What can we learn from a patient - Dustri



What can we learn from a patient on dialysis for 42 years?

#1Department of Nephrology, #2Department of Pathology, #3Department of Orthopedics, Toranomon Hospital, Tokyo, Japan

#4Division of Neurology, Jichi Medical University, Tochigi, Japan

#5Okinaka Memorial Institute for Medical Research, Tokyo, Japan

#1Tatsuya Suwabe, MD; #1,5Yoshifumi Ubara, MD; #2Masafumi Inoue, MD, #3Izuru Kitajima, MD, #2Kenichi Oohashi; MD, #4Imaharu Nakano, MD; and #1,5Kenmei Takaichi, MD

Correspondence to: Tatsuya Suwabe, MD

Department of Nephrology, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki-shi, Kanagawa-ken, 213-0015, Japan

Phone: 81-44-877-5111

Fax: 81-44-877-5333

e-mail: suwabe@toranomon.gr.jp

Key words: dialysis, dialysis-related amyloidosis, beta 2-microglobulin, cardiovascular disease

Running head: Patient on dialysis for 42 years

Abstract

We performed autopsy on a 60-year-old Japanese man who had received dialysis for 42 years. He started on intermittent peritoneal dialysis in 1968, which was combined with hemodialysis in 1969. His serum calcium-phosphate balance and his blood pressure had been controlled well. Carpal tunnel syndrome occurred in 1984. Then lumbar spinal canal stenosis (SCS) occurred in 1997, followed by cervical SCS in 2000, destructive lumbar spondyloarthropathy (DSA) in 2002, and pathological fracture of the right femoral neck due to an enlarging bone cyst in 2006. All of his surgical specimens showed dialysis-related deposition of (2MG amyloid (dialysis-related amyloidosis: DRA). Thereafter, lumbar and cervical spinal palsy progressed. In 2009, he developed severe paralytic ileus with dilatation of the sigmoid colon, and subsequently died of peritonitis due to necrotizing cholecystitis. Autopsy showed massive DRA deposits in his intestinal blood vessels and thickened spinal dura, resulting in the above-mentioned intestinal and spinal complications. However, his arterial tree, including the aorta and coronary arteries, showed very little atheroma. Strict control of the Ca-P balance and blood pressure may have prevented cardiovascular disease, while progress in dialysis technology delayed fatal complications of DRA and allowed this patient to survive on dialysis for 42 years.

　　　 Background

In Japan, renal transplantation from cadaveric donors is not common, so dialysis technology has progressed dramatically and there are almost 20,000 patients who have been on hemodialysis for longer than 20 years(1). However, life expectancy of dialysis patients in Japan is still low, less than 50% of the general population. Dialysis-related amyloidosis (DRA) due to deposition of beta 2-microglobulin ((2MG) remains a problem in long-term dialysis patients(2-7). DRA has been reported to cause osteoarticular disorders such as carpal tunnel syndrome (CTS), osteoarthropathy of the limb joints, and spondylarthropathy(8-13). Extraosteoarticular visceral involvement has also been described, but rarely causes clinical manifestations(14-19). Cardiovascular disease is also an important predictor of mortality in dialysis patients and it accounts for approximately 50 percent of deaths(20). A large number of dialysis patients have traditional risk factors for cardiovascular disease(21). In addition, chronic kidney disease alone is an important risk factor for coronary artery disease(22). High prevalence of coronary artery disease in dialysis patients was reported in Japan(23). Then, there are a small number of patients who are on dialysis for longer than 30 years even in Japan. Here we report the history and histological findings of a 62-year-old man who was on dialysis for 42 years (the longest dialysis duration reported in Japan in 2010), and who showed extensive deposition of (2MG-amyloid in various organs as well as osteoarticular involvement.

Case report

An 18-year-old Japanese man was admitted to our institution with end-stage renal failure in 1968. Renal histology was not confirmed, but treatment was started with intermittent peritoneal dialysis (IPD) twice weekly for 8 hours per session on May 15, 1968. Hemodialysis (HD) with a Kiil flat bed-type dialyzer (8 hours once weekly) was combined with IPD once weekly from May 28, 1969. Then a coil-type dialyzer (EX-03) was utilized from 1972. He was switched to HD alone twice weekly because of peritoneal failure in 1973. A hollow-fiber dialyzer was used from 1977 and his HD protocol was changed to 4 hours three times weekly in 1980. The dialyzer membrane was initially a regenerated cellulose membrane, which was switched to a polymethylmethacrylate (PMMA) membrane in 1987 and then changed to a polysulfone (PS) high flux membrane in 1995. Water purification was done with a reverse osmosis system from 1976. The serum (2M level was respectively 40 and 26 mg/l before and after HD in 1986, but it decreased to 18 and 8 mg/L in 1996.

In 1984, he noted paresthesia of the palmar surface of the first three fingers of his right hand. Carpal tunnel syndrome (CTS) was diagnosed by a nerve conduction velocity study using electromyography, and was treated surgically by carpal tunnel decompression and coraco-acromial ligament release. Surgery for CTS was also done on the left side in 1986, and operations were repeated for this condition a total of 5 times until 1998. Masses measuring 1 cm were resected from the buttocks on the right side in 1995 and the left side in 1998. He noted paresthesia of both legs in 1994, and he complained of numbness and intermittent claudication of the bilateral lower limbs in 1997. Lumbar spinal canal stenosis (SCS) was diagnosed due to thickening of the ligamentum flavum and posterior longitudinal ligament, and laminectomy was performed. In 2000, laminoplasty was performed for numbness of the bilateral upper extremities due to cervical SCS. His lumbar SCS then progressed to destructive spondyloarthropathy (DSA), characterized by loss of the intervertebral disc spaces and erosion of subchondral bone in the adjacent vertebral bodies (Figure 1). In 2002, lumbar fixation surgery was done. Expansion of a bone cyst in the right femoral neck led to pathological fracture in 2006 (Figure 2), so right total hip arthroplasty was performed. Histological examination of specimens obtained at all of his operations disclosed deposition of (2MG-amyloid.

Over 40 years, the mean interdialysis weight gain was 1.85(0.67 kg (3.49% of his dry weight). He maintained a strict diet while on dialysis and he never overate. The serum calcium-phosphate balance was adequately controlled (average values over 42 years: 9.81(0.82 9.20(0.42 mg/dL for calcium, 5.02(1.18 5.67(0.56 mg/dL for phosphate, and: 49.13(10.98 52.16(0.34 mg/dL2 for the calcium ( phosphate product) by using oral calcium (calcium carbonate 3 g three times daily) and a vitamin D3 derivative, with parathyroidectomy (PTx) being performed for secondary hyperparathyroidism in 1995 (Figure 3). The mean intact-PTH level was 382.4(134.5 pg/mL for 8 years before PTx and 59.9(72.3 pg/mL for 15 years after PTx. His mean serum albumin level was 3.66(0.54 g/dL. His lipid profile was normal (total cholesterol: 149.6(14.0 mg/dL). His blood pressure was controlled within the normal range by antihypertensive therapy and diet. His mean systolic BP was 114.2(8.6 mmHg and his mean diastolic BP was 76.8(7.2 mmHg. He did not require statin therapy and did not use angiotensin blockers. There was no history of smoking and no family history of atherosclerotic vascular disease. He was a teacher at a school for clinical engineers.

In September 2009, he was admitted to our hospital for evaluation of fever. He was 170 cm tall and weighed 59.1 kg. Emaciation was apparent. He could walk by himself with difficulty using a stick. His temperature was 38.5(C and his blood pressure was 123/66 mmHg. His hands were deformed and swollen bilaterally, while the lower extremities were edematous. Laboratory findings were as follows: the white blood cell (WBC) count was 4,900/(L, hemoglobin was 8.2 g/dL, total protein was 5.8 g/dL, albumin was 1.8 g/dL, C-reactive protein was 14.8 mg/dL, and (2-microglobulin was 17.1 mg/L. Blood culture revealed no pathogenic bacteria, including tuberculous bacilli or fungi. The Quantiferon test (Cellestis) for tuberculosis was also negative. Diagnostic imaging such as computed tomography and ultrasonography did not reveal any source of his fever. Antibiotics and antimycotic drugs were administered for the fever, but were not effective. Paresthesia and muscle weakness of the bilateral lower extremities recurred in December 2009, while both upper extremities were affected again in January 2010. His symptoms then progressed rapidly to complete paralysis. In February 2010, he developed severe abdominal distension with pain and constipation. CT revealed marked distension of the sigmoid colon (Figure 1), so colostomy was performed. He died of peritonitis in July 2010.

Autopsy findings

A large amount of turbid ascites was seen in the abdominal cavity. Perforation of the gallbladder due to necrotizing cholecystitis with a focus of yeast-like fungus (candida) and bile acid peritonitis appeared to be the main cause of death. Amyloid deposits were present in small arteries and the surrounding tissues in the gallbladder wall. Amyloid deposition was also observed in the small arteries and surrounding tissues of the submucosal and subserosal layers throughout the gastrointestinal tract (Figure 4). These deposits were more massive and nodular in the distal large intestine, and also invaded the proper muscle layer, which might have contributed to his large bowel dysfunction. In the lungs, amyloid deposition caused thickening of the alveolar septal walls and narrowing of alveolar ducts, as well as pleural thickening, which was prominent in the lower lobes (Figure 5). The aorta showed little atheromatous change or calcification (Figure 6), and his coronary arteries were intact, although there were moderate amyloid deposits in the muscle layer of the interfascicular arteries.

In addition to the above-mentioned histological findings obtained from surgical specimens of his spinal lesions, the spinal cord was compressed by thickening of the cervical spinal dura due to amyloid, as well as by crush fractures of the lumbar vertebra, resulting in spinal cord degeneration especially at C7(Figure 7a). Thickening of the dura was also much more prominent at C7 than at other levels (Figure 7b).

Amyloid staining

Immunohistochemical examination was performed on paraffin-embedded specimens using an auto-staining machine (Ventana Benchmark System, Ventana Medical System, Tucson, AZ) according to the manufacturer’s protocol. Some sections were stained with Congo red (Congo red; Dako, Glostrup, Denmark, 1:500). A positive reaction for Congo red was confirmed by detection of apple green birefringence under a polarizing microscope. Furthermore, some deparaffinized sections were immunostained with rabbit polyclonal antibodies for beta 2-microglobulin ((2MG) (Dako, Glostrup, Denmark; 1:1,000), amyloid-P component (Dako; 1:200), kappa light chain (Dako; 1:100,000), lambda light chain (Dako; 1:100,000), and prealbumin (transthyretin) (Dako; 1:3,000), or a mouse monoclonal antibody for amyloid-A component (Dako; 1:200). The deposits were positive for beta 2-microglobulin and amyloid-P component, and also weakly positive for AA-protein, but were negative for kappa and lamda light chains and for prealbumin. Electron microscopy showed randomly arrayed fibrils that were 8-12 nm in diameter in the amyloid deposits (Figures 2, 3, and 5). Accordingly, this patient was diagnosed as having a (2MG amyloidosis.

Discussion

In 1975, Warren first reported carpal tunnel syndrome (CTS) in patients who had been on hemodialysis for 15 years(2). In 1983, Kachel reported that an Deposition of an amyloid—like substance showing positive Congo red staining with green birefringence under polarized light was in the carpal tunnel ligaments of patients with CTS was reported in 1983(3), The next year, Schwartz reported while a significant correlation between the incidence of CTS and the duration of dialysis was demonstrated the next year(4). In 1985, Gejyo showed that amyloid deposits were homologous to beta 2-microglobulin ((2MG) with a molecular weight of 11,000(5), and demonstrated positive staining of (2MG by direct immunofluorescence(6,7). Subsequently, Honda et al. showed that amyloid consists of curvilinear and non-branching amyloid fibrils with a diameter of 6-12 nm on electron microscopic examination(8). Since that time, (2MG amyloid has been known as dialysis-related amyloid (DRA).

Among lesions due to DRA other than CTS, Kuntz reported Destructive spondylarthropathy (DSA) is a peculiar spinal lesion of dialysis patients that predominantly affects the cervical spine, which was first reported in 1984 (9). In 1986, Sebert reported that cervical DSA was shown to be caused by amyloid deposition in the intervertebral discs(10). In 1990, Honda et al. evaluated hemodialysis autopsy cases, and found DSA of the intervertebral discs and posterior longitudinal ligament of the lumbar spine was detected at autopsy after a mean dialysis duration of 29 months(8). In 1992, Ohashi et al. examined the intervertebral discs of 41 autopsied dialysis patients(11). They found that amyloid first appeared in the cervical discs, followed by the lumbar and upper thoracic discs, and finally the middle and lower thoracic discs as the duration of dialysis was prolonged. Lesions were most marked at the C4-5, C5-6, and C6-7 levels, which sustain severe mechanical stress in daily life. They also reported that In two of their patients, cervical DSA had a fatal outcome. Ito et al. reported that Spinal canal stenosis due to hypertrophy of the ligamentum flavum because of amyloid deposition also causes spinal disorders in patients without DSA(12). In 1986, Fenves reported that Moreover, amyloid deposits have been found inside the carpal bone cysts of dialysis patients(13), and Campistol reported DRA has been detected in the synovium of the glenohumeral joint(14).

Regarding visceral involvement by DRA, Honda reported amyloid deposits occur around small vessels of the heart and intestine, but these deposits may not be associated with symptoms, unlike primary amyloidosis(8). However, Kanai et al. reported DRA-related gastrointestinal complications, such as marked dilatation of the ascending and transverse colon and the stomach, paralytic ileus, and perforation of the sigmoid colon, secondary to massive amyloid deposition around small arteries of the gastrointestinal tract have also been reported(15-17). Ohashi et al. stated that (2M amyloid mainly forms nodular lesions affecting the small arterioles of the muscularis propria in these organs, but does not replace the muscle layers, unlike AA or AL amyloid(18). In 1998, Kawano reported In two patients who died of congestive heart failure secondary to dialysis–related cardiac amyloidosis(19), amyloid deposits were not localized to the vessel walls, but were widely disseminated throughout the left ventricular myocardium and replaced muscle fibers. All of these reports were based upon histological materials obtained from patients who started hemodialysis in the 1960s or 1970s. The relatively primitive dialysis technology of that time might have contributed to DRA(24). The general clinical manifestations of DRA are summarized in Table 1. Many efforts to improve technical aspects of dialysis, such as water purification, dialysate composition, and performance of the dialysis membrane, have been made in Japan. Water purification is done to avoid exposing patients to bacteria and chemical contaminants, using ion exchange resins and activated charcoal, as well as reverse osmosis for removal of aluminum (from 1978) and endotoxin adsorption filters (from 2000). In Japan, hemodialysis was started with Kill type-dialyzers in April 1966, These were which were switched to Kolff-type dialyzers in 1971 and to while hollow-fiber dialyzers in were used from 1977. Dialysis membranes were initially low-flux membranes, such as cellulose or cupraammonium cellulose, but clearance of (2-microglobulin was not adequate. From In 1990, high-flux synthetic membranes such as polysulfone polymethylmethacrylate (PMMA), and polyacrylnitrile (PAN) membranes, membranes were introduced for better clearance of (2-microglobulin with less complement activation (more biocompatible), requiring an ultrafiltration control system because of their high water permeability. These changes resulted in better removal of (2MG and improved survival. As noted in the K/DOQI guidelines, high-flux dialyzers are recommended for DRA patients because such dialyzers remove more (2MG than low-flux dialyzers and decrease serum (2MG levels with conventional dialysis, although it is still unclear whether this will prevent the progression of DRA or development of new lesions(25). Renal transplantation is the only modality that appears to slow or halt the progression of DRA. Surgical correction of bone and joint complications by arthroscopic or open surgery, curettage, and arthroplasty may be warranted when debility or pain cannot be controlled with analgesics or other noninvasive therapies.

The 2009 KDIGO practice guidelines provided recommendations for the evaluation and management of chronic kidney disease-mineral and bone disorder (CKD-MBD)(2526). The term CKD-MBD describes a syndrome comprising with mineral, bone, and calcific cardiovascular abnormalities. The guidelines suggest that abnormal mineral and bone metabolism lead to an increase of morbidity and mortality due to extraskeletal calcification. This patient’s history and autopsy findings support the concept of CKD-MBD.

Recently, frequent hemodialysis was reported to achieve better results for the composite outcomes of death/decreased left ventricular mass or death/reduction of blood pressure medications/improved mineral metabolism or physical-health composite score compared with conventional hemodialysis(27,28). However, the present patient suggests that conventional hemodialysis is sufficient for long-term survival provided that BP, fluid volume, and calcium/phosphate are well controlled.

In conclusion, what can we learn from a 60-year-old Japanese man who received dialysis for 42 years? During his first 20 years on hemodialysis, he would have had higher serum (2MG levels like those of patients in many DRA-related papers from the 1980s and 1990s, but during the past 20 years he received more advanced hemodialysis and had lower serum (2MG levels. Although he eventually died of DRA-related intestinal and spinal complications, his arterial system (including the aorta and coronary arteries) showed very little atheromatous change. Strict control of his Ca-P balance and blood pressure may have resulted in such mild cardiovascular disease, while progress in dialysis technology delayed the clinical manifestation of DRA and allowed him to survive on dialysis for 42 years.

Acknowledgement

This study was funded by the Okinaka Memorial Institute for Medical Research and a grant for the Amyloidosis Research Committee from the Ministry of Health, Labour and Welfare, Japan.

Contributions as one of physicians of the patient

Keiichi Sumida, MD; Noriko Hayami, MD; Rikako Hiramatsu, MD; Masayuki Yamanouchi, MD; Eiko Hasegawa, MD; Junichi Hoshino, MD; and Naoki Sawa, MD in Toranomon Hospital.

Comflict of interest

None declared.

References

1. Akizawa T. Current status of dialysis therapy and related clinical guidelines in Japan. JMAJ. 2010; 53(3): 185-7.

2. Warren DJ, Otieno LS. Carpal tunnel syndrome in patients on intermittent haemodialysis. Postgrad Med J. 1975; 51(597): 450-2.

3. Kachel HG, Altmeyer P, Baldamus CA, Koch KM. Deposition of an amyloid-like substance as a possible complication of regular dialysis treatment. Contrib Nephrol. 1983; 36: 127-32.

4. Schwarz A, Keller F, Seyfert S, Pöll W, Molzahn M, Distler A. Carpal tunnel syndrome: a major complication in long-term hemodialysis patients. Clin Nephrol. 1984; 22: 133-7.

5. Gejyo F, Yamada T, Odani S, Nakagawa Y, Arakawa M, Kunitomo T, Kataoka H, Suzuki M, Hirasawa Y, Shirahama T, et al. A new form of amyloid protein associated with chronic hemodialysis was identified as beta 2-microglobulin. Biochem Biophys Res Commun. 1985; 129: 701-6.

6. Shirahama T, Skinner M, Cohen AS, Gejyo F, Arakawa M, Suzuki M, Hirasawa Y. Histochemical and immunohistochemical characterization of amyloid associated with chronic hemodialysis as beta 2-microglobulin. Lab Invest. 1985; 53: 705-9.

7. Gejyo F, Odani S, Yamada T, Honma N, Saito H, Suzuki Y, Nakagawa Y, Kobayashi H, Maruyama Y, Hirasawa Y, et al. Beta 2-microglobulin: a new form of amyloid protein associated with chronic hemodialysis. Kidney Int. 1986; 30: 385-90.

8. Honda K, Hara M, Ogura Y, Nihei H, Mimura N. Beta 2-microglobulin amyloidosis in hemodialysis patients. An autopsy study of intervertebral disks and posterior longitudinal ligaments. Acta Pathol Jpn. 1990; 40: 820-6.

9. Kuntz D, Naveau B, Bardin T, Drueke T, Treves R, Dryll A. Destructive spondylarthropathy in hemodialyzed patients. A new syndrome. Arthritis Rheum. 1984; 27: 369-75.

10. Sebert JL, Fardellone P, Marie A, Deramond H, Lambrey G, Legars D, Galibert P, Smajda A, Fournier A. Destructive spondylarthropathy in hemodialyzed patients: possible role of amyloidosis. Arthritis Rheum. 1986; 29: 301-3.

11. Ohashi K, Hara M, Kawai R, Ogura Y, Honda K, Nihei H, Mimura N. Cervical discs are most susceptible to beta 2-microglobulin amyloid deposition in the vertebral column. Kidney Int. 1992; 41: 1646-52.

12. Ito M, Abumi K, Takeda N, Satoh S, Hasegawa K, Kaneda K. Pathologic features of spinal disorders in patients treated with long-term hemodialysis. Spine. 1998; 23: 2127-33.

13. Fenves AZ, Emmett M, White MG, Greenway G, Michaels DB. Carpal tunnel syndrome with cystic bone lesions secondary to amyloidosis in chronic hemodialysis patients. Am J Kidney Dis. 1986; 7: 130-4.

14. Campistol JM, Cases A, Torras A, Soler M, Muñoz-Gómez J, Montoliu J, López-Pedret J, Revert L. Visceral involvement of dialysis amyloidosis. Am J Nephrol. 1987; 7: 390-3.

15. Kanai H, Kashiwagi M, Hirakata H, Nagashima A, Tada S, Yao T, Nakamoto M, Nakamura S, Fujishima M. Chronic intestinal pseudo-obstruction due to dialysis-related amyloid deposition in the propria muscularis in a hemodialysis patient. Clin Nephrol. 2000; 53: 394-9.

16. Ikegaya N, Kobayashi S, Hishida A, Kaneko E, Furuhashi M, and Maruyama Y. Colonic Dilatation Due to Dialysis-Related Amyloidosis. Am J Kidney Dis. 1995; 25: 807-9.

17. Araki H, Muramoto H, Oda K, Koni I, Mabuchi H, Mizukami Y, Nonomura A. Severe gastrointestinal complications of dialysis-related amyloidosis in two patients on long-term hemodialysis. Am J Nephrol. 1996; 16: 149-53.

18. Kenichi O, Ryuko T, Mitsuru H. Visceral organ involvement and extracellular matrix changes in (2-microglobulin amyloidosis – a comparative study with systemic AA and AL amyloidosis. Virchows Arch. 1997; 430: 479–87.

19. Kawano M, Muramoto H, Yamada M, Minamoto M, Araki H, Koni I, Mabuchi H, Nonomura A. Fatal Cardiac (2-Microglobulin Amyloidosis in Patients on Long-Term Hemodialysis. Am J Kidney Dis. 1998; 31: E4.

20. United States Renal Data System. Excerpts from USRDS 2009 Annual Data Report. U.S. Department of Health and Human Services. The National Insutitus of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Am J Kidney Dis. 2010; 55: S1.

21. Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol. 2002; 13: 1918-27.

22. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003; 108: 2154-69.

23. Ohtake T, Kobayashi S, Moriya H, Negishi K, Okamoto K, Maesato K, Saito S. High prevalence of occult coronary artery stenosis in patients with chronic kidney disease at the initiation of renal replacement therapy: an angiographic examination. J Am Soc Nephrol. 2005; 16: 1141-8.

24. Scbneditz D. Technologic aspects of hemodialysis and peritoneal dialysis. In: Nissenson AR and Fine RN. Clinical Dialysis. 4th ed. The McGraw-Hill companies, New York, US; 2005. P.47-152.

25. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003; 42: S1.

26. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009; 113: S1-130.

27. FHN Trial Group, Chertow GM, Levin NW, Beck GJ, Depner TA, Eggers PW, Gassman JJ, Gorodetskaya I, Greene T, James S, Larive B, Lindsay RM, Mehta RL, Miller B, Ornt DB, Rajagopalan S, Rastogi A, Rocco MV, Schiller B, Sergeyeva O, Schulman G, Ting GO, Unruh ML, Star RA, Kliger AS. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010; 363(24): 2287-300.

28. Culleton BF, Walsh M, Klarenbach SW, Mortis G, Scott-Douglas N, Quinn RR, Tonelli M, Donnelly S, Friedrich MG, Kumar A, Mahallati H, Hemmelgarn BR, Manns BJ. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA. 2007; 298(11): 1291-9.

Figure legends

Figure 1:

CT reveals marked distension of the sigmoid colon (arrows).

MRI shows severe DSA of the lumbar spine (arrows).

Figure 2

Pathological fracture of the right femoral neck (arrows).

Figure 3

Serum Ca, P, Alb, and intact-PTH levels of the patient plotted every 5 years.

Figure 4:

Amyloid deposition (arrows) is observed in small arteries and the surrounding tissues in the submucosal and subserosal layers of the sigmoid colon (Congo Red stain ( 160).

Figure 5:

In lung, amyloid deposition has led to thickening of alveolar septal walls (arrow) and narrowing of alveolar ducts (*) (a: hematoxylin and eosin stain, b: Congo red stain, c: (2MG stain, d: electron micrograph ( 10,000).

Figure 6:

There is little atheromatous change or calcification in the aorta (arrow) (macroscopic appearance).

Figure 7a:

The spinal cord is degenerated according to compression by the cervical dura that is thickened by amyloid at C7 (Kluver-Barrera's stain ( 40).

Figure 7b:

The cervical dura that is thickened by amyloid at C7 (arrows) (a: hematoxylin and eosin stain ( 20, b: (2MG stain ( 20).

(Table 1) General clinical manifestation of DRA

|Clinical manifestations |Site of deposition of (2MG |

|CTS |Carpal tunnel synovium |

|Swollen painful joints |Joint synovial tissue (often affecting the shoulders, hands,|

| |and knees |

|Trigger finger |Flexor tendons of the fingers |

|Bone cyst, pathological fracture |Bone (typically the femoral neck, humerus, and carpal bones)|

|Spondyloarthropathy, DSA |Vertebrae, intervertebral discs, and longitudinal ligaments |

|Gastrointestinal disease, ischemic colitis, malabsorption, colonic |Gastrointestinal tract (typically around small arteries) |

|dilatation, constipation | |

|Heart failure |Heart (typically in vessel walls) |

|Amyloid masses of the buttocks |Subcutaneous tissue |

What can we learn from a patient on dialysis for 42 years?

#1Department of Nephrology, #2Department of Pathology, #3Department of Orthopedics, Toranomon Hospital, Tokyo, Japan

#4Division of Neurology, Jichi Medical University, Tochigi, Japan

#5Okinaka Memorial Institute for Medical Research, Tokyo, Japan

#1Tatsuya Suwabe, MD; #1,5Yoshifumi Ubara, MD; #2Masafumi Inoue, MD, #3Izuru Kitajima, MD, #2Kenichi Oohashi; MD, #4Imaharu Nakano, MD; and #1,5Kenmei Takaichi, MD

Correspondence to: Tatsuya Suwabe, MD

Department of Nephrology, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki-shi, Kanagawa-ken, 213-0015, Japan

Phone: 81-44-877-5111

Fax: 81-44-877-5333

e-mail: suwabe@toranomon.gr.jp

Key words: dialysis, dialysis-related amyloidosis, beta 2-microglobulin, cardiovascular disease

Running head: Patient on dialysis for 42 years

Abstract

We performed autopsy on a 60-year-old Japanese man who had received dialysis for 42 years. He started on intermittent peritoneal dialysis in 1968, which was combined with hemodialysis in 1969. His serum calcium-phosphate balance and his blood pressure had been controlled well. Carpal tunnel syndrome occurred in 1984. Then lumbar spinal canal stenosis (SCS) occurred in 1997, followed by cervical SCS in 2000, destructive lumbar spondyloarthropathy (DSA) in 2002, and pathological fracture of the right femoral neck due to an enlarging bone cyst in 2006. All of his surgical specimens showed dialysis-related deposition of (2MG amyloid (dialysis-related amyloidosis: DRA). Thereafter, lumbar and cervical spinal palsy progressed. In 2009, he developed severe paralytic ileus with dilatation of the sigmoid colon, and subsequently died of peritonitis due to necrotizing cholecystitis. Autopsy showed massive DRA deposits in his intestinal blood vessels and thickened spinal dura, resulting in the above-mentioned intestinal and spinal complications. However, his arterial tree, including the aorta and coronary arteries, showed very little atheroma. Strict control of the Ca-P balance and blood pressure may have prevented cardiovascular disease, while progress in dialysis technology delayed fatal complications of DRA and allowed this patient to survive on dialysis for 42 years.

　　　 Background

In Japan, renal transplantation from cadaveric donors is not common, so dialysis technology has progressed dramatically and there are almost 20,000 patients who have been on hemodialysis for longer than 20 years(1). However, life expectancy of dialysis patients in Japan is still low, less than 50% of the general population. Dialysis-related amyloidosis (DRA) due to deposition of beta 2-microglobulin ((2MG) remains a problem in long-term dialysis patients(2-7). DRA has been reported to cause osteoarticular disorders such as carpal tunnel syndrome (CTS), osteoarthropathy of the limb joints, and spondylarthropathy(8-13). Extraosteoarticular visceral involvement has also been described, but rarely causes clinical manifestations(14-19). Cardiovascular disease is also an important predictor of mortality in dialysis patients and it accounts for approximately 50 percent of deaths(20). A large number of dialysis patients have traditional risk factors for cardiovascular disease(21). In addition, chronic kidney disease alone is an important risk factor for coronary artery disease(22). High prevalence of coronary artery disease in dialysis patients was reported in Japan(23). Then, there are a small number of patients who are on dialysis for longer than 30 years even in Japan. Here we report the history and histological findings of a 62-year-old man who was on dialysis for 42 years (the longest dialysis duration reported in Japan in 2010), and who showed extensive deposition of (2MG-amyloid in various organs as well as osteoarticular involvement.

Case report

An 18-year-old Japanese man was admitted to our institution with end-stage renal failure in 1968. Renal histology was not confirmed, but treatment was started with intermittent peritoneal dialysis (IPD) twice weekly for 8 hours per session on May 15, 1968. Hemodialysis (HD) with a Kiil flat bed-type dialyzer (8 hours once weekly) was combined with IPD once weekly from May 28, 1969. Then a coil-type dialyzer (EX-03) was utilized from 1972. He was switched to HD alone twice weekly because of peritoneal failure in 1973. A hollow-fiber dialyzer was used from 1977 and his HD protocol was changed to 4 hours three times weekly in 1980. The dialyzer membrane was initially a regenerated cellulose membrane, which was switched to a polymethylmethacrylate (PMMA) membrane in 1987 and then changed to a polysulfone (PS) high flux membrane in 1995. Water purification was done with a reverse osmosis system from 1976. The serum (2M level was respectively 40 and 26 mg/l before and after HD in 1986, but it decreased to 18 and 8 mg/L in 1996.

In 1984, he noted paresthesia of the palmar surface of the first three fingers of his right hand. Carpal tunnel syndrome (CTS) was diagnosed by a nerve conduction velocity study using electromyography, and was treated surgically by carpal tunnel decompression and coraco-acromial ligament release. Surgery for CTS was also done on the left side in 1986, and operations were repeated for this condition a total of 5 times until 1998. Masses measuring 1 cm were resected from the buttocks on the right side in 1995 and the left side in 1998. He noted paresthesia of both legs in 1994, and he complained of numbness and intermittent claudication of the bilateral lower limbs in 1997. Lumbar spinal canal stenosis (SCS) was diagnosed due to thickening of the ligamentum flavum and posterior longitudinal ligament, and laminectomy was performed. In 2000, laminoplasty was performed for numbness of the bilateral upper extremities due to cervical SCS. His lumbar SCS then progressed to destructive spondyloarthropathy (DSA), characterized by loss of the intervertebral disc spaces and erosion of subchondral bone in the adjacent vertebral bodies (Figure 1). In 2002, lumbar fixation surgery was done. Expansion of a bone cyst in the right femoral neck led to pathological fracture in 2006 (Figure 2), so right total hip arthroplasty was performed. Histological examination of specimens obtained at all of his operations disclosed deposition of (2MG-amyloid.

Over 40 years, the mean interdialysis weight gain was 1.85(0.67 kg (3.49% of his dry weight). He maintained a strict diet while on dialysis and he never overate. The serum calcium-phosphate balance was adequately controlled (average values over 42 years: 9.81(0.82 mg/dL for calcium, 5.02(1.18 mg/dL for phosphate, and: 49.13(10.98 mg/dL2 for the calcium ( phosphate product) by using oral calcium (calcium carbonate 3 g three times daily) and a vitamin D3 derivative, with parathyroidectomy (PTx) being performed for secondary hyperparathyroidism in 1995 (Figure 3). The mean intact-PTH level was 382.4(134.5 pg/mL for 8 years before PTx and 59.9(72.3 pg/mL for 15 years after PTx. His mean serum albumin level was 3.66(0.54 g/dL. His lipid profile was normal (total cholesterol: 149.6(14.0 mg/dL). His blood pressure was controlled within the normal range by antihypertensive therapy and diet. His mean systolic BP was 114.2(8.6 mmHg and his mean diastolic BP was 76.8(7.2 mmHg. He did not require statin therapy and did not use angiotensin blockers. There was no history of smoking and no family history of atherosclerotic vascular disease. He was a teacher at a school for clinical engineers.

In September 2009, he was admitted to our hospital for evaluation of fever. He was 170 cm tall and weighed 59.1 kg. Emaciation was apparent. He could walk by himself with difficulty using a stick. His temperature was 38.5(C and his blood pressure was 123/66 mmHg. His hands were deformed and swollen bilaterally, while the lower extremities were edematous. Laboratory findings were as follows: the white blood cell (WBC) count was 4,900/(L, hemoglobin was 8.2 g/dL, total protein was 5.8 g/dL, albumin was 1.8 g/dL, C-reactive protein was 14.8 mg/dL, and (2-microglobulin was 17.1 mg/L. Blood culture revealed no pathogenic bacteria, including tuberculous bacilli or fungi. The Quantiferon test (Cellestis) for tuberculosis was also negative. Diagnostic imaging such as computed tomography and ultrasonography did not reveal any source of his fever. Antibiotics and antimycotic drugs were administered for the fever, but were not effective. Paresthesia and muscle weakness of the bilateral lower extremities recurred in December 2009, while both upper extremities were affected again in January 2010. His symptoms then progressed rapidly to complete paralysis. In February 2010, he developed severe abdominal distension with pain and constipation. CT revealed marked distension of the sigmoid colon, so colostomy was performed. He died of peritonitis in July 2010.

Autopsy findings

A large amount of turbid ascites was seen in the abdominal cavity. Perforation of the gallbladder due to necrotizing cholecystitis with a focus of yeast-like fungus (candida) and bile acid peritonitis appeared to be the main cause of death. Amyloid deposits were present in small arteries and the surrounding tissues in the gallbladder wall. Amyloid deposition was also observed in the small arteries and surrounding tissues of the submucosal and subserosal layers throughout the gastrointestinal tract (Figure 4). These deposits were more massive and nodular in the distal large intestine, and also invaded the proper muscle layer, which might have contributed to his large bowel dysfunction. In the lungs, amyloid deposition caused thickening of the alveolar septal walls and narrowing of alveolar ducts, as well as pleural thickening, which was prominent in the lower lobes (Figure 5). The aorta showed little atheromatous change or calcification (Figure 6), and his coronary arteries were intact, although there were moderate amyloid deposits in the muscle layer of the interfascicular arteries.

In addition to the above-mentioned histological findings obtained from surgical specimens of his spinal lesions, the spinal cord was compressed by thickening of the cervical spinal dura due to amyloid, as well as by crush fractures of the lumbar vertebra, resulting in spinal cord degeneration especially at C7(Figure 7a). Thickening of the dura was also much more prominent at C7 than at other levels (Figure 7b).

Amyloid staining

Immunohistochemical examination was performed on paraffin-embedded specimens using an auto-staining machine (Ventana Benchmark System, Ventana Medical System, Tucson, AZ) according to the manufacturer’s protocol. Some sections were stained with Congo red (Congo red; Dako, Glostrup, Denmark, 1:500). A positive reaction for Congo red was confirmed by detection of apple green birefringence under a polarizing microscope. Furthermore, some deparaffinized sections were immunostained with rabbit polyclonal antibodies for beta 2-microglobulin ((2MG) (Dako, Glostrup, Denmark; 1:1,000), amyloid-P component (Dako; 1:200), kappa light chain (Dako; 1:100,000), lambda light chain (Dako; 1:100,000), and prealbumin (transthyretin) (Dako; 1:3,000), or a mouse monoclonal antibody for amyloid-A component (Dako; 1:200). The deposits were positive for beta 2-microglobulin and amyloid-P component, and also weakly positive for AA-protein, but were negative for kappa and lamda light chains and for prealbumin. Electron microscopy showed randomly arrayed fibrils that were 8-12 nm in diameter in the amyloid deposits (Figures 2, 3, and 5). Accordingly, this patient was diagnosed as having a (2MG amyloidosis.

Discussion

In 1975, Warren first reported carpal tunnel syndrome (CTS) in patients who had been on hemodialysis for 15 years(2). Deposition of an amyloid—like substance showing positive Congo red staining with green birefringence under polarized light in the carpal tunnel ligaments of patients with CTS was reported in 1983(3), while a significant correlation between the incidence of CTS and the duration of dialysis was demonstrated the next year(4). In 1985, Gejyo showed that amyloid deposits were homologous to beta 2-microglobulin ((2MG) with a molecular weight of 11,000(5), and demonstrated positive staining of (2MG by direct immunofluorescence(6,7). Subsequently, Honda et al. showed that amyloid consists of curvilinear and non-branching amyloid fibrils with a diameter of 6-12 nm on electron microscopic examination(8). Since that time, (2MG amyloid has been known as dialysis-related amyloid (DRA).

Destructive spondylarthropathy (DSA) is a peculiar spinal lesion of dialysis patients that predominantly affects the cervical spine, which was first reported in 1984 (9). In 1986, cervical DSA was shown to be caused by amyloid deposition in the intervertebral discs(10). In 1990, DSA of the intervertebral discs and posterior longitudinal ligament of the lumbar spine was detected at autopsy after a mean dialysis duration of 29 months(8). In 1992, Ohashi et al. examined the intervertebral discs of 41 autopsied dialysis patients(11). They found that amyloid first appeared in the cervical discs, followed by the lumbar and upper thoracic discs, and finally the middle and lower thoracic discs as the duration of dialysis was prolonged. Lesions were most marked at the C4-5, C5-6, and C6-7 levels, which sustain severe mechanical stress in daily life. In two of their patients, cervical DSA had a fatal outcome. Spinal canal stenosis due to hypertrophy of the ligamentum flavum because of amyloid deposition also causes spinal disorders in patients without DSA(12). Moreover, amyloid deposits have been found inside the carpal bone cysts of dialysis patients(13), and DRA has been detected in the synovium of the glenohumeral joint(14).

Regarding visceral involvement by DRA, amyloid deposits occur around small vessels of the heart and intestine, but these deposits may not be associated with symptoms, unlike primary amyloidosis(8). However, DRA-related gastrointestinal complications, such as marked dilatation of the ascending and transverse colon and the stomach, paralytic ileus, and perforation of the sigmoid colon, secondary to massive amyloid deposition around small arteries of the gastrointestinal tract have also been reported(15-17). (2M amyloid mainly forms nodular lesions affecting the small arterioles of the muscularis propria in these organs, but does not replace the muscle layers, unlike AA or AL amyloid(18). In two patients who died of congestive heart failure secondary to dialysis–related cardiac amyloidosis(19), amyloid deposits were not localized to the vessel walls, but were widely disseminated throughout the left ventricular myocardium and replaced muscle fibers. All of these reports were based upon histological materials obtained from patients who started hemodialysis in the 1960s or 1970s. The relatively primitive dialysis technology of that time might have contributed to DRA(24). The general clinical manifestations of DRA are summarized in Table 1. Many efforts to improve technical aspects of dialysis, such as water purification, dialysate composition, and performance of the dialysis membrane, have been made in Japan. Water purification is done to avoid exposing patients to bacteria and chemical contaminants, using ion exchange resins and activated charcoal, as well as reverse osmosis for removal of aluminum (from 1978) and endotoxin adsorption filters (from 2000). In Japan, hemodialysis was started with Kill type-dialyzers in 1966, which were switched to Kolff-type dialyzers in 1971 and to hollow-fiber dialyzers in 1977. Dialysis membranes were initially low-flux membranes, such as cellulose or cupraammonium cellulose, but clearance of (2-microglobulin was not adequate. In 1990, high-flux synthetic membranes such as polysulfone membranes were introduced for better clearance of (2-microglobulin with less complement activation (more biocompatible), requiring an ultrafiltration control system because of their high water permeability. These changes resulted in better removal of (2MG and improved survival. As noted in the K/DOQI guidelines, high-flux dialyzers are recommended for DRA patients because such dialyzers remove more (2MG than low-flux dialyzers and decrease serum (2MG levels with conventional dialysis, although it is still unclear whether this will prevent the progression of DRA or development of new lesions(25). Renal transplantation is the only modality that appears to slow or halt the progression of DRA. Surgical correction of bone and joint complications by arthroscopic or open surgery, curettage, and arthroplasty may be warranted when debility or pain cannot be controlled with analgesics or other noninvasive therapies.

The 2009 KDIGO practice guidelines provided recommendations for the evaluation and management of chronic kidney disease-mineral and bone disorder (CKD-MBD)(26). The term CKD-MBD describes a syndrome comprising with mineral, bone, and calcific cardiovascular abnormalities. The guidelines suggest that abnormal mineral and bone metabolism lead to an increase of morbidity and mortality due to extraskeletal calcification. This patient’s history and autopsy findings support the concept of CKD-MBD.

Recently, frequent hemodialysis was reported to achieve better results for the composite outcomes of death/decreased left ventricular mass or death/reduction of blood pressure medications/improved mineral metabolism or physical-health composite score compared with conventional hemodialysis(27,28). However, the present patient suggests that conventional hemodialysis is sufficient for long-term survival provided that BP, fluid volume, and calcium/phosphate are well controlled.

In conclusion, what can we learn from a 60-year-old Japanese man who received dialysis for 42 years? During his first 20 years on hemodialysis, he would have had higher serum (2MG levels like those of patients in many DRA-related papers from the 1980s and 1990s, but during the past 20 years he received more advanced hemodialysis and had lower serum (2MG levels. Although he eventually died of DRA-related intestinal and spinal complications, his arterial system (including the aorta and coronary arteries) showed very little atheromatous change. Strict control of his Ca-P balance and blood pressure may have resulted in such mild cardiovascular disease, while progress in dialysis technology delayed the clinical manifestation of DRA and allowed him to survive on dialysis for 42 years.

Acknowledgement

This study was funded by the Okinaka Memorial Institute for Medical Research and a grant for the Amyloidosis Research Committee from the Ministry of Health, Labour and Welfare, Japan.

Contributions as one of physicians of the patient

Keiichi Sumida, MD; Noriko Hayami, MD; Rikako Hiramatsu, MD; Masayuki Yamanouchi, MD; Eiko Hasegawa, MD; Junichi Hoshino, MD; and Naoki Sawa, MD in Toranomon Hospital.

Comflict of interest

None declared.

References

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2. Warren DJ, Otieno LS. Carpal tunnel syndrome in patients on intermittent haemodialysis. Postgrad Med J. 1975; 51(597): 450-2.

3. Kachel HG, Altmeyer P, Baldamus CA, Koch KM. Deposition of an amyloid-like substance as a possible complication of regular dialysis treatment. Contrib Nephrol. 1983; 36: 127-32.

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8. Honda K, Hara M, Ogura Y, Nihei H, Mimura N. Beta 2-microglobulin amyloidosis in hemodialysis patients. An autopsy study of intervertebral disks and posterior longitudinal ligaments. Acta Pathol Jpn. 1990; 40: 820-6.

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10. Sebert JL, Fardellone P, Marie A, Deramond H, Lambrey G, Legars D, Galibert P, Smajda A, Fournier A. Destructive spondylarthropathy in hemodialyzed patients: possible role of amyloidosis. Arthritis Rheum. 1986; 29: 301-3.

11. Ohashi K, Hara M, Kawai R, Ogura Y, Honda K, Nihei H, Mimura N. Cervical discs are most susceptible to beta 2-microglobulin amyloid deposition in the vertebral column. Kidney Int. 1992; 41: 1646-52.

12. Ito M, Abumi K, Takeda N, Satoh S, Hasegawa K, Kaneda K. Pathologic features of spinal disorders in patients treated with long-term hemodialysis. Spine. 1998; 23: 2127-33.

13. Fenves AZ, Emmett M, White MG, Greenway G, Michaels DB. Carpal tunnel syndrome with cystic bone lesions secondary to amyloidosis in chronic hemodialysis patients. Am J Kidney Dis. 1986; 7: 130-4.

14. Campistol JM, Cases A, Torras A, Soler M, Muñoz-Gómez J, Montoliu J, López-Pedret J, Revert L. Visceral involvement of dialysis amyloidosis. Am J Nephrol. 1987; 7: 390-3.

15. Kanai H, Kashiwagi M, Hirakata H, Nagashima A, Tada S, Yao T, Nakamoto M, Nakamura S, Fujishima M. Chronic intestinal pseudo-obstruction due to dialysis-related amyloid deposition in the propria muscularis in a hemodialysis patient. Clin Nephrol. 2000; 53: 394-9.

16. Ikegaya N, Kobayashi S, Hishida A, Kaneko E, Furuhashi M, and Maruyama Y. Colonic Dilatation Due to Dialysis-Related Amyloidosis. Am J Kidney Dis. 1995; 25: 807-9.

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23. Ohtake T, Kobayashi S, Moriya H, Negishi K, Okamoto K, Maesato K, Saito S. High prevalence of occult coronary artery stenosis in patients with chronic kidney disease at the initiation of renal replacement therapy: an angiographic examination. J Am Soc Nephrol. 2005; 16: 1141-8.

24. Scbneditz D. Technologic aspects of hemodialysis and peritoneal dialysis. In: Nissenson AR and Fine RN. Clinical Dialysis. 4th ed. The McGraw-Hill companies, New York, US; 2005. P.47-152.

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Figure legends

Figure 1:

MRI shows severe DSA of the lumbar spine (arrows).

Figure 2

Pathological fracture of the right femoral neck (arrows).

Figure 3

Serum Ca, P, Alb, and intact-PTH levels of the patient plotted every 5 years.

Figure 4:

Amyloid deposition (arrows) is observed in small arteries and the surrounding tissues in the submucosal and subserosal layers of the sigmoid colon (Congo Red stain ( 160).

Figure 5:

In lung, amyloid deposition has led to thickening of alveolar septal walls (arrow) and narrowing of alveolar ducts (*) (a: hematoxylin and eosin stain, b: Congo red stain, c: (2MG stain, d: electron micrograph ( 10,000).

Figure 6:

There is little atheromatous change or calcification in the aorta (arrow) (macroscopic appearance).

Figure 7a:

The spinal cord is degenerated according to compression by the cervical dura that is thickened by amyloid at C7 (Kluver-Barrera's stain ( 40).

Figure 7b:

The cervical dura that is thickened by amyloid at C7 (arrows) (a: hematoxylin and eosin stain ( 20, b: (2MG stain ( 20).

(Table 1) General clinical manifestation of DRA

|Clinical manifestations |Site of deposition of (2MG |

|CTS |Carpal tunnel synovium |

|Swollen painful joints |Joint synovial tissue (often affecting the shoulders, hands,|

| |and knees |

|Trigger finger |Flexor tendons of the fingers |

|Bone cyst, pathological fracture |Bone (typically the femoral neck, humerus, and carpal bones)|

|Spondyloarthropathy, DSA |Vertebrae, intervertebral discs, and longitudinal ligaments |

|Gastrointestinal disease, ischemic colitis, malabsorption, colonic |Gastrointestinal tract (typically around small arteries) |

|dilatation, constipation | |

|Heart failure |Heart (typically in vessel walls) |

|Amyloid masses of the buttocks |Subcutaneous tissue |

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