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
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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 b2MG 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 (b2MG) 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 b2MG-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 b2M 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 b2MG-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/mL, 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 b2-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 (b2MG) (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 b2MG 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 (b2MG) with a molecular weight of 11,000(5), and demonstrated positive staining of b2MG 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, b2MG 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 b2M 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 b2-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 b2-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 b2MG and improved survival. As noted in the K/DOQI guidelines, high-flux dialyzers are recommended for DRA patients because such dialyzers remove more b2MG than low-flux dialyzers and decrease serum b2MG 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.