment is based on corticosteroid therapy and immunosuppressive drugs (cyclophosphamide and azathioprine) and is determine according to validated prognostic criteria (Five-Factor Score). Complete remission occurs in almost 90% of cases, and the 10-year survival rate has reached 79.4%. Relapses are frequent (25% of cases) and even after recovery from vasculitis, most patients (90%) still have asthma requiring corticosteroid treatment.
62. Collapsing focal segmental glomerulosclerosis in a liver transplant recipient on alendronate.
Pascual J, Torrealba J, Myers J et al.
Osteoporos Int. 2007 Apr 3; [Epub ahaed of print].
We describe a case of collapsing focal segmental glomerulosclerosis and severe kidney dysfunction in a liver transplant recipient after the intiation of alendronate for osteopenia. In view of the increasing incidence of chronic kidney disease in long-term liver transplant patients, bisphosphonates need to be used with caution in these patients. The usefulness of bisphosphonates for the prevention of early bone loss after liver transplantation is increasingly reported. However, is little information on the safety and efficacy of these drugs when used in the later stages of liver transplant, particularly in the presence of chronic kidney disease. Bisphosphonates are excreted unchanged via the kidney after reaching the systemic circulation. Some cases of severe kidney injury, in particular collapsing focal segmental glomerulosclerosis, have been described that are associated with use of pamidronate. Alendronate, a widely used bisphosphonates in transplant patients, has not been related to kidney toxicity. We describe a case of collapsing focal segmental glomerulosclerosis and severe kidney dysfunction in a liver transplant recipient soon after the initiation of alendronate for osteopenia. Possible pathogenetic mechanisms are discussed. In view of the increasing incidence of chronic kidney disease in long-term liver transplant patients, bisphosphonate need to be used with caution in patients with a low glomerular filtration rate.
63. Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy.
Heeringa SF, Branten AJ, Deegens JK et al.
Nephrol Dial Transplant. 2007 Apr 18; [Epub ahead of print].
Background The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. Methods We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearence, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine > 135 mumol/l or increase serum creatinine of > 50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. Results We included 53 patients (33M, 20F). mean age was 51 years, serum creatinine 99 mumol/l, and proteinuria 7.0g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). Conclusion FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.
64. Post-allogenic haematopoietic stem cell transplantation membranous nephropathy: Clinical presentation, outcome and pathogenic aspects.
Terrier B, Delmas Y, Hummel A et al.
Nephrol Dial Transplant. 2007 22 (5): 1369-76.
Background Post-allogenic haematopoietic stem cell transplantation (HSCT) membranous nephropathy (MN), a rare complication of HSCT, remains an ill-defined entity. We describe the clinical and biological characteristics and outcome of five patients with post-HSCT MN, review the previously reported cases and discuss the pathogenic aspects of this nephropathy. Methods Cases were identified by using a questionnaire sent to nephrologists and pathologists in French university and general hospitals. Medical records and kidney biopsy specimens were reviewed and relevant data were collected. Moreover, the IgG subclasses in glomerular deposits and the presence of chimeric renal cells were studied. Results Five patients were identified. All had a history of chronic graft-vs-host disease (cGVHD) and all had active manifestations of cGVHD at MN diagnosis. Mean time between HSCT and diagnosis of MN was 24.4 months. renal insufficiency was present in four patients. Renal biopsy examination showed typical features of MN in all patients. IgG1 and IgG4 were the predominant IgG subclasses in the glomerular deposits. No chimeric glomerular cell was detected. Initial treatment for MN consisted in corticosteroids and immunosuppressors (ciclosporin, mycophenolate mofetil, rituximab, chlorambucil) in all patients. Complete remission of nephrotic syndrome (NS) occured in two patients, partial remission in one patient, while treatment was inefficacious in one (data not available for one patient). Most interestingly, the evolution of NS paralleled the evolution of cGVHD in all patients. Conclusion Our data suggest an association between cGVHD and post-HSCT MN. Treatment, mainly steroids and ciclosporin, should be aimed at the control of acute manifestations of cGVHD.
65. Nephrotic syndrome as a clinical manifestation of systemic sclerosis.
Wielosz E, Majdan M, Suszek D et al.
Rheumatol Int. 2007 Apr 11; [Epub ahead of print].
We have described the unusual case of coexistence of membranous nephropathy resulting in nephrotic syndrome with systemic sclerosis. A 60-year-old patient was admitted to the Department of Nephrology with marked proteinuria and oedema. The renal biopsy specimen disclosed the features characteristic of membranous glomerulonephritis. The patient was treated with chlorambucil for 1 month followed by prednisone for 1 month. However, her condition still did not improve. Therefore, the other causes of nephrotic syndrome were investigated. Once anti-Scl-70 antibody was detected the patient was transferred to the Department of Rheumatology and Connective Tissue Diseases. Physical examination revealed Raynaud phenomenon, sclerodactylia, thickened skin of the chest and back. The patient was diagnosed with diffuse systemic sclerosis. The cyclophosphamide therapy was instituted and the patient’s condition improved.
66. C4B deficiency associated with membranoproliferative glomerulonephritis.
Tsuda T, Moriguchi M, Asanuma Y et al.
Intern Med. 2007 46 (11): 765-70.
A 10-year-old girl was noted to have microscopic hematuria and proteinuria in 1986. As her urinary abnormalities were persistent, she underwent a renal biopsy on 4 occasions until 2003. Although the appearances of the renal biopsies were strongly suspicious of systemic lupus erythematosus, she never exhibited specific antibodies or distinctive symptoms. She received corticosteroid therapy and the urinary findings responded. The 4th component of complement remained low during the period of the observation. Both genotyping and allotyping analysis revealed complete C4B deficiency. Some case reports have mentioned renal disease associated with C4B deficiency and we consider the nephropathy in this case to be related to the C4B deficiency.
67. Nocardial cerebral abscess associated with mycetoma, pneumonia and membranoproliferative glomerulonephritis.
Elmaci I, Senday D, Silav G et al.
J Clin Microbiol. 2007 Apr 11; [Epub ahead of print].
Nocardial brain abscesses remain a clinical challenge. We successfully treated a patient with nocardial brain abscess, mycetoma, pneumonia, and glomerulonephritis. Nocardial tissue involvement, mycetoma, is well known. However, the fact that Actinomycetoma can metastasize may not be as well apprecitated. Association between nocardiosis and glomerulonephritis should be better clarified.
68. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.
Ding H, He Y, Li K et al.
Clin Immunol. 2007 123 (2): 227-34.
Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earlist signs of renal tubular injury, hinderling our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinae-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-d-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were signficantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost not change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.
69. Association between serum adiponectin levels and arteriolosclerosis in IgA nephropathy patients.
Takahashi M, Otsubo S, Uchida K et al.
Intern Med. 2007 46 (8): 453-9.
Objective Adiponectin has attracted great attention because of its anti-atherogenic properties; however, to date the relationship between serum adiponectin and arterioloclerosis has not been reported. It our study, we aimed to examine whether or not serum adiponectin levels are associated with arteriolosclerosis in patients with IgA nephropathy which is the most common form of chronic glomerulonephritis. Material and Methods We enrolled 35 patients aged 35.0 +/- 14.6, who underwent renal biopsy from August 2004 to February 2006 in our hospital, and were confirmed to have IgA nephropathy. We examined serum adiponectin, high-sensitive C-reactive protein, total cholesterol and triglyceride level, urinary protein excretion, body mass index (BMI), and the presence of arteriolosclerosis in the renal specimens. Since the serum adiponectin level is strongly affected by renal function, we classified the patients by creatinine clearence. Results Multiple regression analysis showed the associations of adiponectin with creatinine clearence (p < 0.001), BMI (p < 0.001), serum triglyceride (p = 0.001) and urinary protein excretion (p = 0.001). We observed a positive relation of adiponectin with urinary protein excretion and an inverse relation of adiponectin with creatinine clearence, serum triglyceride, and BMI. We could not detect any relation between the presence of arteriolosclerosis and adiponectin in the IgA nephropathy patients as a whole; however, in patients whose creatinine clearence was 90-120 ml/min/1.73 m2, the serum adiponectin level of patients with arteriolosclerosis was lower than in those without arteriolosclerosis (p = 0.025). Conclusion The serum level of adiponectin was related to arteriolosclerosis in IgA nephropathy patients whose renal function was almost normal. Adiponectin may prevent renal arteriolosclerosis.
70. Tonsillar focal infectious disease involving IgA nephropathy, pustulosis, and ossification.
Noda K, Kodama S, Suenaga S et al.
Clin Exp Nephrol. 2007 11 (1): 97-101.
We report a rare case of IgA nephropathy (IgAN), that was considered as showing tonsillar focal infection, involving pulmoplantar pustulosis (PPP), and sternocostoclavicular hyperostosis (SCCH). A 53-year-old man with a 3-year history of PPP had hematuria and proteinuria, and he sometimes had anterior chest pain. He was also diagnosed with IgAN and SCCH. We performed tonsillectomy as a treatment. The tonsillectomy was done with the patient under general anesthesia, and this treatment was followed by steroid therapy. Interestingly, all the symptoms of IgAN, PPP, and SCCH were alleviated 6 months after the tonsillectomy. Thus, tonsillectomy and steroid therapy may be effective and could be considered as treatment for these diseases.
71. Obesity and kidney disease: A big dilemma.
Kramer H. Luke A.
Curr Opin Nephrol Hypertens. 2007 16 (3): 237-41.
Purpose of review Obesity is the number one preventable risk factor for chronic kidney disease. Obesity is, however, associated with improved survival in patients with end-stage renal disease (ESRD). Recent findings Multiple observational studies have documented an association between obesity and risk of kidney disease even after adjusment for obesitiy-related co-morbidity conditions, including diabetes. Prevalence of a body mass index of at least 35 kg/m among incident dialysis patients has increased by 64% over the past decade, and if trends continue 20% of all patients will initiate dialysis with this degree of obesity. Weight loss improves glomerular hemodynamics in morbidity obese adults and may retard progression of chronic kidney disease. In contrast, once a patients reaches ESRD, the degree of adiposity correlates with survival, and weight loss may not necessarily be beneficial. Summary Weight loss appears to be beneficial in obese patients both with and without chronic kidney disease. The safety of international weight loss in obese ESRD patients, however, remains questionable. The preclusion of obese ESRD patients from kidney transplantation needs to be readdressed and more studies are needed to determine effective strategies for addressing the obesity epidemic in the chronic kidney disease and ESRD populations.
72. Hyperinsulinemia in pediatric patients with chronic kidney disease: The role of tumor necrosis factor-alpha.
Lai HL, Kartal J, Mitsnefes M.
Pediatr Nephrol. 2007 Jun 1; [Epub ahead of print].
We sought to determine the prevalence of hyperinsulinemia and insulin resistance in pediatric patients with chronic kidney disease (CKD) stages 2-4. Data were collected on 43 subjects, aged 6-21 years with mean glomerular filtration rate (GFR = 47 ml/min per 1.73 m(2) body surface area. Patients were grouped by body mass index (BMI) as either non-lean (> 85th percentile) or lean ( 82.1 nmol/l (1.10 mg/l) had the best characteristics as a screening tool for detecting moderate CKD (< 60 ml/min per 1.73 m (2)) when compared with creatinine-based methods. At the upper threshold for mild CKD (< 90 ml/min per 1.73 m (2)), cystatin C also had greater diagnostic accuracy than creatinine, but had similar diagnostic accuracy when compared with creatinine-based formulae for predicting renal function. Conclusions This study suggest that the clinical and biochemical parameters associated with serum cystatin C levels are closely linked to those associated with GFR and highlights the potential usefulness of screening for moderate or mild CKD in subjects with diabetes by simply measuring serum cystatin C levels.
86. Estimated glomerular filtration rate, albuminuria and mortality in type 2 diabetes: The Casale Monferrato study.
Bruno G, Merletti F, Bargero G et al.
Diabetologia. 2007 Mar 2; [Epub ahead of print].
Aims/Hypothesis Estimated glomerular filtration rate (eGFR) predicts mortality in non-diabetic populations, but its role in people with type 2 diabetes is unknown. We assessed to what extent a reduction in eGFR in people with type 2 diabetes predicts 11-year all-cause and cardiovascular mortality, independently of AER and other cardiovascular risk factors. Materials and Methods The study population was the population-based cohort (n = 1.538; median age 68.9 years) of the Casale Monferrato Study. GFR was estimated by the abreviated Modification of Diet in Renal Disease Study equation. Results At baseline, the prevalence of chronic kidney disease (eGFR < 60 ml min (-1) 1.73 m (-2)) was 34.3% (95% CI 33.0-36.8). There were 670 deaths in 10.708 persons-years of observation. Hazard ratios of 1.23 (95% CI 1.03-1.47) for all-cause mortality and 1.18 (95% CI 0.92-1.52) for cardiovascular mortality were observed after adjusting for cardiovascular risk factors and AER. When five levels of eGFR were analysed we found that most risk was conferred by eGFR 15-29 ml min (-1) 1.73 m (-2), whereas no increased risk was evident in people with eGFR values between 30 and 59 ml min (-1) 1.73 m (-2). In analysis stratified by AER categories, a significant increasing trend in risk with decreasing eGFR was evident only in people with macroalbuminuria. Conclusion/Interpretation Our study suggest that in type 2 diabetes macroalbuminuria is the main predictor of mortality, independently of both eGFR and cardiovascular risk factors, whereas eGFR provides no further information in normoalbuminuric people.
87. Lipoprotein metabolism in chronic renal insufficiency.
Saland JM, Ginsberg HN.
Pediatr Nephrol. 2007 Mar 28; [Epub ahead of print].
Chronic renal insufficiency (CRI) is associated with a characteristic dyslipidemia. Findings in children with CRI largely parallel those in adults. Moderate hypertriglyceridemia, increased triglyceride-rich lipoproteins (TRL) and reduced high-density lipoproteins (HDL) are the most usual findings, whereas total and low-density lipoprotein cholseterol (LDL-C) remain normal or modestly increased. Qualitative abnormalities in lipoproteins are common, including small dense LDL, oxidized LDL, and cholesterol-enriched TRL. Measures of lipoprotein lipase and hepatic lipase activity are reduced, and concentrations of apolipoprotein C-III are markedly elevated. Still an active area of research, major pathophysiological mechanisms leading to the dyslipidemia of CRI include insulin resistance and nonnephrotic proteinuria. Sources of variability in the severity of this dyslipidemia include the degree of renal impairment and the modality of dialysis. The benefits of maintaining normal body weight and physical activity extend to those with CRI. In addition to multiple hypolipidemic pharmaceuticals, fish oils are also effective as a triglyceride-lowering agent, and the phosphorous binding agent sevelamer also lower LDL-C. Emerging classes of hypolipidemic agents and drugs affecting sensitivity to insulin may impact future treatment. Unfortunately, cardiovascular benefit has not been convincingly demonstrated by any trial designed to study adults or children with renal disease. Therefore, it is not possible at this time to endorse general recommendations for the use of any agent to treat dyslipidemia in children with chronic kidney disease.
88. Diagnosis and management of renovascular disease and renovascular hypertension.
Bloch MJ, Basile J.
J Clin Hypertens. (Greenwich). 2007 9 (5): 381-9.
Renovascular disease is a common but complex disorder, the most common causes of which are fibromuscular dysplasia and atherosclerosis. Clinically, it can present as asymptomatic renal artery stenosis, renovascular hypertension, or ischemic nephropathy. Assessing the clinical index of suspicion remains essential in determining an appropriate diagnostic strategy. For diagnosis in patients with suspected fibromuscular disease, it may be reasonable to proceed directly to renal angiography, however, for most patients with suspected atherosclerotic disease, there are a number of nooninvasive tests available that can aid in decision making. The choice of the most appropriate initial test should be based on patients characteristics, clinical presentation, and local expertise. Treatment options include medical, surgical, or percuatenous approaches. Generally, in patients with fibromuscular disease, percutaneous intervention provides durable eimprovement or cure of hypertension. In patients with atherosclerotic disease, the data are less consistent, and there does appear to be a group of patients who well to medical management alone. As technology advances, the diagnostic and treatment paradigms will continue to evolve.
89. A prospective national study of acute renal failure treated with RRT: Incidence, aetiology and outcomes.
Prescott GJ, Metcalfe W, Baharani J et al.
Nephrol Dial Transplant. 2007 May 21; [Epub ahead of print].
Background Acute renal failure (ARF) is a diverse condition with no standardized definition and is managed in several sub-specialty areas within hospitals. Its incidence and aetiology are unknown and studies show a wide range of incidences. ARF is becoming more common as the population ages leading to the hypothesis that the incidence is much higher than previous estimates. Methods This prospective population study investigated the incidence, aetiology and outcomes of ARF based on a standardized classification of ARF treated by renal replacement therapy (RRT) in all-sub-specialty areas within hospitals were such treatment takes place. Data were collected prospectively on all patients starting RRT for ARF within three 12-week periods in 2002. Results Two hundred eighty-six adults per million population (pmp) per year received RRT for ARF. The incidence increased with age and pre-existing comorbid illness. Two hundred twelve adults pmp per year had no evidence of pre-existing chronic kidney disease (CKD) and the remainder had acute on CKD. The median age was 67 years. Fity-one percent of the patients received their first RRT treatment in a critical care setting. Sepsis was the most common aetiological insult contributing to ARF in 48% of the patients. Mortality was high with 48% dying within 90 days of starting RRT. Age, comorbidity, sepsis and recent surgery were independent risk factors for death in those with no pre-existing CKD. Discussion This is the first national study to describe ARF treated with RRT in all hospital locations. The hypothesis that ARF occurs more frequently than previously thought has been confirmed. This study provides data upon which to base effective decision making for prevention, patient care and resource planning for patients with ARF.
90. Patients at high risk of adverse events from intravenous contrast media after computed tomography examination.
Reddan D.
Eur J Radiol. 2007 Mar 24; [Epub ahead of print].
Adverse reactions to iodinated contrast media (CM) may occur and require prompt recognition and treatment. Although adverse reactions to radiocontrast agents cannot be eliminated, an important first step toward reducing their incidence is to identify patients at greatest risk. Prior to examinations using CM, patients should be adequately assessed by obtaining thorough medical histories and using simple screening tests. Studies have demonstrated that patients with a history of asthma, allergy, hyperthyroidism, and previous reaction to CM are at risk for severe reactions to iodinated CM. Renal adverse reactions reportedly occur more frequently in patiens with pre-existing chronic kidney disease, especially those with diabetic nephropathy. Patients with congestive heart failure, dehydration, older age, and those who use nephrotoxic medications are also at risk for developing contrast-associated nephropathy. The occurence of adverse events may be further increased in patients with multiple risk factors. As the number of patients undergoing computed tomography procedures continues to increase, it is essential for physicians to be able to identify patients at risk for adverse events of CM. Patient-related risk factors are discussed and simple tools for risk stratification presented.
91. Different types of renal dysfunction in patients with acute myocardial infarction treated with percutaneous coronary intervention.
Kowalczyk J, Lenarczyk R, Kowalski O et al.
J Interv Cardiol. 2007 20 (2): 143-52.
Background The prognostic significance of different types of renal dysfunction in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI) has not been well characterized. Methods The single-center AMI registry encompassed 1.486 consecutive AMI patients treated with PCI, who were followed by mean 29.7 months. Subjects with an estimated glomerular filtration rate < 60 mL/min 1.73 m (2) at baseline selected (n = 283, 19.0%) and incorporated into the kidney disease (CKD) group. The contol group consisted of 1.203 subjects with normal renal function (81.0%). The CKD patients were divided into subgroups: with contrast-induced nephropathy - CKD + CIN (n = 68, 4.6%) and without - CKD-CIN (n = 215, 14.5%). Results Remote mortality rate was significantly higher in CKD group (34.6%) and in partcular subgroups: CKD + CIN (47.0%), CKD-CIN (31.0%) than in controls (9.1%, P < 0.001 for all study groups vs controls). Multivariate analysis identified CKD as an independent predictor of any-cause death in the whole population (hazard ratio fHR] 1.77 95% confidence interval [cI] 1.60-1.94, P < 0.001). Similarly, CKD + CIN had significant and independent influence on remote survival in study population (HR 2.16, 95% CI 1.95-2.37, P < 0.001). Conclusions CKD and its types have significant, negative influence on long-term survival in AMI patients treated with PCI. It is especially strongly expressed in those CKD patients who develop contrast-induced nephropathy, which occurence is an independent risk factor of mortality associated with over twofold increase of death hazard.
92. Myocardial ultrasound tissue characterization in patients with chronic renal failure.
Salvetti M, Muiesan ML, Paini A et al.
J Am Soc Nephrol. 2007 Apr 18; [Epubahead of print].
The objective is this study was to detect ultrastructural changes in myocardium related to collagen content by ultrasound tissue characterization in patients with chronic kidney disease (CKD) and in uncomplicated hypertensive control subjects. In 25 hemodialysis (HD) patients, in 25 patients with moderate to severe chronic renal failure (CRF), and in 10 patients with essential hypertension (EH) and normal renal function matched for age, BP, and left ventricular mass index, left ventricular anatomy and function were evaluated by conventional echocardiography, and integrated backscatter signal (IBS) was analyzed by acoustic densiometry. IBS mean reflectivity increased from 48% in patients with EH to 56% in patients with CRF to 62% in HD patients (ANOVA P < 0.01). IBS mean cyclic variation was progressively increased from 4.35 +/-1.2 dB in HD patients to 5.27 +/- 0.90 in patients with CRF to 6.50 +/- 1.6 dB in patients with EH (ANOVA P < 0.01). At multivariate analysis, IBS mean reflectivity was positively related to age and serum creatinine (beta 0.351, P = 0.036; and beta = 0.408, P = 0.016, respectively). IBS mean cyclic variation was inversely related to age and serum creatinine (beta = -0.274, P = 0.025; and beta = -0.262, P = 0.024, respectively) and positively related to left ventricular midwall fractional shortening and transmitral E/A ratio (beta = 0.269, P < 0.05; and beta = 0.314, P < 0.001, respectively). The data support the hypothesis that interstitial collagen deposition may appear early in the course of CKD and suggest that acoustic densitometry may represent a useful tool for the assessment of myocardial tissue changes in patients with CKD.
IV. TREATMENT
IV/1.
1. Which optimal antihypertensive bitherapy for kidney patients?
Bonne JF, Shahapuni I, Mailliez S et al.
Nephrol Ther. 2007 3 (3): 79-88.
On this editorial review on the optimal antihypertensive treatment for chronic kidney disease (CKD) patients, we start with the controversy triggered by Casas et al., for proposing a bitherapy optimal not only for nephroprotection, but also for global cardiovascular protection. The incidence of cardiovascular compications are indeed much greater than the occurence of end stage renal disease (ESRD) in these patients, so that their prevention has at least the same priority. We explain the huge amount of discordant papers, on the basis of methodology deficiencies in the studies aiming at evidencing the truth of 2 antinomic concepts underlying this controversy: 1). ’’The correction by antihypertensive drugs of the cardiovascular risk excess in hypertensive patients is exclusively related to their blood pressure lowering effect, the optimal blood pressure (BP) level being defined by epidemiologists at 115/75 mmHg’’; 2). ’’Independently of BP lowering effect, antihypertesive drugs may have intrinsic, protective or deleterious, renal and cardiovascular effects which may be variable according to the target organ’’. We think that truth is conciliating and that both mechanisms should be exclusive. However more rigorous studies are still needed to evidence it. Meanwhile we propose the optimal therapy by hypokalemic diuretics (thiazides +/- loop diuretics according to glomerular filtration decline) + inhbitors of the angiotensin AT1-receptor (ACE inhibitors or AT1RB), in preference to the association of dihydropyridines with diuretics. This recommendation is strong, however, only for CKD patients with macroproteinuria. The priority that we give to diuretic therapy is based on the evidence that this class confers good prevention against both heart failure and strokes, which is not the case for all AT1-inhibitors and dihydropyridines. Furthermore the diuretics are the drugs with the longest antihypertensive effect (many weeks) and their efficiency in CKD patients is proportional to the sodium depletion they initially induce and therefore to the dose (specially of the loop diuretics). Indeed volemia control is an incontrovertible factor for optimal BP control in renal insufficiency. As regards the use of betablockers, they should no more be considered as first drug for hypertension because they have the strongest diabetogenic effect. They should be used selectively for their specific cardiologic indications such as angina, heart failure, arrhythmia and as substitute for ACEI or AT1RB when general anesthesia is considered. Regarding the choice between ACEI and AT1RB, on the basis of indirect comparisons, we think that the latter may grant a comparable cardiac protection while giving a better cerebral protection. We shall have to wait the results of ONTARGET study to have or not the evidence for this preference. Finally, we want to stress the necessity to individualize the treatment by taking into account coexistence of cardiovascular complications and of other disease, as well as the tolerance of the treatment (which may be influenced by seasons, in particular the canicula one), and the cost of the drugs.
2. Proteinuria as a therapeutic target in patients with chronic kidney disease.
Palmer BF.
Am J Nephrol. 2007 27 (3): 287-93.
Patients excreting large amounts of urinary protein, who are otherwise deemed to be optimally treated, should still be considered at high risk for renal disease progression. The observation that reductions in urinary protein excretion, in a graded fashion over a relatively short period of time, correlate with long-term preservation of renal function supports the idea of using urinary protein excretion as a guide to implementation of renoprotective therapies. The association between residual proteinuria and renal outcomes suggests that minimization of proteinuria is an important therapeutic goal in the management of proteinuric chronic kidney disease patients. This article reviews the evidence for using proteinuria as a target for the implementation of therapies shown to have renal protective effects.
3. Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor.
Costa-Scharplatz M, van Asselt AD, Bachmann LM et al.
Pharmacogenet Genomics. 2007 17 (5): 359-68.
Objective This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. Methods We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was condcuted to determine the robustness of the results. Results Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356 000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. Conclusion The study suggest that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice.
4. No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy - - report from the ItalKid Project database.
Ardissino G, Vigano S, Testa S et al.
Nephrol Dial Transplant. 2007 May 25; [Epub ahead of print].
Background Chronic kidney disease (CKD) tend to progress to end-stage renal failure (ESRF). As it has been demonstrated that angiotensin-converting enzyme inhibitors (ACEi) have a renoprotective effect in adults with proteinuric disease and may be effective in reducing hyperfltration and proteinuria, they are also frequently used as anti-progression agents in paediatric patients with CKD despite the lack of data confirming their role in the nephropathies peculiar to children. The aim of this study was to investigate whether patients with hypodysplastic CKD (the most common cause of ESRF in children) treated with ACEi show significantly slower decline in creatinine clearence (Ccr). Methods The analysis was based on the information available in the database of the ItalKid Project, a nationwide, population-based registry of chronic renal insufficiency (CRI) in children in Italy. Of the 822 patients with CRI due to hypodysplasia, we selected those who had been treated with ACEi; the control patients were identified from the same diagnostic group and matched for gender, age and baseline Ccr. Results Progression was analysed as the slope of Ccr in a total of 164 patients; 41 cases and 123 matched controls. There were no significant between-group differences in blood pressure, duration of follow-up or pre-study slope of Ccr (-0.31 +/- 2.26 vs -0.33 +/- 3.58 ml/min/1.73m (2) / year; P = NS). After an average of 4.9 +/- 2.3 years, the mean slope of Ccr was 40% lower in the ACEi-treated cases in comparison to controls (-1.08 +/- 2.08 vs -1.80 +/- 4.42 ml/min/1.73m (2) / year), however, this difference was not statistically significant (P = 0.31). Conclusions We conclude that ACEi treatment does not significantly modify the naturally progressive course of hypopdysplastic nephropathy in children and further studies are necessary before such treatment is routinely proposed for anti-progression purpose in children with CKD.
5. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria.
Coppo R, Peruzzi L, Amore A et al.
J Am Soc Nephrol. 2007 18 (6): 1880-8.
This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhbitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (> 1 and < 3.5 g/d per 1.73 m (2) ) and creatinine clearence (CrCl) > 50 ml/min per 1.73 m (2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as > 30% decrease of CrCl; secondary outcomes were (1). a composite end point of > 30% decrease of CrCl or worsening of proteinuria until >/= 3.5 g/d per 1.73 m (2) and (2). proteinuria partial remission (< 0.5 g/d per 1.73 m (2) ) or total remission (< 160 mg/d per 1.73 m (2)) for > 6 mo. Analysis was by intention to treat. A single patients (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed worsening of CrCl > 30%. The composite end point of > 30% decrease of CrCl or worsening proteinuria until nephrotic range was reached by one (3.1%) of 32
patiens in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients on the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12,5% of ACE-I-treated patients and in none in the placebo group (lon-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.
6. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: A meta-analysis.
Jennings DL, Kalus JS, Coleman CI et al.
Diabet Med. 2007 Mar 15, [Epub ahead of print].
Aims Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevent the progression of diabetic nephropathy (DN). Studies suggest that combination renin-angiotensin-aldosterone system (RAAS)-inhibiting therapy provides additive benefit in DN. However, these studies are small in size. We performed a meta-analysis of studies investigating combination therapy for DN. Methods Studies were identified through a search of medline, embase, cinahl and the Cochrane Database. All trials involving combined ACEI and ARB for slowing progression of DN were included. The primary end point was 24-h urinary protein excretion. Blood pressure, serum potassium and glomerular filtration rate (GFR) were secondary end points. Results In the 10 included trials, 156 patients received ACEI + ARB and 159 received ACEI only. Most studies were 8-12 weeks in duration. Proteinuria was reduced with ACEI + ARB (P = 0.01). This was associated with significant statistical heterogeneity (P = 0.005). ACEI + ARB was associated with a reduction in GFR [3.87 ml/min (7.32-0.42); P = 0.03] and a trend towards an increase in serum creatinine (6.86 micromol/l 95% CI -0.76-13.73; P = 0.09). Potassium was increased by 0.2 (0.08-0.32) mmol/l (P < 0.01) with ACEI + ARB. Systolic and diastolic blood pressure were reduced by 5.2 (2.1-8.4) mmHg (P < 0.01) and 5.3 (2.2-8.4) mmHg (P < 0.01), respectively. Conclusions This meta-analysis suggest that ACEI + ARB reduces 24-h proteinuria to a greater extent than ACEI alone. This benefit is associated with small effects on GFR, serum creatinine, potassium and blood pressure. These results should be interpreted cautiously as most of the included studies were short duration and the few long-term studies (12 months) have not demonstrated benefit.
7. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease.
Berger AK, Duval S, Manske C et al.
Am Heart J. 2007 153 (6): 1064-73.
Background Patients with coexistent heart failure and chronic kidney disease (CKD) have a poor prognosis, possibly related to the underuse of standard medical therapies - - angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). Methods We performed a retrospective analysis of the Minnesota Heart Survey, identifying patients hospitalized in 2000 in the Minneapolis-St Paul metropolitan area with heart failure. The main outcome measure was the association of ACE-I and ARB use on 30-day and 1-year mortality, stratified by glomerular filtration rate (GFR). Results Compared to patients with heart failure with preserved renal function (GFR > or = 90 mL/min), patients with severely impaired renal function (GFR < 15 mL/min) were far less likely to receive ACE-I or ARB during hospitalization (52.0% vs 69.5%, P < .000l) or at discharge (50.5% vs 65.1%, P < .0001). Worsening renal function was associated with increased mortality, both at 30 days and at 1 year. The inhospital use of either an ACE-I or ARB was associated with significantly reduced 30-day mortality (OR 0.45, 95% CI 0.28-0.59) after adjusing for multiple risk factors. Similarly, the discharge prescription of either an ACE-I or ARB was associated with a significant reduction in adjusted 1-year mortality (OR 0.72, 95% CI 0.58-0.91). However, among patients on dialysis, there was no benefit of ACE-I or ARB on either 30-day or 1-year mortality. Conclusions Angiotensin-converting enzyme inhibitors and ARB are underused in patients with heart failure with chronic kidney disease. Given the reduction in 30-day and 1-year mortality, these medications should be considered in most patients with heart failure, independent of underlying renal function. Among patients on hemodialysis, further investigation is warranted.
8. Toward better renoprotection: Lessons from angiotensin receptor blockers.
Miyata T, Takizawa S.
Hemodial Int. 2007 11 (2): 164-8.
The rising tide of chronic kidney disease (CKD), especially diabetic nephropathy, has become a worldwide catastrophe. However, therapeutic options to prevent or retard the progression of CKD still very limited. The understanding of its molecular mechanisms and the delineation of the tools able to modify them are thus of critical importance. The discovery that some antihypertesnive agents inhibiting the renin-angiotensin system, such as angiotensin II type 1 receptor blockers, protect the kidney opens new therapeutic perspectives. In this article, we focus on their renoprotective actions beyond blood pressure lowering.
9. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: Post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.
Eijkelkamp WB, Zhang Z, Remuzzi G et al.
J Am Soc Nephrol. 2007 18 (5): 1540-6.
Albuminuria reduction could be renoprotective in hypertensive patients with diabetic nephropathy. However, the current use of renin-angiotensin-system intervention is targeted to BP only. Therefore, this study investigated the adequacy of this approach in 1428 patients with hypertension and diabetic nephropathy from the placebo-controlled Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Investigated were the extent of discordance in treatment effects on systolic BP (SBP) and albuminuria and its association with renal outcome in a multivariate Cox model. Among patients with a reduced SBP during treatment, a lack of albuminuria reduction was observed in 37, 26, and 51% (total, losartan, and placebo, respectively) at month 6. SBP or albuminuria reduction was associated with lower risk for ESRD, whereas combined SBP and albuminuria reduction was associated with the lowest risk for events. Across all categories of SBP change, a progressively lower ESRD hazard ratio was observed with a larger albuminuria reduction. A lower residual level of albuminuria was also associated with lower ESRD risk. In conclusion, changes in albumiuria are not concordant in a substantial proportion of patients when titrated for BP. Meanwhile, the ESRD risk showed a clear dependence on albuminuria reduction. The ESRD risk also showed dependence on the residual level of albuminuria, even in patients who reached the current SBP target. Antihypertensive treatment that is aimed at improving renal outcomes in patients with diabetic nephropathy may therefore require a dual strategy, targeting both SBP and albuminuria reduction.
10. A randomized trial of the effect of statin and fibrate therapy on arterial function in CKD.
Dogra G, Irish A, Chan D et al.
Am J Kidney Dis. 2007 49 (6): 776-85.
Background Although patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease (CVD), the roles of lipid-modifying therapies in decreasing CVD risk are unclear. Our aim is to compare the effects of statin and fibrate therapy on arterial function as a risk marker of CVD. Study design Double-blind, randomized, placebo-controlled, parallel-group study. Setting & Participants Ambulatory patients with stages 3 to 5 CKD. Intervention 6 weeks of atorvastatin, 40 mg/d, or gemfibrozil, 600 mg twice daily, with placebo. Outcomes & Measurements primarily outcome was arterial function assessed by means of endothelial-dependent flow-mediated dilatation (FMD) and small-artery compliance (C1). Secondary outcomes included endothelial-independent glyceryl trinitrate-mediated dilatation (GTNMD), large-artery compliance (C2), and levels of lipids, lipoproteins, and oxidized low-density lipoprotein, as well as markers of insulin resistance and inflammation. Results Compared with placebo, atorvastatin significantly decreased low-density lipoprotein (-52%), triglyceride (-30%), and oxidized low-density lipoprotein levels (-41%; P < 0.0001). gemfibrozil significantly decreased triglyceride levels (-40%) and increased high-density lipoprotein levels (+20%; P < 0.0001). Neither atorvastatin nor gemfibrozil had a significant effect on markers of insulin resistance or inflammation. There were no significant change in FMD, GTNMD, or C1 with either atorvastatin or gemfibrozil. There was improvement in C2 with atorvastatin (+1.1mL/mm Hg × 100) compared with placebo (P = 0.024), but not with gemfibrozil compared with placebo. Limitations Small sample size leading to inadequate power, short duration of therapy, and use of a heterogenous group of patients with CKD and dialysis patients. Conclusion In patients with advanced CKD, atorvastatin is associated with improvement in dyslipidemia and small-artey stiffness, but not endothelial function. Gemfibrozil impoves dyslipidemia, but has no effect on arterial function.
11. Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure.
Baber U, Toto RD, de Lemos JA.
Am Heart J. 2007 153 (4): 471-7.
Background Although numerous large-scale trials have firmly estabilished the benefits of statins for primary and secondary prevention of coronary artery disease, the role of this class of agents in patients with impaired renal function remains unclear. Methods and Results In the following review, we evaluate current evidence regarding the role of statins in patients with both chronic kidney disease (CKD) and end-stage renal disease (ESRD) on hemodialysis. Although statins do appear to reduce cardiovascular risk in patients with CKD, it remains unclear whether such benefit extends to the ESRD population. Thus far, 1 randomized placebo-controlled trial failed to demonstrate a statistically significant reduction in the primary endpoint of cardiovascular death, stroke, and nonfatal myocardial infarction among patients with ESRD on hemodialysis. This finding contrast with observational analyses suggesting improved outcomes among patients with ESRD taking statins. Conculsions Risk factors unique to the CKD population, which may not be modifiable with statins, could contribute to the increased cardiovascular morbidity among patients with ESRD. These include alterations in mineral meatbolism, elevation in serum homocysteine, and increased oxidative stress. Larger prospective studies are needed to elucidate the role of statins in patients with chronic kidney disease, including those with ESRD on dialysis. Pending further data, we currently recommended using statins in patients with CKD.
12. The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: A pooled analysis of double-blind, randomized trials.
Holdaas H, Wanner C, Abletshauser C et al.
Int J Cardiol. 2007 117 (1): 64-74.
Background Individuals with chronic kidney disease are at high risk for cardiovascular disease and have a high prevalence of hyperlipidemia. Lipid-lowering therapy may help patients with renal disease reduce their risk for cardiovascular events. Methods A pooled analysis of 30 completed clinical trials compared the efficacy and safety profiles of fluvastatin in subgroups of patients with moderate to severe renal insufficiency (creatinine clearence < 50 ml/min) and patients with normal renal function or mild renal insufficiency (creatinine clearence > or = 50 ml/min). Results Changes in lipid parameters with fluvastatin treatment were similar for the compared subgroups. Fluvastatin treatment reduced combined cardiac death and myocardial infarction by 41% compared with placebo among patients with moderate to severe renal insufficiency (hazard ratio, 0.59, p = 0.007) and by 30% among patients with normal renal function or mild renal insufficiency (hazard ratio, 0.70; p = 0.009). The relative reduction in the risk of major adverse cardiac events, a composite endpoint comprising cardiac death, nonfatal myocardial infarction, and coronary intervention procedures, with fluvastatin treatment was not significant for patients with moderate to severe renal insufficiency (hazard ratio, 0.83; p = 0.18); in this patient subgroup, the incidence of coronary intervention procedures was similar between treatment groups. The safety profiles were similar for fluvastatin- and placebo-treated patients. Conclusions The results of this pooled analysis indicate that fluvastatin is safe and effective for reducing cardiac death and nonfatal myocardial infarction in patients with moderate to severe renal insufficiency. Fluvastatin did not reduce the rate of coronary intervention procedures.
13. Statin use and hospitalization for sepsis in patients with chronic kidney disease.
Gupta R, Plantiga LC, Fink NE et al.
JAMA. 2007 297 (13): 1455-64.
Context Patients with chronic kidney disease are at high risk for sepsis and sepsis-related mortality. Objective To assess whether statin use is associated with a reduction in hospitalizations for sepsis in dialysis patients. Design, Setting, and Patients National prospective cohort study that enrolled 1041 incident dialysis patients at 81 US not-for-profit outpatinet dialysis clinics from October 1995 to June 1998, with follow-up to January 2005. Statin use was determined by medical record reciew. Rates of hospitalization for sepsis between statin users and control patients were compared using multivariate regression models, with adjusment for potential confounders in the overall cohort and in a subcohort in which control patients were matched to statin users according to their likelihoood (propensity) to have been prescribed a statin. Main outcome measure Hospitalizations for sepsis were determined through hospital records from the United States Renal Data System (mean follow-up, 3.4 years). Results There were 303 hospitalization for sepsis. Rates of sepsis-related hospitalizations were significantly lower in patients receiving statins (crude incidence rate, 41/000 patients-years) than in those not receiving statins (crude incidence rate, 110/1000 patient-years) (P < 0.001). With adjusment for demographics and dialysis modality, statin users were substantially less likely to be subsequently hospitalized for sepsis (incidence rate ratio, 0.41; 95% confidence interval [CI], 0.25-0.68). Further adjusment for comorbidities and laboratory values continued to show this protective association (incidence rate ratio, 0.38; 95% CI, 0.21-0.67). In the propensity-matched subcohort, statin use was even more protective (incidence rate ratio, 0.24; 95% CI, 0.11-0.49). Conclusions Use of stains was strongly and independently associated with a reduction in the risk of hospitalization for sepsis in patients who had chronic kidney disease and were receiving dialysis. Randomized trials of statins in patients with chronic kidney disease should examine the prevention of sepsis as a potentially important benefit.
14. Effect of stains on contrast-induced nephropathy in patients with acute myocardial infarction treated with primary angioplasty.
Zhao JL, Yang YJ, Zhang YH et al.
Int J Cardiol. 2007 Apr 24; [Epub ahead of print].
We investigated whether pretreatment with statin may prevent contrast-induced nephropathy in patients who underwent primary coronary intervention for acute myocardial infaction (AMI). A total of 279 consecutive patients who underwent successfull primary angioplasty for a first AMI were studied. Contrast-induced nephropathy was defined as an increase in serum creatinine of > / = 5 mg/dL after the primary PCI. 56 patients receiving statin treatment before admission had lower incidence of the contrast-induced nephropathy than those without it (7.1% and 20.6%, P < 0.01). Multivariable logistic regression analysis revealed that absence of statin pre-treatment was a significant predictor of the reperfusion arrhythmia along with anterior AMI, baseline creatinine value, time-to-reperfusion, higher volme of the contrast agent. Pre-treatment with statin could reduce the contrast-induced nephropathy after primary coronary intervention in patents with AMI.
15. Development, worsening, and improvement of diabetic microangiopathy in older people: Six-year prospective study of patients under intensive diabetes control.
Katakura M, Naka M, Kondo T et al.
J Am Geriatr Soc. 2007 55 (4): 541-7.
Objectives To examine retinopathy and nephropathy in elderly patients with diabetes mellitus (DM) under intensive multifactoral DM control. Design Six-year interventional observation study. Setting Multicenter study including four hospitals. Participants Four hundred thirteen elderly (>/= 65) patients with type 2 DM attending each hospital for 1 year or longer; those receiving hemodialysis or with uncured malignancy were excluded. Measurements Development, worsening, and improvement of retinopathy and nephropathy and respective risk factors. Results The mean baseline hemoglobin (HbA1c), blood pressure (BP), and total cholesterol were 6.8%, 137/74 mmHg, and 5.13 mmol/L, respectively. Retinopathy developed in 45 of 168 (27%) patients, and 63 with nonproliferative retinopathy, worsened and improved in 11 (17%) and 23 (37%), respectively. Nephropathy developed in 53 of 227 (23%) patients and improved in 13 of 51 (25%) having it baseline. The mean change in glomerular filtration rate (DeltaGFR, baseline GFR - GFR at the end of the study period) in those with nephropathy at baseline was 21.5 mL/min. HbA1c was related to development of retinopathy (P = .001, odds ratio (OR) = 1.91), and serum creatinine (P = .03, OR = 1.02), systolic BP (SBP) (P = .03, OR = 1.22), and prior stroke (P = .005, OR = 3.21) were related to development of nephropathy. In patients with nephropathy at baseline, SBP (P = .03, Spearman’s rho (rho) = 0.310), total cholesterol (P = .01 rho = 0.361), and low-density lipoprotein cholesterol (P = ,03, rho = 0.322) were correlated with DeltaGFR. Conclusion In elderly patients under intensive control for DM, the outcome of microangiopathy is favorable. Modifiable risk factors were hyperglycemia for development of retinopathy and hypertension and hypercholesterolemia for development or worsening of nephropathy; prior stoke was an unmodifiable risk factor for development of nephropathy.
16. Combined effect of pioglitazone and simvastatin on urinary liver-type fatty acid-binding protein concentration in diabetic patients with microalbuminuria.
Wei J, Ma C, Ly YM.
Diabetologia. 2007 May 23; [Epub ahead of print].
Aims/Hypothesis Urinary liver-type fatty acid-binding protein (L-FABP) is a useful marker for renal tubulointerstitial injury. It has been reported that treatment with pioglitazone or pitavastatin alone effectively reduces urinary L-FABP in patients with diabetic nephropathy. However, the combined effect of pioglitazone and simvastatin on urinary L-FABP remains unknown. Thus, the aim of this study was to determine whether pioglitazone and simvastatin have a synergestic effect on urinary L-FABP in diabetic patients with microalbuminuria. Material and Methods Fifty-seven patients with type 2 diabetes and microalbuminuria were randomised to 6 months of treatment with pioglitazone (30 mg/day, n = 19), simvastatin (20 mg/day, n = 20) or pioglitazone (30 mg/day) plus simvastatin (20mg/day, n = 18). Urinary albumin excretion (UEA) and urinary L-FABP concentrations pre- and post-treatment were compared in the treated groups and in 20 age-matched healthy volunteers. Results Before treatment, UAE and urinary L-FABP levels were significantly higher in diabetic patients than in healthy volunteers (p < 0.001). After 6 months of treatment, levels of UEA and urinary L-FABP were significantly decreased n the three treated groups compared with those prior to treatment (p < 0.01). The combination of pioglitazone and simvastatin decreased UAE and urinary L-FABP levels more markedly than the other treatments (p < 0.01). Conclusions/Interpretation Pioglitazone and simvastatin appear to have synergestic effects in reducing UAE and urinary L-FABP levels in diabetic patients with microalbuminuria, suggesting that combined use of these agents in early diabetic nephropathy may have a renoprotective effect. However, larger, longer term studies are needed to determine the precise mechanisms involved.
17. The treatment of anemia in chronic kidney disease: Understandings in 2006.
Levin A.
Curr Opin Nephrol Hypertens. 2007 16 (3): 267-71.
Purpose of review Anemia is a well recognized complications of chronic kidney disease and is associated with significant morbidity. It is important for clinical care to identify appropriate treatments and targets for hemoglobin. This review describes current understandings of the treatment of anemia using the most recent published articles. Recent findings Numerous studies, including observational and randomized control trials, of varying sizes and using both surrogate and hard outcomes have been published. On balance, there is little to support normalization of hemoglobin in the chronic kidney disease population. While some studies have described harm, there are some issues related to overinterpretation based on study trial reporting. The treatment of anemia can be successfully achieved with the use of oral or intravenous iron and erythropoietin-stimulating agents. Caution should be exercised when treating those with significant cardiovascular morbidity, and those who require very high doses of erythropoietin agents to achieve normal hemoglobin. Summary Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and randomized control trials fail to show a benefit of normalized hemoglobin. Anemia therapy does improve quality of life. In the current era of aggressive chronic kidney disease management, it does not appear that anemia therapy attenuates left ventricular growth or changes cardiovascular outcomes.
18. Nononcologic use of human recombinant erythropoietin therapy in hospitalized patients.
Fischer MA, Morris CA, Winkelmayer WC et al.
Arch Int Med. 2007 167 (8): 840-6.
Background Human recombinant erythropoietin (rHuEPO) is widely used to stimulate red blood cell production in patients with anemia due to cancer, renal disease, and other medical conditions, but concern has grown about its overuse and potential for harm. Little is known about the nature of rHuEPO use in hospitalized patients who receive rHuEPO therapy for nononcologic indictaions. Methods We reviewed the drug utilization data from a large academic medical center for all patients admitted during 3 years to identify all patients without cancer who received at least 1 dose of rHuEPO, including their age and sex; diagnoses; hematocrit and hemoglobin and iron levels; and use of supplemental iron. We also compared the rates of laboratory testing and iron supplementation in patients with and without chronic kidney disease (CKD). Results A total of 1360 distinct patients with 3094 hospitalizations received at least 1 dose of rHuEPO. In 2959 admission for which hematocrit was determined within 14 days before rHuEPO use, mean values were less than 33% in 1792 (61%) and greater than 36% in 533 (19%). Patients with CKD were more likely than patients without CKD to receive rHuEPO with hematocrit greater than 36% (22% vs 8%; P < 0.001). Monitoring of iron status was more common in patients with CKD than in those without CKD (64% vs 45%; P < 0.001). Almost one fourth (23%) of rHuEPO recipients in whom iron levels were measured had absolute iron deficiency (serum ferritin concentration < 100 ng/mL). In patients with CKD, only about half (54%) had adequate iron stores at the time of rHuEPO administration; this rate was even lower in patients without CKD (33%; P < 0.001). Only 66% of patients with documented iron deficiency who were receiving concomitant iron supplementation; this rate did not differ between patients with or without CKD. Conclusions There is significant variability in the degree of anemia, completeness of iron measurement, and use of iron supplementation in hospitalized patients without cancer who are prescribed rHuEPO. Our results identify potential targets for quality improvement in patients both with and without CKD.
19. Reengineering clinical operations in a medical practice to optimize the management of anemia of chronic kidney disease.
Joy MS, Candiani C, Vaillancourt BA et al.
Pharmacotherapy. 2007 27 (5): 734-44.
Objectives To describe the clinic design, clinical evaluations, and treatment approaches used in a multidisciplinary clinic for management of anemia chronic kidney disease (CKD), and to evaluate several selected clinical outcomes associated with this approach to anemia management. Setting University-affiliated, division of nephrology, outpatients multidisciplinary model CKD clinic headed by a clinical pharmacist. Patients One hundred sixty-six patients with anemia of CKD who were referred by nephrologists and primary care providers to the multidisciplinary clinic from March1, 2002-July 31, 2004. Measurements and Main Results Patients received darbepoetin alfa dosed on an every-other-week basis. If patients were already receiving once-weekly recombinant human erythropoietin (r-HuEPO), the darbepoetin alfa dose was calculated by using the darbepoetin alfa package insert conversion table. If patients were naive to previous erythropoietic therapy, the darbepoetin alfa dose was either 60 mug or 0.7 mug/kg. The dose and frequency of darbepoetin alfa and oral iron supplement were adjusted to achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for hemoglobin levels and iron measures. The primary outcome analyzed was the proportion of patients with at least 30 days who achieved a target hemoglobin level of 11.0 d/dl or greater. Of 128 patients who received at least 30 days of treatment, 100 (78%) attained the hemoglobin level (mean +/- 11.7 +/- 4 g/dl). Ninety-nine of 128 patients were originally naive to erythropoietic therapy; 77 (78%) of these 99 patients achieved the hemoglobin target in a mean +/- SD of 7.9 +/- 7.5 weeks. These data contrast with the data of 29 patients seen in the year previous to the reengineered clinic process, whereby only 12 (41%) of these comparable patients reached hemoglobin target with r-HuEPO therapy. Of the 77 previously erythropoietic-naive patients, 82% were receiving darbepoetin alfa every other week, 14% every 3 weeks, and 4% every 4 weeks at the time the hemoglobin target was achieved. Oral iron administration significantly increased the chance of achieving the K/DOQI targets for hemoglobin and iron. Conclusion Redefining roles and practices of members of a clinical practice and reengineering processes for anemia management were effective in achieving and maintaining target hemoglobin and iron levels.
20. Pyridoxal phosphate prevents progression of diabetic nephropathy.
Nakamura S, Li H, Adijiang A et al.
Nephrol Dial Transplant. 2007 Apr 20; [Epub ahead of print].
Background We have demonstrated that pyridoxal 5’-phosphate (PLP), an active form of vitamin B6, inhibits formation of advanced glycation end-products (AGEs) by trapping 3-deoxyglucosone. The present study aimed to clarify if PLP could exert beneficial effects on nephropathy in diabetic rats. Methods Streptozotocin (STZ)-induced diabetic rats were treated by oral administration of PLP or Pyridoxamine (PM), another active form of vitamin B6, at a dose of 600 mg/kg/day for 16 weeks. Ages [imidazolone, N(epsilon)-(carboxymethyl)lysine (CML) and N(2)-carboxyethyl-2’-deoxyguanosine (CEdG)], transforming growth factor-beta1 (TGF-beta1), type l collagen and fibronectin were detected in the kidneys using immunohistochemistry. Gene expression of TGF-beta1 and receptor for AGEs (RAGEs) in the kidneys was determined using real-time quantitative polymerase chain reaction. Results Administration of PLP significantly inhibited albuminuria, glomerular hypertrophy, mesangial expansion, and interstitial fibrosis as compared with diabetic rats. PLP markedly inhibited accumulation of AGEs such as imidazolone, CML and CEdG, a DNA-linked AGE, in glomeruli. PLP significantly inhibited expression of TGF-beta1, type 1 collagen, fibronectin and RAGE in the kidneys. PLP was superior to PM in inhibiting accumulation of AGEs, expression of TGF-beta1, type 1 collagen, and fibronectin, and the development of diabetic nephropathy. Conclusions PLP prevented progression of nephropathy in STZ-induced diabetic rats by inhibiting formation of AGEs. PLP is considered a promising active form of vitamin B6 for the tratment of AGE-linked disorders such as diabetic nephropathy.
21. Nutrition assessment and hormonal influences on body composition in children with chronic kidney disease.
Graf L, Candelaria S, Doyle M et al.
Adv Chronic Kidney Dis. 2007 14 (2): 215-23.
Malnutrition is a serious complcation of chronic kidney disease (CKD) in the pediatric population. Management of the nutritional status of children presents the challenge of ensuring sufficient energy to promote linear growth, development of brain and organs, and maintenance of appropriate fat and muscle stores, while preventing excess protein intake and controlling electrolytes. Aggressive nutrition intervention in the early stages of CKD may be critical in the prevention of more serious complications further in the disease process. Nutrition assessment involves analysis of dietary intake, anthropometric parameters, and laboratory data. Currently, no guidelines are available for nutritional management of pediatric patients with CKD before the onset of dialysis. The content and algorythms in this article are intended to serve as a guide in the management of the nutritional status of children with CKD. Although adequate calorie and protein intake is critical in prevention of malnutrition, it is only part of a complex mechanism in the development of cachexia in CKD. Research suggest that the effects of inflammatory cytokines and hormones such as leptin and ghrelin play a role in the development of malnutrition in CKD. As a more thorough understanding of this mechanism emerges, new treatments aimed at inhibiting cachexia can be developed.
22. Effect of raloxifene-a selective oestrogen receptor modulator on kidney function in post-menopausal women with type 2 diabetes: Results from a randomized, placebo-controlled pilot trial.
Hadjadj S, Gourdy P, Zaoui P et al.; For the RADIAN (Raloxifene in Diabetic Nephropathy) Study Group.
Diabet Med. 2007 Apr 19; [Epub ahead of print].
Aims Epidemiological and experimental data suggest that activation of the oestrogen receptor pathway limits the incidence and progression of diabetic nephropathy. We tested the hypothesis that raloxifene protects against increasing urinary albumin excretion in post-menopausal women with type 2 diabetes in a randomized pilot clinical trial. Methods We included 39 post-menopausal women with type 2 diabetes and micro- or macro-albuminuria in a 6-month, double-blind, placebo-controlled trial: 20 received placebo and 19 received 60 mg raloxifene per day. The albumin : creatinine ratio (ACR) in urine was determined on three consecutive days during the week before randomization and during the week before the final visit. Results One patients each group dropped out in the first 3 weeks, leaving 37 patients for the analysis (19 on placebo and 18 on raloxifene). From randomization to the final visit, mean ACR was unchagend in the placebo group {277 microg/mg (67; 651) [median (interquartile range)] vs. 284 microg/mg (79; 1508)} but decreased slightly in the raloxifene group [376 microg/mg (67; 615) vs. 243 microg/mg (103; 549)]. This correspond to a change of +24 (-37; +517) for the placebo group vs. -10 microg/mg (-36; +16) for the raloxifene group (P = 0.11). In multivariate analysis, raloxifene treatment (P (adjusted) = 0.013), baseline low-density lipoprotein (LDL) cholesterol (P (adjusted) = 0.023) and change in LDL cholesterol (P (adjusted) = 0.008) were related to the absolute change in ACR. Adverse effects were similar in the two groups. Conclusions These results suggest that raloxifene may limit the progression of albuminuria in post-menopausal women with diabetes; further studies in a larger population are warranted.
23. Doxycycline: A pilot study to reduce diabetic proteinuria.
Naini AE, Harandi AA, Moghtaderi J et al.
Am J Nephrol. 2007 27 (3): 269-73.
Background Activity of matrix metalloproteinases (MMPs), the enzymes primarily responsible for the deposition of extracellular matrix proteins, contributes to the pathogenesis of diabetic proteinuria. We evaluated the effect of doxycycline, a potent nonselective MMPs inhibitor, on reduction of proteinuria in diabetic patients. Material and Methods In a self-control clinical trial, 35 patients with overt diabetic nephropathy (proteinuria > 300 mg/24 h) received oral doxycycline 100 mg/day for 2 months. Twenty-four-hour urine volume, Cr and protein excretion were measured at baseline, after 1 and 2 months of treatment, and after 4 months of its discontinuation. Treatment-related side effects were closely monitored and documented. Results Mean (+/- SD) 24-hour urine protein was 888 +/- 419 mg at baseline, 884 +/- 368 mg after 1 months, and 643 +/- 386 mg after 2 months of doxycycline treatment. There was statistically significant reduction in proteinuria at 2 months of treatment vs. at baseline (p < 0.001). Mean 24-hour urine protein excretion increased to 1.021 +/- 422 mg 4 months after doxycycline was discontinued. The changes in serum sodium, potassium, BUN and Cr concentrations, and blood pressure measurements during the 2 months of treatment and follow-up period were not statistically significant. Conclusion Proteinuriaa in patients with diabetic nephropathy can be reduced with low dose doxycycline therapy over a 2-month period of drug administration. Further studies are to determine the long term effect, the optimal dose, and the optimal duration of this potentially novel therapy.
24. Diabetes mellitus does not preclude stabilization or improvement of renal function after stent revascularization in patients with kidney insufficiency and renal artery stenosis.
Silva JA, Potluri S, White CJ et al.
Catheter Cardiovasc Interv. 2007 69 (6): 902-7.
Objective To assess the impact of stent revascularization on the renal function of diabetic and nondiabetic patients with renal insufficiency. Background Renal artery revascularization has been shown to stabilize or improve renal function in patients with significant artery stenosis and impaired renal function. However, some studies have suggested negligible or no benefit of renal function in diabetic patients with the same condition. Methods We retrospectively compared data from 50 consecutive patients undergoing renal artery stent placement with renal insuficiency (serum creatinine > / = 1.5-4.0 mg/dl) and global ischemia (bilateral or solitary [single] kidney/renal artery stenosis). There were 17 diabetic (DM) and 33 nondiabetic (NDM) patients. The endpoints included the follow-up measurements of renal function, blood pressure, and number of antihypertensive medications. Results After stent placement, at a mean follow-up of 42 +/- 18 months (range: 6-62 months), 79% NDM (N = 26), and 76% DM patients (N = 13) (P = NS) had improvement in the slope of the reciprocal of creatinine (1/SCr), indicating a beneficial effect in renal function in many patients. Conclusion Renal artery stent placement to be equally beneficial in preserving renal function in DM and NDM patients with ischemic nephropathy and global renal ischemia.
25. Are high-protein, vegetable-based diets safe for kidney function? A review of literature.
Bernstein AM, Treyzon L, Li Z.
J Am Diet Assoc. 2007 107 (4): 644-50.
In individuals with chronic kidney disease, high-protein diets have been shown to accelerate renal deterioration, whereas low-protein diets increase the risk of protein malnutrition. Vegetarian diets have been promoted as a way to halt progression of kidney disease while maintaining adequate nutrition. We review the literature to date comparing the effects of animal and vegetable protein on kidney function in health and disease. Diets with conventional amounts of protein, as well as high-protein diets, are reviewed. The literature shows that in short-term clinical trials, animal protein causes dynamic effects on renal function, whereas egg white, dairy, and soy do not. These differences are seen both in diets with conventional amounts of protein and those with high amounts of protein. The long-term effects of animal proteins on normal kidney function are not known. Although data on persons with chronic kidney disease are limited, it appears that high intake of animal and vegetable proteins accelerates the underlying disease process not only in physiologic studies but also in short-term interventional trials. The long-term effects of high protein intake on chronic kidney disease are still poorly understood. Several mechanisms have been suggested to explain the different effects of animal and vegetable proteins on normal kidney function, including differences in postprandial circulating hormones, sites of protein metabolism, and interaction with accompanying micronutrities.
26. Effects of a supplemented hypoproteic diet in chronic kidney disease.
Mircescu G, Garneata L, Stancu SH et al.
J Ren Nutr. 2007 17 (3): 179-88.
Objective We assessed the effect of a severe hypoproteic diet supplemented with ketoanalogues (SVLPD) for 48 weeks on certain metabolic disorders of chronic kidney disease (CKD). Design We performed a protective, open-label, parallel, randomized, controlled trial. Setting The study took place in the Nephrology Department at the Dr Carol Davila Teaching Hospital of Nephrology, Bucharest, Romania. Patients A total of 53 nondiabetic patients with CKD with an estimated glomerular filtration rate less than 30 mL/min/1.73 m(2) (Modified of Diet in Renal Disease formula), proteinuria less than 1 g/g urinary creatinine, good nutritional status, and anticipated good compliance with the diet were randomly assigned to two groups. Intervention Group I (n = 27) received the SVLPD (0.3 g/kg/d of vegetable proteins and ketonanlogues, 1 capsule for every 5 kg of ideal boody weight per day). Group II (n = 26) continued a conventional low mixed protein diet (0.6 g/kg/d). Outcome measures Nitrogen waste products retention and calcium-phosphorous and acid-base disturbance were primary efficacy parameters, and ’’death’’ of the kidney or the patient and the estimated glomerular filtration rate were secondary efficacy parameters. The nutritional status and compliance with the diet were predefined as safety variables. There were no difference between groups in any parameter at baseline. Results In the SVLPD group, serum urea significantly decreased (56 +/- 7.9 mmol/L vs. 43.2 +/- 10 mmol/L), and significant improvements in serum bicarbonate (23.4 +/- 2.1 mmol/L vs. 18.1 +/- 1.5 mmol/L), serum calcium (1.10 +/- 0.17 mmol/L vs. 1.00 +/- 0.15 mmol/l at baseline, serum phosphates (1.45 +/- 0.66 mmol/L vs. 1.91 +/- 0.68 mmol/L) and calcium-phosphorous product (1.59 +/- 0.11 mmol (2) / L (2) vs. 1.91 +/- 0.10 mmol (2) / L (2)) were noted after 48 weeks. No death was registered in any group. Significantly lower percentage of patients in group I required renal replacement therapy initiation (4% vs. 27%). After 48 weeks, estimated glomerular filtration rate did not significantly change in patients receiving SVLPD (0.26 +/- 0.08 mL/s vs. 0.31 +/- 0.08 mL/s at baseline) but significantly decreased in controls (0.22 +/- 0.09 mL/s vs. 0.30 +/- 0.07 mL/s). The commpliance with the keto-diet was good in enrolled patients. No significant changes in any of the parameters of the nutritional status and no adverse reactions were noted. Conclusion SVLPD seems to ameliorate the nitrogen waste products retention and acid-base and calcium-phosphorous metabolism disturbances and to postpone the renal replacement therapy initiation, preserving the nutritional status in patients with CKD.
27. AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases.
Ueda H, Shibahara N, Takagi S et al.
Ther Apher Dial. 2007 11 (3): 189-95.
The effects of an oral adsorbent, AST-120, in chronic kidney disease (CKD) patients was evaluated by the 24-month dialysis-free rate and 50% dialysis-free period. This study retrospectively analyzed 193 patients to the Osaka Medical College Hospital between January 1994 and December 2001 because of CKD and who later started dialysis. The propensity score on multiple factors was used to match two groups of patients (AST-120 group, n = 78; non-AST-120 group, n = 78). Then, the proportion of patients remaining dialysis-free and the 50% dialysis-free period during the 24 months after starting treatment with or without AST-120 were analyzed. The impact of AST-120 on the risk of dialysis initiation was also determined by multivariate analysis. There were no significant differences in the clinical background and laboratory values after matching the two groups using the propensity score. The 50% dialysis-free period was significantly prolonged in the AST-120 group for all patients analyzed, as well as for the subgroup with diabetic or non-diabetic renal disease. When AST-120 treatment was started at a serum creatinine level below 3 mg/dL, the dialysis-free period was longer than 24 months in the AST-group, compared with 16.2 months in the non-AST-120 group. The 24-month dialysis-free rate was higher in the AST-120 group every patient category. The risk of dialysis initiation was increased 3.48-fold in patients who were not administered AST-120. These results show that AST-120 delays the initiation of dialysis in CKD patients. Thus, AST-120 is an effective supplementary therapy to prevent the initiation of dialysis in CKD patients.
28. Nandrolone decanoate as anabolic therapy in chronic kidney disease: A randomized Phase II dose-finding study.
Macdonald JH, Marcora SM, Jibani MM et al.
Nephron Clin Pract. 2007 106 (3): c125-35.
Background/Aims In patients with chronic kidney disease (CKD) receiving adequate erythropoietin therapy, the ideal dose of nandrolone decanoate (ND) to enhance muscle mass is not known. In this phase II dose-finding study, 54 patients with CKD stage 5 were randomized to either low, medium or high doses of ND (50, 100 or 200 mg/weeks, respectively, in males; doses halved in females), while 7 patients acted as non-randomized controls. The primary outcome measure was appendicular lean mass (ALM) by dual-energy X-ray absorptiometry. Fluid overload (hydration of the fast-free mass) and indicators of physical functioning were secondary measures. Harms were also recorded. Data were analysed using Quade’s (1967) non-parametric analyses of covariance. Results ND increased ALM in a dose-responsive manner (change scores = 0.3 +/- 0.3 vs. 0.8 +/- 0.3 vs. 1.5 +/- 0.5 vs. 2.1 +/- 0.4 kg, control vs. low vs. medium vs. high dose groups, respetively, P < 0.001) with no increases in fluid overload but no consistent effect on physical functioning. The highest dose of ND (100 mg/week was intolerable in females because of virilizing effects. Conclusion If goals of future studies are to improve body composition, dosing of ND up to 200 mg/week in males and 50 mg/week in females should be investigated. However, to realize improvements in physical functioning, future phase III trials of ND may require additional interventions such as exercise training.
29. Nutritional effect of nandrolone decanoate in predialysis patients with chronic kidney disease.
Eiam-Ong S, Buranaosot S, Wathanavaha A et al.
J Ren Nutr. 2007 17 (3): 173-8.
Objective The study objective was to examine the nutritional effect of nandrolone decanoate, and androgen derivate, in predialysis patients with chronic kidney disease (CKD). Design This was a prospective and experimental study. Setting The study was performed at the institutional level of clinical care. Patients Twenty-nine predialysis patients with CKD, with a glomerular filtration rate between 5 and 30 mL/min and moderate to severe malnutrition, were included and randomly divided into control (n = 13) and nandrolone decanoate (NAN, n = 16) groups. Intervention Patients in the control group receiving optimally conventional treatment of CKD. Patients in the NAN group, in additon to the conventional treatment, were intramuscularly injected with nandrolone decanoate at the dose of 100 mg per for 3 months. Main Outcome Measure Nutritional markers, including lean body mass (LBM), normalized protein catabolic rate, serum albumin, and lipids, were determined at baseline and 3-month periods. Results Baseline parameters in both groups were not different. After 3 months, the patients in the NAN group had increased LBM (P < 0.01) and decreased serum albumin levels (P < 0.05), but no changes in the values of normalized protein catabolic rate, serum lipids, hematocrit, and glomerular filtration rate. No alterations in all parameters were identified in the control group. Changes in LBM in the NAN group were significantly higher in the control group (P < 0.05). Minor adverse effects were observed in a few patients in the NAN group. Conclusion Nandrolone decanoate express an anabolic effect on LBM without altering the renal function and thus would provide nutritional benefit in predialysis patients with CKD.
30. The potential for vitamin D receptor activation in cardiovascular research.
Wu-Wong JR.
Expert Opin Investig Drugs. 2007 16 (4): 407-11.
Vitamin D (3) needs to be activated into 1, 25-dihydroxyviatmin D (3) in order to bind to vitamin D receptor (VDR) for functional responses. Studies in the past have focused on the role of VDR in mineral homeostasis, with VDR activators used mainly to treat hyperparathyroidism secondary to chronic kidney disease. Chronic kidney disease patients encounter a higher risk of cardiovascular disease than the general public and experience an extremely high cardiovascular-related mortality rate. Recent clinical observations show that VDR therapy reduces mortality and morbidity in chronic kidney disease. Preclinical studies demonstrate that VDR is likely to be involved in the cardiovascular pathophysiology.
31. Biological therapies: New treatment options for ANCA-associated vasculitis?
Aries PM, Lamprecht P, Gross WL.
Expert Opin Biol Ther. 2007 7 (4): 521-33.
Biological therapies enable us to apply highly selective targeting components to modulate the immune response. Until now, a few controlled studies investigated the efficacy of TNF-alpha blocking agents in systemic vasculitis have been carried out, but, in general, they were falling short of expectations. However, there is conductive evidence that TNF-alpha blockers are advantageous in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, at least in selected disease stages. Likewise, although the efficacy of the monoclonal CD20 antibody rituximab in ANCA-associated vasculitis is obvious, the effect on predominatly granulomatous disease activity in Wegener’s granulomatosis is less clear. In addition, interferon-alpha is used for induction treatment particularly in Churg-Strauss syndrome. Even though the effectiveness and safety of short-term administration was confirmed by case series, severe side effects after long-term treatment relativized the initial results. This review presents the recent data on the use of biologicals in vasculitis and appraises the knowledge in the clinical context.
32. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis.
Metzler C, Miehle N, Manger K et al.
Rheumatology (Oxford). 2007 May 22; [Epub ahead of print].
Objectives Results of open-label trials suggest that methotrexate (MTX) and leflunomide (LEF) are effective for maintenance of remission in Wegener’s granulomatosis (WG), but data from randomized controlled clinical trails are not yet available. Methods In this multicentre, prospective randomized controlled clinical trial, patients with generalized WG were treated with oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with cyclophosphamide. The primary endpoint was the incidence of relapse. Secondary outcome parameters were DEI, BVAS, SF-36, cANCA-titre, ESR and CRP. Results Fifty-four patients were included in the study, 26 in the LEF-limb, 28 in MTX-limb. In the LEF-group, six patients relapsed after a median time of 7 months, thereof one major relapse with a new pulmonary manifestation. In the MTX-group, 13 relapses occured in 6 months, or which seven major: rapidly progressive glomerulonephritis (n = 4), pulmonary hemorrhage (n = 2) and one cerebral granuloma. The significantly higher incidence of major relapses in the MTX-limb (P = 0.037) led to premature termination of the study. In the LEF-limb, four patients were withdrawn due to hypertension (n = 2), peripheral neuropathy (n = 1) and leucopenia (n = 1). Conclusion LEF at a dosage of 30 mg/day appears to be effective in the prevention of major relapses in WG, however, this is associated with an increased frequency of adverse events. Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patients cohort.
33. Membranous nephropathy: When and how to treat.
Lai KN.
Kidney Int. 2007 71 (9): 841-3.
The treatment of idiopathic membranous nephropathy is heavily debated because of wide variation in outcome. A rational treatment strategy is needed to appropriately administer conservative treatment to the low-risk group but immunosuppressive therapy to those with medium or high risk of renal deterioration. Currently, combination of steroids with alkylating agents are best studied. Newer forms of immunosuppressive treatment are currently under study.
34. Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: Higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs.
Goumenos DS, Katopodis KP, Passadakis P et al.
Am J Nephrol. 2007 27 (3): 226-31.
Background/Aim Idiopathic membranous nephropathy, the most common cause of nephrotic syndrome in adults, has been traditionally treated with corticosteroids and cytotoxic drugs. Ciclosporin A (CsA) is used in resistant cases, but also as a first-line treatment, due to serious side effects of cytotoxic drugs. In this study, the remission rates of nephrotic syndrome and the incidence of side effects of corticosteroids and low CsA doses are compared with those after treatment with cytotoxic drugs. Methods Seventy-seven nephrotic patients with well-preserved renal function who treated with
methylprednisolne and CsA (n = 46) or cytotoxic drugs (n = 31) were studied. The effects of treatments were estimated on the basis of remission rates of nephrotic syndrome and preservation of the renal function. Results Remission (complete or partial) of nephrotic syndrome was observed in 85% of the patients treated with CsA and in 55% of the patients treated with cytotoxic drugs (p < 0.01). Deterioration of the renal function, more common in patients with multiple relapses and interstitial fibrosis, was observed in 26 and 23% of the patients, respectively (p = NS). Serious side effects and discontinuation of treatment were more frequent in patients treated with cytotoxic drugs (10 vs. 4%). Conclusion The combination of corticosteroids with CsA represents a better regimen for patients having idiopathic membranous nephropathy, since it is associated with higher remission rates of nephrotic syndrome and less severe side effects than corticosteroids and cytotoxic drugs.
35. Steroid-resistant idiopathic childhood nephrosis: Overdiagnosed and undertreated.
Ehrich JH, Geerlings C, Zivicnjak M et al.
Nephrol Dial Transplant. 2007 May 15; [Epubahead of print].
Background The rate of complete remission after therapy for steroid-resistant nephrotic syndrome (SRNS) due to either focal segmental glomerulosclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) has been reported to be < 50%. The present retrospective study investigated 86 children with SRNS due to FSGS and MCNS and found improved rates of complete remission in children with idiopathic FSGS and MCNS after combination therapioes using ciclosporin A (CSA) and prednisolone (PRED). Methods Eighty-six children with FSGS or MCNS and with SRNS receiving standard oral PRED therapy were analysed in a retrospective, non-randomized study. Fifty-two patients had idiopathic FSGS (group 1), 14 patients had MCNS (group 2), and 20 patients had genetic FSGS or syndrome-associated FSGS (group 3). In group 1A (n = 25), induction therapy consisted of CSA (initial dose 150 mg/day 150 mg/day/m (2) divided into two doses) given in combination with intravenous methylprednisolone (IV-MPRED 300-1000 mg/day/m (2) for 3-8 days) and oral PRED. In group 1B (n = 27), CSA was combined with oral PRED (40 mg/m (2) on alternate days). Results In group 1, patients with idiopathic FSGS receiving IV-MPRED + oral PRED + CSA had a significantly better outcome than patients treated with oral PRED + CSA (84 vs 64% cumulative proportion of sustained complete remission, respectively; P = 0.02, log-rank test). Sixteen (40%) out of 40 children entering complete remission had a first relapse after a median interval of 1 year. All relapses were successfully treated with IV-MPRED + oral PRED + CSA or oral PRED + CSA. Three out of forty responding children developed stage 2 chronic kidney disease (CKD), and none advanced to stage 3-5; in contrast of 12 children with persistent nephrotic syndrome (NS) developed CKD stage 2-5 (8 vs 75%, respectively; P < 0.001, Fisher’s exact test). In group 2, all children with steroid resistant MCNS went into remission after receiving PRED + CSA (n = 11) or IV-MPRED + oral PRED + CSA (n = 3). No patient developed CKD. In group 3, NS persisted in all 20 children having a genetic or syndromic type of FSGS receiving either PRED + CSA (n = 9) or PRED alone (n = 11). Seventeen out of 20 patients enetered stage 5 CKD and were successfully transplanted; one patient developed recurrent NS. Conclusion Prolonged and intensified treatment of children with idiopathic non-genetic SRNS (FSGS or MCNS) with combined PRED + CSA therapy including IV-MPRED pulses resulted in a higher rate of remission when compared with previous reports on using CSA mono-therapy or other immunosuppressive combination therapies.
36. Does cyclosporine achieve a real advantage for treatment of idiopathic nephrotic syndrome in children? A long-term efficacy and safety study.
Sheashaa H, Mahmoud I, El-Basuony F et al.
Int Urol Nephrol. 2007 Apr 20; [Epub ahead of print].
Background Cyclosporine (CsA) was found to be efficient in decreasing proteinuria in both steroid-dependent and steroid-resistant nephrotic patients. We aimed to explore the potential long-term benefits and hazards of CsA and their predictors among a large group of nephrotic patients. Methods In this retrospective analysis, we included 197 pediatric patients with idiopathic nephrotic syndrome (INS) of whom 103 were steroid dependent and 94 steroid resistant. Results CsA induced complete remission in 132 (67%) and partial response in 13 (6.6%). Cyclosporine was received for a period of 22.16 +/- 12.21 months. Univariate analysis showed that the response to CsA was significantly better in steroid-dependent children, in minimal change disease (MCD), diffuse mesangial proliferative glomerulonephritis (DMP) and focal segmental glomerulosclerosis (FSGS) than in other pathological lesions and in those who had lower quantities of pretreatment proteinuria. Only the prior response to steroids and concomitant use of ketokonazole with CsA were valid predictors for better response to CsA with multivariate analysis. Discontinuation of the drug in 40 patients resulted in relapse in 26 patients while the remaining 14 patients maintained remission. Renal dysfunction developed in 18 patients of whom 12 recovered completely on drug discontinuation. Thirty-seven patients developed hypertension. Multivariate analysis showed that all side-effects were significantly more prevalent in CsA-resistant patients. Conclusion CsA is effective and well tolerated in the long-term treatment of INS in children, however, two thirds of cases showed relapse after CsA discontinuation.
37. A randomized, contolled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.
Jha V, Ganguli A, Saha TK et al.
J Am Soc Nephrol. 2007 18 (6): 1899-904.
Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Universal consensus regarding the need for and the modality of therapy has not been formed because of a lack of controlled trials of sufficient size, quality, and duration. This study compared the effect of a 6-mo course of alternating prednisolone and cyclophosphamide with supportive treatment in adults with nephrotic syndrome caused by IMN on doubling of serum creatinine, development of ESRD, and quality of life in a randomized, controlled trial. Patients were followed up for 10 yr. Data were analyzed on an intention-to-treat basis. A total of 93 patients completed the study. Of the 47 patients who received the experimental protocol, 34 achieved remission (15 complete and 19 partial), compared with 16 (five complete, 11 partial) of 46 in the control group (P < 0.0001). The 10-yr dialysis-free survival was 89 and 65% (P = 0.016), and the likelihood of survival without death, dialysis, and doubling of serum creatinine were 79 and 44% (P = 0.0006) in the two groups. Treated patients exhibited significantly lower prevalence of edema, hypertension, hypoalbuminemia, hyperlipidemia that required therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, and better quality of life on follow-up. The incidence of infections was similar in the two groups. In conclusion, untreated IMN with nephrotic syndrome is associated with a high risk for deterioration of renal function. A 6-mo regimen of cyclophosphamide and steroids induces remissions in a high proportion, arrests progression of renal insufficiency, and improves quality of life.
38. Plasma exchange combined with immunosuppressive treatment in a child with rapidly progressive IgA nephropathy.
Fujinaga S, Ohtomo Y, Umino D et al.
Pediatr Nephrol. 2007 22 (6): 899-902.
Although diffuse crescentic formation in immunoglobulin A (IgA) nephropathy, histologically characterized by extensive extracapillary proliferation, is assumed to have a poor prognosis, there has still been no established treatment because of the low prevalence of the condition, especially in pediatric patients. This paper reports on a 5-year-old boy with rapidly progressive IgA nephropathy requiring dialysis for 1 month. He had been treated with plasma exchange (PE) combined with immunosuppressive treatment, including steroids and mizoribine, because renal function deteriorated rapidly despite initial treatment with intravenous methylprednisolone pulse. The histological findings at that time revealed IgA nephropathy, with large circumferential cellular crescent formation in approximatelly 80% of the glomeruli. Three weeks after PE initiation, serum levels of creatinine and IgA-containing immune-complexes returned to normal, and urinary protein excretion gradually decreased. The second renal biopsy taken 7 months later demonstrated mild IgA nephropathy with small fibrocellular crescents. This case report indicates that PE combined with immunosuppressive treatment may benefit children with rapidly progressive IgA nephropathy, even when extensive crescent formations are present.
39. Mycophenolate mofetil treatment for therapy-resistant glomerulopathies.
Sahin GM, Sahin S, Kantarci G et al.
Nephrology (Carlton). 2007 12 (3): 285-8.
Background The management of steroid-resistant glomerulopathies remained a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies. Methods All patients underwent renal biopsies, and immunoflurescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period. Results The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13,9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9 +/- 12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3 +/- 2.6 g/dL (0.6-9.6) and decreased significantly to 0.87 +/- 1.1 g/dL (0-5.5) at the end of the MMF treatment period (P = 0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29 +/- 0.55 mg/dL (0.6-3.0) to 1.14 +/- 0.38 mg/dL (0.5-2.4) post MMF therapy (P = 0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5 +/- 28 mL/min per 1.73 m (2) to 78.1 mL/min per 1.73 m (2) (P = 0.021). renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulpathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed. Conclusion In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.
40. Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial.
Praga M, Barrio V, Juarez GF et al.
Kidney Int. 2007 71 (9): 924-30.
Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achive a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patients in the tacrolimus group showed a relapse during the tapper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We concluded that tacrolimus is a vary useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.
41. HIV-associated nephropathy in the era of antiretroviral therapy.
Wyatt CM, Klotman PE.
Am J Med. 2007 120 (6): 488-92.
With impoved survival in the era of antiretroviral therapy, kidney disease has emerged as an important complication of Human Immunodeficiency Virus (HIV) infection and antiretroviral therapy. The classic kidney disease of HIV infection, HIV-associated nephropathy, occurs almost exclusively in patients of African descent. HIV-associated nephropathy is characterized by collapsing focal segmental glomerulosclerosis with associated tubular dilatation and interstitial inflammation, although the histology may be more subtle in patients receiving antiretroviral therapy. Renal epithelial cells are infected by HIV-1, which results in epithelial cell proliferation and induction of local inflammatory pathways. Even with apporpriate therapy, the kidney is a reservoir for HIV-1. Although the widespread introduction of antiretroviral therapy has had a benficial impact on the epidemiology of HIV-associated nephropathy, the burden of kidney disease is likely to increase as a result of antiretroviraly toxicity, reduction in competing mortality risks, and the increasing prevalence of HIV-1 infection in patients at risk for kidney disease.
42. The S1P modulator FTY720 limits matrix expansion acute anti-thy1 mesangioproliferative glomerulonephritis.
Martini S, Kramer S, Loof T et al.
Am J Physiol Renal Physiol. 2007 Mar 13; [Epub ahead of print].
FTY720 is a novel immune modulator whose primary action is blood lymphocyte depletion through interaction with sphingosine-1-phosphate (S1P) receptors. The present study analyses the effect of FTY720 on both the early mesangial cell injury and the subsequent matrix expansion phase in experimental mesangioproliferative glomerulonephritis. Disease was induced by injection of OX-7 anti-thy1 antibody into male Wistar rats. In both protocols, FTY720 administration (0.3 mg/kg body weight in a selective and very marked reduction in blood lymphocyte count. In the injury experiment, the S1P receptor modulator was given starting 5 days before and continued until 1 day after antibody injection, but did not significantly affect the degree of anti-thy1-induced mesangial cell lysis and glomerular inducible NO production. In the matrix expansion experiment, FTY720 treatment was started 1 day after antibody injection and continued until day 7. In this protocol, the S1P modulator reduced proteinuria, histological matrix expansion and glomerular protein expression of TGF-beta1, fibronectin and PAI-1. Glomerular collagen III staining intensity was decreased. FTY720 reduced markedly glomerular lymphocyte number per cross section and to a lesser degree macrophage infiltration. In conclusion, FTY720 significantly limits TGF-beta overexpression and matrix protein expression following induction of acute anti-thy glomerulonephritis, involving reductions in blood and glomerular lymphocyte numbers. The results suggest that lymphocytes actively contribute to matrix expansion in experimental mesangioproliferative glomerulonephritis. Our study expands on findings on FTY72’s beneficial effects on tubulointerstitial and functional disease progression previously reported in anti-thy1-induced chronic glomerulosclerosis.
Key words: glomerulonephritis, FTY720, lymphocytes.
43. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study.
Chanan-Khan AA, Kaufman JL, Mehta J et al.
Blood. 2007 109 (6): 2604-6.
Patients with multiple myeloma (MM) frequently present with concomitant renal dysfunction, and those requiring dialysis have particularly poor outcomes. Bortezomib is a reversible proteosome inhibitor with significant activity in MM. This retrospective case analysis evaluated the feasibility and activity of bortezomib-based therapy in MM patients (n = 24) requiring dialysis support for advanced renal failure. All but 1 patients were undergoing dialysis at the time of therapy. Patients received bortezomib alone or bortezomib-based combination therapy. Among 20 patients with available response data, overall response rate (complete response [CR] + partial response) was 75%, with 30% CR + near CR. One patients was spared dialysis, and 3 other patients became independent of dialysis following bortezomib-based treatment. These encouraging results suggest that bortezomib or bortezomib-based regimens can be used in MM patients requring dialysis, with manageable toxicities. Further studies will formally evaluate the impact of bortezomib-based regimens in this population.
44. Endothelin-1 antisense oligonucleotide suppresses the proliferation of glomerular mesangial cells stimulated with angiotensin-II.
Lee JJ, Shin SJ, Chiu YW et al.
Kaohsiung J Med Sci. 2007 23 (4): 170-5.
Antisense oligonucleotide (AON) has been applied to modern molecular pharmacology. We have previously demonstrated that angiotensin-II (Ang-II) is an active stimulator of endothelin-1 (ET-1) production in glomerular mesangial cells. This study was designed to investigate the specific effect of ET-1 AON on inducing proliferation of cultured rat mesangial cells stimulated with Ang-II. ET-1 was measured by radioimmunoassys. The results were: (1) Ang-II enhanced ET-1 production of mesangial cells; (2) ET-1 production of mesangial cells was significantly suppresssed by ET-1 AON, and this production was not affected by either ET-1 sense or scramble oligonucleotide in different concentrations; (3) Ang-II increased [3H]-thymidine uptake of mesangial cells, which was suppressed to 25% by ET-1 AON but not by ET-1 sense or scramble oligonucleotide. Our results indicate that ET-1 AON effectively suppresses the ET-1 production and the Ang-II-stimulated proliferation of mesangial cells, and therefore may offer treatment for proliferative glomerulonephritis.
45. Glucose responsive insulin production from human embryonic germ (EG) cell derivates.
Clark GO, Yochem RL, Axelman J et al.
Biochem Biophys Res Commun. 2007 356 (3): 587-93.
Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and beta-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivates may eventually serve as a source of insulin producing cells for the treatment of diabetes.
46. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipoctes.
Kunter U, Rong S, Boor P et al.
J Am Soc Nephrol. 2007 18 (6): 1754-64.
Glomerulonephritis (GN) is a major cause of renal failure. This study sought to determine whether intrarenal injection of rat mesenchymal stem cells (MSC) can preserve renal function in a progressive rat model of GN. Early in GN (day 10), fluorescently labeled rat MSC localized to more than 70% of glomeruli, ameliorated acute renal failure, and reduced glomerular adhesions. Fifty days later, proteinuria had progressed in controls to 40 +/- 25 mg/d but stayed low in MSC treated rats (13 +/- 4 mg/d; P < 0.01). Renal function on day 60 in the MSC group was better than in medium controls. Kidneys of the MSC group as compared with controls on day 60 contained 11% more glomeruli per 1-mm (2) section of cortex but also significantly more collagen types I, III, and IV and alpha-smooth muscle actin. Approximately 20% of the glomeruli of MSC-treated rats contained single or clusters of large adipocytes with pronounced surrounding fibrosis. Adipocytes exhibited fluorescence in their cytoplasm and/or intracellular lipid droplets. Lipid composition in these adipocytes in vivo mirrored that of MSC underwent adipogenic differentiation in vitro. Thus, in this GN model, the early beneficial effect of MSC of preserving damage glomeruli and maintaining renal function was offset by a long-term partial maldifferentiation of intraglomerular MSC into adipocytes accompained by glomerular sclerosis. These data suggest that MSC treatment can be a valuable therapeutic approach only if adipogenic maldifferentiation is prevented.
47. Prevention of contrast-induced nephropathy in the Emergency Department.
Sinert R, Doty CI.
Ann Emerg Med. 2007 May 17; [Epub ahead of print].
Study objective Contrast-induced nephropathy is the third leading cause of hospital-acquired acute renal failure. Expanded use of contrast-enhanced imaging exposes an ever-widening number of patients to this renal toxin. We perform an evidence-based emergency medicine review comparing different therapies to prevent contrast-induced nephropathy. We limit our review to prophylactic therapies that are practical for an emergency department setting. Methods We searched MEDLINE, EMBASE, and the Cochrane Library for randomized trials comparing a wide range of medications to prevent contrast-induced nephropathy. We defined contrast-induced nephropathy by a commonly used surrogate measure of renal failure: a 25% or 0.5 mg/dL absolute increase in serum creatinine level from baseline 48 to 72 hours postcontrast. We limited our review to only trials for patients with baseline renal insufficiency, who are most at rsik for contrast-induced nephropathy. We excluded prophylactic protocols requiring more than 2 hours precontrast to initiate and any trials of experimental medications or those that required invasive monitoring. We used standard criteria to appraise the quality of published trials. Results We found 7 randomized trials; 3 using N-acetylcysteine, 2 using theophylline, and 1 each using bicarbonate and ascorbic acid. Although many of these trials showed statistically significant reductions in the risk for contrast-induced nephropathy, none were sufficiently powered to detect reductions in mortality rate or the need for dialytic therapy. Conclusion Evidence from randomized trials shows that these interventions (theophylline, bicarbonate, and ascorbic acid) under review were appropriate to an ED setting and decreased the risk of contrast-induced nephropathy. The case for the effectiveness (N-acetylcysteine) was less certain.
48. The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention: The RENO Study.
Recio-Mayoral A, Chaparro M, Prado B et al.
J Am Coll Cardiol. 2007 49 (12): 1283-8.
Objectives This study was designed to determine the effectiveness of a protocol for rapid intravenous hydration to prevent contrast-induced nephropathy (CIN) in patients undergoing emergency percuatenous coronary intervention (PCI). Background Contrast-indcued nephropathy frequently complicates PCI, resulting in prolonged hospitalization and increased in-hospital and long-term morbidity and mortality. Little is known regarding prevention of CIN in patients undergoing urgent PCI. Methods We conducted a prospective, controlled, randomized, single-center trial in 111 consecutive patients wit acute coronary syndrome undergoing emergency PCI. As part of the hydration therapy, 56 patients (group A) received an infusion of sodium bicarbonate plus N-acetylcysteine (N-AC) started just before contrast injection and continued for 12 h after PCI. The remaining 55 patients (group B) received the standard hydration protocol consisting of intravenous isotonic saline 12 h after PCI. In both groups, 2 doses of oral N-AC were administered the next day. Results The 2 groups were similar with respect to age, gender, diabetes mellitus, and baseline serum creatinine. A serum creatinine concentration > 0.5 mg/dl from baseline after emergency PCI was observed in 1 patients in group A (1.8%) and in 12 patients in group B (21.8%; p < 0.001). Acute anuric renal failure observed in 1 patient (1.8%) in group A and 7 patients (12.7%) in group B (p = 0.032). Conclusions Rapid intravenous hydration with sodium bicarbonate plus N-AC before contrast injection is effective and safe in the prevention of CIN in patients undergoing emergency PCI.
V. TRANSPLANTATION
1. Renal pathology in the pediatric transplant patients.
Vogler C, Wang Y, Brink DS et al.
Adv Anat Pathol. 2007 14 (3): 202-16.
Renal transplantation is a therapeutic goal for children with advanced chronic kidney disease. There are many causes of renal dysfunction in children with allografts - the transplanted kidney can develop a variety of morphologic alterations leading to dysfunction. Evaluation of the kidney biopsy is one of the best methods of determining the cause of graft dysfunction. Rejection is a major cause of renal allograft failure in children. The morphologic hallmarks of acute antibody-mediated and cell-mediated rejection and chronic allograft nephropathy have been codified in classification strategies that are useful in adults and children. Viral infection and Epstein-Barr virus-driven posttransplant lymphoproliferative disease also occur in the pediatric transplanted kidney. Drug toxicity from immunosuppressive agents also causes characteristic morpholigic alterations in the renal allograft. As the survival of pediatric heart and liver transplant patients improves, the incidence of immunosuppression therapy-related disease in the native kidney in these patients will likely become more important clinically. In addition to renal lesions related to the allograft state, glomerular disease can recur or occur de novo in renal allografts. Here, we describe the pathology of the more common morphologic lesions in kidneys of children with a renal allograft.
2. Expression of the chemokine receptor CCR1 in human renal allografts.
Mayer V, Hudkins KL, Heller F et al.
Nehrol Dial Transplant. 2007 22 (6): 1720-9.
Background Chemokines are involved in the recruitment of leukocytes to vascularized allografts. CCR1 is a receptor for various inflammatory chemokines and CCR1 blockade reduces renal allograft injury in rabbits. The purpose of the study was to characterize CCR1-positive cells in human renal allografts. Methods Formalin-fixed, paraffin-embedded allograft nephrectomies (n = 9) an non-involved parts of tumour nephrectomies (n = 10) were studied. Immunohistochemistry for CCR1, CD3 and CD68 was performed on consecutive sections. Double immunoflurescence 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 the 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.
3. Chronic renal failure in kidney transplant recipients. Do they receive optimum care? Data from the UK Renal Registry.
Ansell D, Udayaraj UP, Steenkamp R et al.
Am J Transplant. 2007 7 (5): 1167-76.
We report the prevalence of chronic kidney disease (CKD) and related complications in a national cohort of RTR (n = 9542), and compare this with dialysis patients. The majority of RTR were classified as having CKD stage 2T (21.6%) or 3T (57.5%) with 15.7% classified as CKD stage 4T and 3.1% as stage 5T. Only 2.1% of RTR were in CKD stage 1T. The proportion of patients with stage 4T and 5T CKD who lost their garft in the following year was 8% and 49%, respectively. The prevalence of anemia (hemoglobin < 11 g/dL) increased from 4.4% in stage 1T to 51.5% in stage 5T and compared with 30% in dialysis patients (p < 0.0001). Hypertension, hyperphosphatemia, elevated Ca×PO (4), raised iPTH and hypoalbuminemia rose with increasing CKD stage. For many variables, the achievement of standards was lower in stage 5T RTR than in dialysis patients. There were center differences in median estimated glomerular filtration rate and percentage of patients with hemoglobin < 11 g/dL (p < 0.0001). In conclusion, many patients in stage 4T-5T have CKD-related complications that fall below targets established for nontransplant CKD patients. They are at increased risk of graft loss. More attention needs to be paid to managing these complications and preparing these patients for a return to dialysis and/or retransplantation.
4. Diurnal blood pressure changes one year after kidney transplantation: Relationship to allograft function, histology, and resistive index.
Wadei HM, Amer H, Taler SJ et al.
J Am Soc Nephrol. 2007 18 (5): 1607-15.
Loss of circadian BP change has been linked to target organ damage and accelerated kidney function loss in hypertensive patients with and without chronic kidney disease. Ambulatory BP-derived data from 119 consecutive kidney transplant recipients who presented for the first annual evaluation were examined in relation to allograft function, histology, and ultrasound findings. A total of 101 (85%) patients were receiving antihypertensive medications (median 2), and 85 (71%) achieved target awake average systolic BP (SBP) of < 135 mmHg. A day-night change in SBP by 10% or more (dippers) was detected in 29 (24%). Dipping status was associated with younger recipient age, lack of diabetes, low chronic vascular score, and low resistive index. Nondippers and reverse dippers had lower GFR compared with dippers (P = 0.04). For every 10% nocturnal drop in SBP, GFR increased by 4.6 ml/min per 1.73 m(2) (R = 0.3, P = 0.003). Nondippers and reverse dippers were equally common in recipients with normal histology and in those with pathologic findings on surveillance biopsy. On multivariate analysis, percentage of nocturnal fall in SBP and elevated resistive index independently correlated with GFR. This study indicates that lack of nocturnal fall in SBP is related to poor allograft function, high chronic vascular score, and high resistive index irrespective of allograft fibrosis. Further studies are needed to determine whether restoration of normal BP pattern will confer better allograft outcome.
5. Association of functional heme oxygenase-1 gene promoter polymorphism with renal transplantation outcomes.
Courtney AE, McNamee PT, Middleton D et al.
Am J Transplant. 2007 7 (4): 908-13.
Heme oxygenase-1 (HO-1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT) (n) polymorphism, within the HO-1 promoter, regulates gene expression; a short number of repeats (S-allele 20% triangle upLVM over time. Results Patients with baseline LVH (n = 37; 61%) had a higher body mass index (BMI) than those without LVH (n = 23; 39%) (P = 0.013). BMI, haemoglobin levels (P = 0.047) and non-use of angiotensin-converting enzyme inhibitors (ACEI) (P = 0.057) were associated with baseline left ventricular mass index (LVMI). Twelve out of 23 patients (52%) with normal LVM at baseline, developed either de novo LVH or > 20% triangle upLVMI at follow-up. On the other hand, 29 (78%) of those with initial LVH maintained this abnormality, and 8 (22%) normalized LVM post-transplantation. Factors associated with triangle upLVMI were age (P = 0.01), pre-dialysis LVMI (P < 0.0001), serum creatinine (P = 0.012) and the use of ACEI post-transplantation (P = 0.009). In Cox analysis, pre-dialysis LVMI was associated with de novo LVH or > 20% triangle upLVMI over time (hazard ratio 1.009; 95% confidence interval 1.004 to 1.015; P = 0.001). Conclusions Successful KT may not completely normalize LVM post-transplantation. Pre-dialysis LVMI, traditional risk factors and no use of ACEI may perpetuate cardiac growth following KT.
8. Prevalence and determinants of coronary and aortic calcifications assessed by chest CT in renal transplant recipients.
Nguyen PT, Coche E, Goffin E et al.
Am J Nephrol. 2007 27 (4): 329-35.
Background Coronary artery calcifications independently predict cardiovascular events (CVE) in the general population. We assessed the prevalence and determinants of coronary (CAC) and thoracic aorta (AoC) calcifications in renal transplant recipients (RTR). Methods Consecutive RTR living in Belgium, with an isolated kidney graft functioning for more than 1 year, were asked to participate. They underwent a 16-slice spiral computerized tomography in order to measure calcium mass. Demographic, clinical, biochemical and urinary parameters were collected. Results We included 281 patients. CAC and AoC were detected in 81 and 85%, with geometric means (SD) of 52.2 (4.9) 99.3 (8.2) mg, respectively. By multiple linear regression, independent predictors of both types of calcifications included older age, longer time on dialysis, and history of CVE, of multiple transplantations and of smoking. Other determinants of CAC were male gender, current statin use and history of parathyroidectomy, and other determinants of AoC included higher pulse pressure, shorter time under mycophenolate mofetil and current use of anti-vitamin-K. Conclusion The prevalence of both CAC and AoC is substantial in RTR. We delineate independent determinants either common to both CAC and AoC or specific to one, and known as classic or chronic kidney disease related risk factors.
9. Pseudotumor of gout in the patella of a kidney transplant recipient.
Staub-Zahner T, Garzoni D, Fretz C et al.
Nat Clin Pract Nephrol. 2007 3 (6): 345-9.
Background A 33-year-old renal transplant recipient presented with painless swelling of the right knee. Physical examination revealed an impressive knee joint effusion with no signs of inflammation. The patients did not remember a recent trauma, but he mentioned a strain 3 years earlier; radiographic findings had been normal at the time. The patients had suffered from end-stage renal disease due to chronic glomerulonephritis and had previously undergone two transplantations. At presentation, his kidney function was stable under treatment with ciclosporin, azathioprine and steroids. Investigations Conventional radiography revealed a tumor at the superolateral pole of the right patella. Extensive soft tissue invasion and bone destruction was seen on MRI. A knee arthroscopy with biopsy, performed to aid diagnosis, showed extensive chondrocalcinosis macroscopically; histologically, gouty tophi were found. Diagnosis Pseudotumor of gout in the patella. Management Uric-acid-lowering therapy with benzbromarone was started immediately after diagnosis. A local arthroscopic debridement of the rgiht knee joint was performed 4 months later, and the patient remained asymptomatic for the next 3 years.
10. Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.
Flechner SM, Goldfarb D, Solez K et al.
Transplantation. 2007 83 (7): 883-92.
Background We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function. Methods Sixty-one patients were randomized to either sirolimus (n = 31) or cyclosporine (n = 30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10-12 ng/mL for at least 6 months. Results 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs, 90%, P = 0.681), acute rejection rate (12.9 vs 23.3% vs P = 0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P = 0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P = 0.72), and overall medical and surgical morbidity (P = NS). Although unadjusted patients survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P = 0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P = 0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P = NS). Conclusions This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elemination should be subjected to controlled trials.
11. Combination therapy with ribavirin and amantadine in renal transplant patients with chronic hepatitis C virus infection is not superior to ribavirin alone.
Calanca LN, Fehr T, Jochum W et al.
J Clin Virol. 2007 39 (1): 54-8.
Background Standard treatment of chronic hepatitis C virus (HCV) infection based on interferon is not an option in renal transplant recipients due to the high risk of acute allograft rejection. Objectives To assess efficacy and tolerability of combined treatment with ribavirin and amantadine regarding viral clearencs, normalization of liver enzymes, and improvement of HCV-related hepatopathy and graft nephropathy in HCV-RNA-positive renal transplant patients. Study design Prospective randomized controlled study comparing ribavirin, 1000 mg daily (n = 7), versus ribavirin, 1000 mg, in combination with amantadine, 200 mg daily (n = 8), for 12 months, verus no therapy (controls, n = 26). Results were evaluated by intention-to-treat anaylsis. Results No relevant differences among treatment groups were found regarding liver enzymes, HCV viremia, liver histology and renal parameters. However, antiviral treatment was limited by anemia, resulting in premature withdrawal from therapy and requiring substitution with recombinant human erythropoietin in most patients. The best predictor for tolerability of active treatment was a creatinine clearence rate > 50 ml/min. Conclusions Addition of amantadine to ribavirin seems no to be superior to ribavirin monotherapy in renal transplant patients with chronic replicating HCV infection. However, this may be explained in part by the poor tolerability of both ribavirin and amantadine in patients with impaired renal function, resulting in drop-outs and subtherapeutic drug dosage.
12. Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low-dose cyclosporine A.
Pape L, Ahlenstiel T, Ehrich JH et al.
Pediatr Transplant. 2007 11 (3): 291-5.
Until now there have been no good therapeutic options in children with biopsy-proven transplant nephropathy (TN) and loss of glomerular filtration rate (GFR) while receiving cyclosporine A (CsA), mycophenolate mofetil (MMF) and prednisolone (Pred). In 13 kidney transplanted children (mean age 13 yr, SD 4) with CsA/MMF/Pred immunosuppression, renal biopsy revealed significant TN. MMF was dicontinued, CsA dose was reduced to 50% and Everolimus was started (1.6 mg/m(2)/day). Pred was stopped in 10 of 13 patients. The mean GFR was 55 mL/min/1.73 m(2) (SD 24) one yr before switch, 45 mL/min/1.73 m(2) (SD 16. p < 0.05) at the time of switch and 47 mL/min/1.73 m(2) (SD 18, p < 0.05) 12 months later. There were no severe side-effects or acute rejections. Lactate dehydrogenase, cholesterol, creatinine kinase, and U-albumin/creatinine ratio did not increase significantly. After six months, the mean certican-C0 level was 4.0 microg/L (SD 1.5) and mean CsA-C0 level was 52 ng/mL (SD 23). The GFR of transplanted kidneys in children with TN improved by changing immuosuppression from CsA/MMF/Pred to everolimus and low-dose CsA.
13. Sirolimus is not always responsible for new-onset proteinuria after conversion for chronic allograft nephropathy.
Adurrahman Z, Sarwal M, Millan M et al.
Pediatr Transplant. 2007 11 (3): 336-9.
An eight-yr-old combined liver and kidney transplant recipient for hyperoxaluria type I developed significant proteinuria and hypertension after conversion of a Tacrolimus, MMF, and corticosteroids-based immunosuppression to Sirolimus, low-dose Tacrolimus, and corticosteroids six and a half yr after the transplant for chronic allograft nephropathy. There was only one class I HLA match and the recipient had a multiple blood exposures prior to transplantation. The patient was treated with combined hemodialysis and peritoneal dialysis while awaiting transplantation to reduce the oxalete load. A renal biopsy revealed a de novo transplant glomerulopathy that was associated with specific HLA antibodies unrelated to the donor (HLA DR 17 and 18). After reintroduction of MMF, these antibodies became undetectable and the proteinuria completely resolved. We hypothesize that HLA antibodies may cause transplant glomerulopathy even if they are not donor-specific. Their production appears more susceptible to MMF therapy. A thorough work-up of new-onset proteinuria after conversion to Sirolimus should be performed, including an immunological work-up and a renal biopsy.
14. Treatment of patients with chronic hepatitis C before and after renal transplantation.
Tornai I, Matyus J.
Orv Hetil. 2007 148 (11): 489-94.
The prevalence of hepatitis C virus infection among patients on hemodialysis is about ten times higher than in the normal population. The infection can induce chronic glomerulonephritis, as an extrahepatic manifestation, which can lead to end stage renal disease. However, in the majority of the patients with hepatitis C virus is acquired as a nosocomial infection during the hemodialysis. In most of the infected patients the liver enzymes are usually normal and need regular screeing of the hepatitis C antibody to detect the infection. Despite of the normal liver enzymes, the liver disease may progress to cirhosis. A part of the patients wait for renal transplantation. The immunosuppressive treatment after the renal transplantation results in a significantly increased viral replication which might induce further progression of the liver disease. Interferon treatment given after the transplantation can induce rejection and graft failure. Therefore the antiviral treatment should be administered during the hemodialysis or earlier. Only limited data are available with the treatment of patients with impaired renal function. Mostly alfa-interferon was used in these patients. Due to the impaired renal clearence and higher serum concentration interferon seems to be more effective, but less tolerable in patients with end stage renal disease than in normal patients. Ribavirin is also excreted exclusively by the kidney and the anemia is even more pronounced in these patients, therefore it is contraindicated in patients on hemodialysis. The pharmacokinetics of the pegylated interferon alfa-2a is very advantageous for the patients with end stage renal disease. The safety and efficacy of peginterferon alfa-2a is now being confirmed in many publications.
15. Posttransplant prophylactic intravenous immunoglobulin in kidney transplant patients at high immunological risk: A pilot study.
Anglicheau D, Loupy A, Suberbielle C et al.
Am J Transplant. 2007 7 (5): 1185-92.
The effects of posttransplant prophylactic intravenous immunoglobulin (IVIg) were investigated in renal transplant recipients at high immunological risk. Thirty-eight deceased-donor kidney transplant recipients with previous positive complement-dependent cytotoxicity crossmatch (n = 30), and/or donor-specific anti-HLA antibodies (n = 14) were recruited. IVIg (2 g/kg) was administered on days 0, 21, 42 and 63 with quadruple immunosuppresssion. Biopsy-proven acute cellular and humoral rejection rates at month 12 were 18% and 10%, respectively. Glomerulonephritis was observed in 31% and 60% of patients at months 3 and 12, respectively, while allograft glomerulopathy rose from 3% at month 3 to 28% at 12 months. Interstitial fibrosis/tubular atrophy increased from 18% at day 0 to 51% and 72% at months 3 and 12 (p < 0.0001). GFR was 50 +/- 17 mL/min1.73 m (2) and 48 +/- 17 mL/min/1.73 m (2) at 3 and 12 months. PRA decreased significantly after IVIg (class I: from 18 +/- 27% to 5 +/- 12%, p < 0.01; class II: from 25 +/- 30% to 7 +/- 16%, p < 0.001). patient and graft survival were 97% and 95%, respectively and no graft was lost due to rejection (mean follow-up 25 months). In conclusion, prophylactic IVIg in high-immunological risk patients is associated with good one-year outcomes, with adequate GFR and a profound decrease in PRA level, but a significant increase in allograft nephropathy.
16. Management of growth retardation in pediatric recipients of renal allografts.
Fine RN.
Nat Clin Pract Nephrol. 2007 3 (6): 318-24.
Growth retardation frequently accompanies chronic kidney disease in children. Unfortunately, this retardation persists in magnitude despite assiduous therapeutic efforts, adequate dialytic intervention, and successful transplantation. The age of the patients at transplantation, allograft function, and corticosteroid dosage are the major factors that contribute to persistent suboptimal growth following renal transplantation. Recent data indicate that the use of recombinant human growth hormone might efficaciously improve growth velocity in the persistently growth-retarded allograft recipient. Attainment of optimum final adult height is predicted on optimum height at the time of transplantation, persistent optimum allograft function, minimization or avoidance of corticosteroid treatment, and, possibly, use of recombinant human growth hormone, especially to potentially maximize the pubertal growth spurt.
17. Use of rhGH in children with chronic kidney disease: Lesson from NAPRTCS.
Seikaly MG, Salhab N, Warady BA et al.
Pediatr Nephrol. 2007 May 25; [Epub ahead of print].
We evaluate the utilization and potential benefits of recombinant human growth hormone (rhGH) in children with chronic kidney disease (CKD) and following renal transplantation in a large patient cohort. We queried the chronic renal insufficiency (CRI), dialysis, and transplant registries of the North American Pediatric Renal Trials and Collaborative Sudies (NAPRTCS) to characterize the relationship between rhGH usage and catch-up growth. Data from 6.505, 5.122. and 4.478 CRI, dialysis, and transplant patients, respectively, was evaluated. Percentage utilization of rhGH 2 years after entry was 22%, 33%, and 3% in children with a height standard score (SDS) < -1 and age < 17 years (termed candiadate group) in CRI, dialysis, and transplant patients, respectively. Multivariate logistic regression analysis showed that the likelihood of using rhGH was significantly correleted with age, gender, geographical region of residence and height category within the candidate group (p < 0.01). The use of rhGH was associated with catch-up growth in 27%, 11%, and 25% of candidate CRI, dialysis, and transplant patients, respectively. In the candidate group, percentage catch-up growth was highest in children who were Tanner stage 1-2, who comprised 19.4%, 7.1%, and 25.5% of the CRI, dialysis, and transplant patients, respectively. Using multiple regression analysis, the estimated impact of rhGH on final adult height (age > 19 years) was 0.80, 0.50, and 0.19 SDS, in CRI, dialysis, and transplant patients, respectively. Thus, rhGH can improve height gain in some children with CKD. The use of rhGH appears to be most effective in prepubertal children with CRI.
18. Early withdrawal of calcineurin inhibitors and rescue immunosuppression with sirolimus-based therapy in renal transplant recipients with moderate to severe renal dysfunction.
Wali RK, Mohanlal V, Ramos E et al.
Am J Transplant. 2007 7 (6): 1572-83.
Mamalian Target-of-Rapamycin inhibitors (mTOR inhibitors) can be used to replace the calcineurin inhibitors (CNIs) to prevent progression in chronic kidney disease (CKD) following organ transplantation. Discontinuation of tacrolimus in 136 recipients of kidney transplants with progressive renal dysfunction significantly decreased the rate of loss of estimated glomerular filtration rate (eGFR, mL/min/1.73 m (2)) (pre-intervention vs. post-intervention slopes, -0.013 vs. -0.002, p < 0.0001). Discontinuation of tacrolimus was associated with a sustained and significant improvement in graft function (pre-eGFR vs. post-eGFR; 26.0 +/- 1.1 vs. 47.4 +/- 2.1, p < 0.0001) in 74% of patients. This intervention was ineffective if the mean and (median) values of creatinine (mgdL) and eGFR were 3.8 +/- 0.2 (3.4) and 18.4 +/- 1.9 (22.4), respectively, at the time of conversion therapy. During the follow-up (range, 1.5-34.6, months), a total of 13 patients had their first acute rejection following the conversion therapy, an annual incidence of less than 10% and none of these episodes resulted in graft loss. The salutary effects of sirolimus therapy following discontinuation of tacrolimus in patients with moderate to severe graft dysfunction due to allograft nephropathy even in high-risk patients improves kidney function and prevents acute rejection.
19. Impact of NOD2/CARD15 haplotypes on the outcome after kidney transplantation.
Kruger B, Boger CA, Schroppel B et al.
Transplant Int. 2007 May 10; [Epub ahead of print].
Chronic allograft nephropathy and (cardiovascular) death with functioning graft are major cause of late graft loss. NOD2/CARD15 (nucleotide oligomerization domain-2/caspase-recruiting activating domain-15), an intracellular receptor, that is part of the innate immunity reportoire, has convincingly been shown to be involved in infection/inflammation-associated diseases. Specifically, NOD2/CARD15 polymorphisms are clearly associated with Crohn’s disease and transplant-associated mortality after bone marrow transplantation. The aim of this study was to clarify the relevance of NOD2/CARD15-haplotypes in kidney transplantation. Three hundred fifty-two patients receiving their first kidney transplant were genotyped for the three major NOD2/CARD15 polymoprphisms R702W, G908R and 1007fs with subsequent reconstruction of the different haplotypes. Four different NOD2/CARD15-haplotypes were observed in our population [CG(-): 89.8%, CGC: 3.5%, CC(-): 1.6%, TG(-): 5.1%). After stratifying the different haplotypes into diplotypes (wild type: CG(-)/CG(-), n = 284, mutated haplotype, n = 68) we found a significant association with all-cause and cardiovascular mortality, also after adjusting to different covariates, and (only) in univariate analysis with graft survival. In conclusion, we found different effects of the NOD2/CARD15-haplotypes on disorders, like cardiovascular and all-cause mortality, which may be considered at least in part as chronic inflammation driven. Further studies are needed to confirm and work out the association between these disorders and the NOD2/CARD15-haplotypes.
20. Distribution of donor-specific antibodies in the cortex and the medulla of renal transplants with chronic allograft nephropathy.
Bocrie O, Hussein Aly AA, Guignier F et al.
Transplant Immunol. 2007 17 (3): 227-9.
Background Emerging data suggest that donor-specific HLA antibodies should be more frequently found onto the transplant itself than in the bloodstream. It is now possible to detect such antibodies in kidney transplant needle biopsy samples by flow cytometry. In order to know if the detection of antibodies into such blind biopsy samples depends of the site of the biopsy, we have studied the distribution of antibodies in both the cortex and medulla of 12 transplants removed after graft loss due to chronic allograft nephropathy, and in 10 controls. Methods Donor-specific HLA antibodies were extracted from the cortex and the medulla of each removed transplant by an acid elution and characterized by Luminex (R) assays. Results They were found in 58.3% of transplants with chronic allograft nephropathy and never in other kidney samples. The same antibodies were found in the bloodstream at the time of tranplantectomy in only 16.6% of the recipients. The distribution between the cortex and medulla was concordant in 75% of cases. However, we observed 2 discrapancies: one in favor of the cortex and one in favor of the medulla. A majority (5/7) transplants with CAN and intra-graft donor-specific antibodies had also C4d deposits along peritubular capillaries. Conclusion Testing for donor-specific HLA antibodies in kidney transplant needle biopsies can be of value provided the biopsy includes both cortex and the medulla.
21. Thickening of the peritubular capillary basement membrane is a useful diagnostic marker of chronic rejection in renal allografts.
Aita K, Yamaguchi Y, Horita S et al.
Am J Transplant. 2007 7 (4): 923-9.
In kidney transplantation, the multilayering of the peritubular capillary basement membrane (MLPTC) in electron microscopy (EM) has been recognized as feature of chronic rejection (CR). In this study, thickening of the peritubular capillary (PTC) basement membrane was evaluated by light microscopy (LP) to determine whether it corresponds to the MLPTC in EM and whether it can be used as a diagnostic marker of CR. Forty-eight patients with late renal allograft were divided into chronic allograft nephropathy (CAN) with CR (group 1, n = 23), CAN without CR (group 2, n = 19) and CAN-free (group 3, n = 6). The tihickening of the PTC basement membrane (ptcbm) was scored from grades 0 to 2 (ptcbm score), and the MLPTC thickness was measured in EM. Interobserver agreement on ptcbm scores was statistically significant (Kappa coefficient = 0.63). LM and EM lesions corresponded very well. The ptcbm score was highest in Group 1, and ptcmb2 corresponded closely with CR. Group 1 showed significantly thicker MLPTC than Groups 2 and 3. The results validated the usefulness of the ptcmb score and suggested that the thickening of the PTC basement membrane can be a novel diagnostic marker of CR.
22. Evaluating the accuracy of functional biomarkers for detecting histological changes in chronic allograft nephropathy.
Yilmaz S, Isik I, Afrouzian M et al.
Transplant Int. 2007 May 22, [Epub ahead of print].
The most common cause of late kidney transplant failure is chronic allograft nephropathy (CAN). Much research has focused on identifying biomarkers (or correlates) that would predict subsequent CAN and allow timely intervention. Functional biomarkers such as serum creatinine and estimated glomerular filtration rate (eGFR) have been widely adopted, even though they have not been rigorously evaluated as surrogate markers. This study evaluated serum creatinine and eGFR for predicting the early histopathological changes seen in transplant protocol biopsies (TBP). We prospectively followed 289 kidney transplant patients in the Southern Alberta Transplant Program who had TPB at 6-12 months post-transplant. Tissue samples (n = 280) were independently examined by renal pathologists. The ability of serum creatinine or eGRF to predict the treshold level for abnormal histopathology was evaluated by calculating the area under the receiver operator characteristic curve. Serum creatinine and eGFR had poor predictive value (most confidence intervals included 0.5, indicating no predictive ability) for ten individuals histological measurements (Banff 97 scores), and the Chronic Allograft Damage Index. We conclude that serum creatinine and eGFR have a limited clinical role in predicting the early histopathological changes that precede CAN and should not be used for this purpose.
23. Nephrology: Renal transplantation.
Ott U, Steiner T, Schubert J et al.
Med Klin (Munich). 2007 102 (3): 219-29.
Renal transplantation is currently the best option for renal replacement therapy. Quality of life will improve and lifetime extended compared to patients staying on dialysis. New findings in the fields of pathogenesis, diagnostics and treatment make renal transplantation an effective standard procedure. In Germany, there is an imbalance between available donor kidneys and recipients. The increasing waiting time is a challenge in the treatment of patients suffering from end-stage renal disease. In the last few years great efforts were undertaken to expand the donor pool. Problems are the unreadiness for organ donation on the one hand and extended indication for renal transplantation on the other hand. Transplantation of so-called marginal organs will implicate new problems. A main focus of further research is the chronic allograft nephropathy. Advances in the field of immunosuppressive treatment lead to better results in organ and patients survival. Individualization of immunosuppression becomes one of the most important points. New markers are necessary for monitoring. The aftercare in the tranplant center in close collaboration with nephrologists and family doctors is essential for a succesfull transplantation.
24. Cigarette smoking and chronic allograft nephropathy.
Zitt N, Kollerits B, Neyer U et al.
Nephrol Dial Transplant. 2007 May 21; [Epub ahead of print].
Background Smoking has been demonstrated to decrease patients and graft survival after kidney transplantation. Data on histological changes associated with smoking in renal allografts are lacking. Methods Smoking habits before and after renal transplantation were evaluated by questionnaire in 279 patients. A transplant biopsy was performed more than 1 year after transplantation in 76 of them. Histological changes were classified according to Banff 97 criteria. Linear regression analysis and proportional odds models for histological changes including the factors age, gender, diabetes, body mass index, donor age, time since transplantation, history of acute rejection and smoking status were calculated. Results Overall 22% of patients continued smoking after transplantation, with the proportion decreasing from 38% of those transplanted before 1990 to 13% of those transplanted after 2000. Serum creatinine was non-significantly higher in smokers (2.3 +/- 2.7 mg/dl vs 1.8 +/- 1.4 mg/dl, P = 0.21). A renal biopsy was performed in 24% of non-smokers and 39% of smokers (P = 0.02), and smokers were biopsied on average 1.5 years earlier. Among biopsied patients current smokers tended to suffer more often from diabetes (25.0% vs 13.5%, P = 0.33), to develop transplant failure (33.3% vs 21.2%, P = 0.25) or experience a cardiovascular event (29.2% vs 15.4%, P = 0.16). The frequency of acute rejection was comparable between smokers and smokers (25.0% vs 34.6%, P = 0.40). Glomerular sclerosis was associated with diabetes (P = 0.03). Severity of vascular initimal fibrous thickening was associated with current smoking (P = 0.004), whereas the degree of arteriolar hyalinosis (P < 0.001) and chronic/sclerosing nephropathy (P = 0.05) were associated with time since transplantation. Conclusions The number of patients who continue cigarette smoking after renal transplantation had decreased in recent years. The main allograft lesion associated with smoking is fibrous initimal thickening of small arteries.
25. Efficiency of rituximab treatment for recurrence of membranous glomerulopathy after renal transplantation.
Weclawiak H, Ribes D, Modesto A et al.
Nephrol Ther. 2007 3 (2): 65-8.
Idiopathic membranous glomerulonephritis (MGN) is a rare cause of end-stage renal failure, which can lead to chronic hemodialysis. This glomerulopathy can recur after renal transplantation despite immunosuppressive therapy. To date, there is no confirmed therapy for treatment of renal grafts after recurrence of MGN. Herein, we report on a 27-year-old man who underwent cadaveric renal transplantation for MGN in September 2001. At 2 months posttransplant, a renal biopsy showed membranous deposition on immunofluorescence staining evocative of recurrence of MGN. Proteinuria developed progressively and, at one year, was estimated at 7.65 g/24 h, with hypoalbuminemia of 24 g/l. This persisted despite symptomatic treatment with anti-proteinuric agents (enalapril 20 mg/day and irbesartan 75 mg/day) and atorvastatin (10 mg/day). By March 2004, his proteinuria was 11 g/day; therefore, therapy with rituximab (monoclonal anti-CD20) at 375 mg/m(2) weekly was initiated for four consecutive weeks, followed by the same dosage every four months for one year. Biological controls performed two weeks after the fourth infusion of rituximab showed a fall in proteinuria, assessed at 1 g/24 h, with albuminemia of 29 g/l and normalized lipidic results. A renal biopsy performed 6 months after the first infusion was unchanged. Follow-up at 30 months showed consistent remission of membranous nephropathy, demonstrated by a serum creatinine level of 150 mumol/L, microalbuminuria of 107 mg/24 h and normal albuminemia of 43.7 g/l. There were no side effects; in particular, no infectious complications occured, despite CD19 lymphocytes being still negative after 30 months. Monoclonal CD-20 antibodies hav shown efficacy against MGN compared to conventional therapies in native kidneys. It has recently been shown that CD20 mRNA is overexpressed in the renal interstitium in patients suffering from MGN and that the interstitial infiltrates is mainly composed of B-cell lymphocytes in these patients. These data may explain the efficiency of rituximab in these circumstances.
26. Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosuppression.
Gera M, Griffin MD, Specks U et al.
Kidney Int. 2007 Apr 4; [Epub ahead of print].
Progressive glomerulonephritis and attendant end-stage renal disease (ESRD) result from antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The optimum time of kidney transplantation in patients with ESRD due to ANCA-associated vasculitis (AAV) and the risk of renal or nonrenal recurrence of vasculits after transplantation are unknown. To answer some of these questions, we followed 35 transplant recipients with diagnosis of microscopic polyangiitis (20 patients) and Wegener’s granulomatosis (15 patients). The medain time from diagnosis to transplantation was 25 months with all patients being in clinical remission. Fifteen were ANCA-positive at time of the transplant with 13 preemptive transplants. The most common immunosuppressive strategy included antibody induction, corticosteroid, mycophenolate mofetil, and tacrolimus with acute rejection occuring in eight cases. Overall and death-censored graft survival were 94 and 100%, respectively, 5 years post-transplantation. Nonrenal relapse occured in three patients with a satisfactory response to treatment. No clear risk factor to relapse emerged and no detrimental effect to renal function was found. We conclude that transplantation should be considered as the treatment of choice for ESRD due to AAV. Potent antirejection regimens are well tolerated in these patients, are associated with a low risk of recurrence and an absence of AAV-related graft dysfunction.
27. Polyomavirus-associated nephropathy risk in kidney transplants: The influence of recipient age and donor gender.
Khamash HA, Wadei HM, Mahale AS et al.
Kidney Int. 2007 Apr 4; [Epub ahead of print].
Polyomavirus-associated nephropathy (PVAN) is a frequent cause of kidney transplant failure. We determined the risk factors for biopsy-proven PVAN among 1027 recent kidney transplant recipients by univariate and multivariate analyses. The rate of PVAN was determined over an univariate and multivariate analysis over an average of 30 months of follow-up of patients receiving predominantly living donor grafts with antibody indcution and sequential surveillance biopsies to detect subclinical graft disease. Seventy-four transplant recipients were diagnosed with PVAN with the finding made on suveillance biopsy in 40 patients. These 40 cases did not differ from the 34 non-surveillance cases with respect to baseline clinical characteristics or initial histological features. Older recipient age and female donor gender were independent risks associated with PVAN. Factors not linked to PVAN risk included the use and type of induction agent, use of tacrolimus vs sirolimus, the number of human lymphocyte antigen (HLA) mismatches, or the frequency of acute rejection. We conclude that PVAN preferentially affects older age patients and allografts from female donors but is unrelated to immunological risk, choice of immunosuppression, or rejection history.
28. Cross-sectional study of BK virus infection in pediatric kidney transplant recipients.
Fogeda M, Munoz P, Luque A et al.
Pediatr Transplant. 2007 11 (4): 394-401.
BKV reactivation is associated with impaired graft function in adult kidney transplant patients. The clinical impact of BKV infection in the pediatric transplant population has not yet been fully evaluated. The objective of our study was to determine the prevalence of BKV infection in consecutive pediatric kidney transplant recipients in our center. Forty consecutive unselected pediatric kidney transplant recipients were studied. Mean age at screening was 15.6 +/- 5.3 yr and samples were obtained a median of 60.5 months after transplantation (3-123). BKV-DNA was analyzed in urine and plasma by qualitative nested-PCR. A review of the literature was performed. Prevalence of viruria and viremia was 50% and 12.5%, respectively. Viremia was associated with the presence of hematuria (P = 0.02). The mean creatinine level in children without BKV replication was 1.6 mg/dL, BKV viruria was 0.9 mg/dL, and BKV viremia was 0.8 mg/dL. A literature review showed that viruria and viremia were found in 28.2% and 8.5% of cases, respectively; BKV nephropathy was found in 3.8% and graft loss in 11% of patients with BKV nephropathy and 0.4% of the children studied. Recipient serostatus was the most important risk factor. The rate of BKV replication and nephropathy among pediatric kidney recipients is similar to that of adults, but the incidence of graft loss is significantly lower.
29. Polyomavirus BK-specific cellular immune response to VP1 and large T-antigen in kidney transplant recipients.
Binggeli S, Egli A, Schaub S et al.
Am J Transplant. 2007 7 (5): 1131-9.
Polyomavirus BK (BKV) is the primary cause of polyomavirus-associated nephropathy (PVAN) in kidney transplant (KT) recipients. Using ELISpot assays, we compared the frequency of interferon-gamma (IFN-gamma) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools covering BKV large T-antigen LT) and VP1 capsid proteins (VP1). In 10 healthy donors, LT and VP1 responses were low with median 24 (range 15-95) and 25 (7-113) spot-forming units/10 (6) PBMC (SFU), respectively. In 42 KT patients with current or recent plasma BKV loads, LT and VP1 responses of 29 (0-524) and 114 (0-1432) SFU were detected, respectively. In KT patients with decreasing or past plasma BKV loads, significantly higher median BKV-specific IFN-gamma responses were detected compared to KT patients with increasing or persisting BKV loads [LT: 78 (8-524) vs. 22 (0-120) SFU, p = 0.003; VP1: 285 (45-1432) vs. (0-423) SFU, p = 0.001, respectively]. VP1-specific IFN-gamma responses were higher and more likely to involve CD4 (+) T cells, while CD8 (+) T cells were more frequently directed against LT. Stimulation with JCV-specific VP1 and LT peptides indicated only low-level cross-recognition. The data suggest that control of BKV replication is correlated with differentiated expansion of BKV-specific cellular immune responses.
30. Human Polyomavirus type 1 (BK virus) agnoprotein is abundantly expressed, but immunologically ignored.
Leuenberger D, Andresen PA, Gosert R et al.
Clin Vaccine Immunol. 2007 May 30; [Epub ahead of print].
Impaired BK virus (BKV)-specific immunity is a key factor of polyomavirus-associated nephropathy (PVAN). We hypothesized that BKV agnoprotein might constitute an important immune target as it is highly expressed after infection in vitro. We demonstrate abundant expression of BKV agnoprotein in vivo by immunostaining of kidney transplant (KT) biopsies. Antibody response to recombinant affinity-purified BKV agnoprotein, LT and VP1 anigens were compared in 146 sera from 38 KT patients and in 19 sera from 16 healthy donors (HD) by enzyme immunoassay. In HD, low titers of anti-agno IgG were found in 15% compared to anti-LT in 41% and anti-VP1 in 63%. No anti-BKV IgM were detectable. In KT patients, anti-agno IgG and IgM were found in 8% and 3.6%, compared to anti-LT IgG and IgM in 63% and 18%, and anti-VP1 in 80% and 41%, respectively. Anti-LT and anti-VP1, but not anti-agnoprotein activities increase during and after BKV viremia in KT patients. To compare specific cellular immune responses, we compared interferon-gamma production in PBMC by ELISPOT assay in 10 HD and 30 KT patients. In HD, the median interferon-gamma spot forming units per million PBMC for agnoprotein, LT and VP1 peptides were 1, 23 and 25, respectively, Whereas the respomse in KT patients were 2, 24 and 99, respectively. We comclude that BKV agnoprotein, though abundantly expressed in vivo, is poorly recognized immunologically.
31. Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy.
Bracamonte E, Leca N, Smith KD et al.
Am J Transplant. 2007 7 (6): 1552-60.
Tubular basement membrane immune deposits (TBMID) are rare in renal allografts and usually have been found in association with immune complex mediated glomerular injury. We report an association TBMID and BK polyomavirus nephropathy (BKN). We reviewed clinical data and results of allograft biopsies of 30 patients with BKN (16 with and 14 without TBMID). TBMID were detected by immunofluorescence or electron microscopy. Initial and follow-up biopsies were assessed degree of interstitial inflammation and fibrosis and severity of viral infection, and were correlated with patients’ clinical data. Biopsies initially diagnosis for BKN with TBMID, compared to BKN biopsies without deposits, demonstrated more severe interstitial inflammation and fibrosis, and greater number of virally infected cells. Similar findings were present in follow-up biopsies. Utilizing three different antibodies directed against viral epitopes, viral antigens could not be detected within TBMID. Thirty percent of patients with TBMID and 70% without deposits had follow-up biopsies, in which virus could not be detected immunohistochemically. Treatment for all included decreasing immunosuppression, cidofovir and/or leflunomide. Clinical data correlated well with histological findings. We conclude that a significant proportion of patients with BKN show TBMID on kidney biopsy. The prognostic significance of this finding remains to be elucidated.
32. BK virus infection, replication, and diseases in pediatric kidney transplantation.
Acott PD, Hirsch HH.
Pediatr Nephrol. 2007 Mar 22; [Epub ahead of print].
Polyomavirus-associated nephropathy is diagnosed in 2-8% of pediatric renal transplants and often precedes renal allograft dysfunction. Without intervention, however, significant graft dysfunction is observed in more than 50% of cases, although progressive early graft loss is reported in only three of 32 (95) of cases. No specific treatment is available, but early decrease in immunosuppression is followed by declinig human polyomavirus type 1 (BK virus) replication and improved outcome. The data suggest differences between pediatric and adult kidney transplantation. Possibly, pediatric patients might be able to mount a more vigorous BK virus-specific immune response than adult patients under similar modulation of immunosuppression. Also the role of cidofovir and leflunomide is still unresolved in pediatric patients. Larger prospective trials are needed to better define the impact of BK virus immunity for replication and disease as well as the role of reducing immunosppression with or without cidofovir or lefunomide in pediatric transplant patients.
*33. BK virus subtype IV nephropathy occuring 5 years after kidney transplantation.
Takayama T, Suzuki K, Otsuka A et al.
Clin Exp Nephrol. 2007 11 (1): 102-6.
We report on a BK virus-associated nephropathy in a 28-year-old man. His symptoms occured 5 years after he had received a kidney transplantation. He was treated with tacrolimus, azathioprine, and prednisolone. The progress of the disease was monitored by quantitative real-time polymerase chain reactions for BK virus DNA. An analysis of viral DNA showed that the BK virus in the patient’s plasma belonged to genotype IV.
34. Ureteric and urethral stenosis: A complications of BK virus infection in a pediatric renal transplant patients.
Rajpoot DK, Gomez A, Tsang W et al.
Pediatr Transplant. 2007 11 (4): 433-5.
Viral infection remain an Achilles heel in solid organ transplant. In recent years, incidence of BK virus infection in the kidney transplant population is on rise. BK virus known to cause renal dysfunction, ureteric stenosis, and hemorrhagic cystitis in renal transplant patients. Most of the reviews and prospective studies on BKV nephropathy pertain to the adult population. Although ureteral stenosis is known to occur BK infection, urethral stenosis is not being reported in the literature. In this report, we describe a case of BKV nephropathy in a 19-yr-old male presenting with ureteric and urethral stenosis. To our knowledge this is the first case report of its kind in a pediatric transplant population.
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