Joint Disease in End-Stage Renal Disease

The joint diseases that are encountered in chronic dialysis have been reviewed. There are two general categories: de novo disease and arthropathy anteceding ESRD. The de novo joint diseases include categories that are probably the direct result of ESRD. Microcrystalline CaOHapatite and CaPPD arthritis is associated with hyperparathyroidism and a high Ca X P. Aluminum phosphate joint disease is the result of aluminum toxicity. Both types have severe disease of the adjacent bone: osteitis fibrosa with CaOHapatite-CaPPD arthropathy and osteomalacia with aluminum phosphate. Calcium oxalate joint disease probably results from renal oxalate retention in ESRD and conversion of ascorbate to oxalate. The evidence for uric acid arthropathy in the absence of primary gout or lead toxicity is not convincing. Amyloid is the most frequent cause of the carpal tunnel syndrome and is related to retention of β-2 microglobulin. Infective arthritis may be Seen, often occumng as a result of bacteremia from an infected fistula site. A degenerative arthritis different from osteoarthritis has also been described. Pathologic fractures can occur with both amyloid deposition in bone and aluminum osteomalacia. Long-term steroid therapy can lead to avascular necrosis of femoral or humeral heads. Diabetes mellitus with neuropathy can give rise to a very destructive Charcot joint. Tendon ruptures occur, but the mechanism is obscure. It is most important that the nephrologist work closely with the rheumatologist. Carefbl and sophis ticated examination of synovial fluid and tissue is mandatory in the microcrystalling diseases. Immunohistochemical methods may be required, particularly for tissue removed during decompression of the median nerve. Together the subspecialists can establish the diagnosis and determine the appropriate therapy for the iarge number of joint disorders to which the dialysis patient is subject.     

Oxalate removal by hemodialysis in end-stage renal disease

Because of mounting evidence of precipitation of calcium oxalate in the soft tissues of patients with end-stage renal disease (ESRD) on maintenance hemodialysis, the plasma oxalate concentrations and calculated dialysis removal of oxalate were studied in seven patients without evidence of either primary or absorption hyperoxaluria prior to ESRD. A reversed-phase high-pressure liquid chromatographic method was developed to quantitate serum oxalate. Mean value +/- SE in four healthy controls was 28 +/- 5 mumol/L, and in the seven patients it was 187 +/- 15 mumol/L predialysis and 89 +/- 11 mumol/L postdialysis. Oxalate deposition in the soft tissues of ESRD patients is the consequence of sustained hyperoxalemia. Oxalate removal by dialysis was calculated from the four-hour oxalate clearance. Since the ionic radii of phosphate and oxalate are similar, total oxalate clearance was calculated midpoint of dialysis. Mean oxalate removal/dialysis was 3.01 +/- 0.283 mmol. On a daily basis this value was 1.645 +/- 0.155 mmol, which is about threefold the normal oxalate excretion rate. It is not significantly different from the excretion rate in absorption oxalurias but is less than that in primary hyperoxaluria. Therefore, it is concluded that hyperoxalemia in ESRD results from loss of renal excretion, failure of hemodialysis to remove enough oxalate to maintain a normal serum concentration, and increased intestinal absorption of oxalate and/or increased endogenous production.     

Sporadic aluminum osteomalacia: identification of patients at risk

Chronic dialysis patients at risk for aluminum osteomalacia in areas of low water-aluminum content are not well identified. We, therefore, studied retrospectively a cohort of 59 patients who underwent bone biopsy at two hospital-based dialysis centers in Montreal (water aluminum content less than 10 micrograms/L). Overall, 25% of patients biopsied had aluminum-related osteomalacia defined by aluminum staining of more than 30% of the trabecular surface and low levels of bone formation as measured by tetracycline labeling. Multiple linear regression analysis showed high predialysis serum creatinine (P less than .05) and the amount of aluminum prescribed per month (P less than .05) as the most important determinants of aluminum staining. We conclude that aluminum-related osteomalacia can be a frequent disease entity in areas of low water-aluminum content. Our findings also suggest predialysis serum creatinine and the amount of aluminum prescribed per month are risk factors for the development of aluminum-related osteomalacia. Though the relationship between serum creatinine and aluminum staining of trabecular bone is unclear, serum creatinine is probably a marker for adequacy of dialysis in these patients.     

The effects of lanthanum carbonate and calcium carbonate on bone abnormalities in patients with end-stage renal disease

BACKGROUND: Renal osteodystrophy is a common complication of end-stage renal disease (ESRD) and is a major cause of morbidity in patients with ESRD. High serum levels of phosphorus, calcium and parathyroid hormone are associated with the development of this disease. The effects on bone of treatment with lanthanum carbonate, a new phosphate binder, and calcium carbonate were assessed in patients with ESRD. METHODS: This was an open-label, multicenter, parallel-group study. Patients were recruited within 12 weeks of commencing dialysis. Following screening, phosphate binder administration was stopped, tetracycline labeling administered and a transiliac bone biopsy taken. After randomization to lanthanum carbonate or calcium carbonate, patients were titrated to an optimum dose for 8 weeks and maintained at this dose for 44 weeks. The bone was then labeled and a second biopsy taken. Biopsy samples were analyzed histomorphometrically. RESULTS: Paired bone biopsies from 33 lanthanum carbonate- and 30 calcium carbonate-treated patients were suitable for analysis. None of the patients on either treatment developed osteomalacia. Assessment of activation frequency changes showed that 41% of biopsies from lanthanum carbonate-treated patients moved towards normal (observed values at the follow-up biopsy were closer to expected values than were the baseline values, so patients were considered to be improved) compared with 23% of calcium carbonate-treated patients (p = 0.15). CONCLUSIONS: This study indicates that there was no evidence of aluminum-like toxicity with lanthanum carbonate after 1 year of treatment in ESRD patients commencing dialysis, and there appeared to be a beneficial effect on bone-cell function and activity compared with calcium carbonate.     

Osteoarthritis and inflammatory arthritis

The term ‘arthritis’ encompasses most of the pathology that causes joint symptoms or dysfunction. Arthritis can be broadly categorized into osteoarthritis, which is a degenerative disease, and inflammatory arthropathies, in which there is true inflammation of the affected joints and their associated structures. Osteoarthritis is the most common form of arthritis. It is, to an extent, part of the ageing process, but it can arise as a consequence of joint damage resulting from other diseases or injury and some individuals have an increased risk of osteoarthritis owing to hereditary factors. The management of osteoarthritis is symptomatic up to the point of serious joint dysfunction, when surgical approaches are used. Inflammatory arthropathies can be due to infection, crystal deposition within joints and their associated structures (gout, pyrophosphate arthropathy and hydroxyapatite arthropathy) or autoimmune disease. All of the autoimmune inflammatory arthropathies also have extra-articular manifestations. Rheumatoid arthritis is the most common of the inflammatory arthropathies, and is characterized by progressive, deforming inflammation of joints owing to a destructive synovitis. Another group of diseases (ankylosing spondylitis, reactive arthritis/Reiter’s syndrome, psoriatic arthritis) are characterized by enthesitis and are associated with HLA-B27. Treatment of these diseases is becoming more effective with the development of targeted biological treatments.     

Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria

BACKGROUND: Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that results in overproduction of oxalate. The disease is characterized by severe calcium oxalate nephrolithiasis and nephrocalcinosis, resulting in end-stage renal disease (ESRD) early in life. Most patients eventually require dialysis and kidney transplantation, usually in combination with the replacement of the liver. Reduction of urinary oxalate levels can efficiently decrease calcium oxalate depositions; yet, no treatment is available that targets oxalate biosynthesis. In previous in vitro studies, we demonstrated that pyridoxamine can trap reactive carbonyl compounds, including intermediates of oxalate biosynthesis. METHODS: The effect of PM on urinary oxalate excretion and kidney crystal formation was determined using the ethylene glycol rat model of hyperoxaluria. Animals were given 0.75% to 0.8% ethylene glycol in drinking water to establish and maintain hyperoxaluria. After 2 weeks, pyridoxamine treatment (180 mg/day/kg body weight) started and continued for an additional 2 weeks. Urinary creatinine, glycolate, oxalate, and calcium were measured along with the microscopic analysis of kidney tissues for the presence of calcium oxalate crystals. RESULTS: Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. CONCLUSION: These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases.     

End-stage renal disease in liver transplants

Renal dysfunction is one of the most significant problems following orthotopic liver transplantation (OLTx). Since the major risk factor for delayed renal dysfunction following OLTx is presumed to be cyclosporine (CsA) nephrotoxicity, it has been suggested that CsA is the most probably cause of end-stage renal disease (ESRD) in this population of patients. To test this hypothesis the records of OLTx patients in our center who developed ESRD requiring dialysis were reviewed. There were 132 consecutive adult patients with end-stage liver disease (ESLD) who received 146 OLTxs between 1990 and 2000. Five patients (3.4%) developed ESRD requiring dialysis. Four of the five patients developed nephrotic range proteinuria prior to reaching ESRD. Renal biopsy in four patients showed focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy and cyclosporine toxicity. The underlying hepatic and metabolic disease may have played a role in the genesis of glomerular diseases in these OLTx patients. Perhaps if more renal biopsies are performed in OLTx patients with chronic renal failure, we might discover that, although CsA/tacrolimus therapy is a definite risk factor for post-transplantation chronic renal failure, other disease processes may also play a significant role.     

Survival and development of cardiovascular disease by modality of treatment in patients with end-stage renal disease.

Patients undergoing dialysis are at high risk for cardiovascular disease (CVD). The aim of this study was to evaluate the influence of hemodialysis (HD) versus peritoneal dialysis (PD) on survival and the risk of developing de novo CVD. Of the 4191 patients with end-stage renal disease (ESRD) who started renal replacement treatment (RRT) in Lombardy between 1994 and 1997, 4064 (who were on dialysis 30 d after the start of RRT) were considered for survival analysis: 2772 were on HD (mean age 60.9 yr; 21.2% diabetic) and 1292 on PD (mean age 63.6 yr; 16% diabetic). The 3120 patients who were free of CVD at the start of RRT were included in the analysis of the risk of developing de novo CVD. HD and PD were compared by use of a Cox-regression proportional hazard model, stratified by diabetic status; the explanatory covariates were age and gender. The death rate was 13.3 per 100 patient-years (13.0 on HD and 13.9 on PD); 197 (6.3%) of the 3120 patients included in the CVD analysis developed de novo CVD (128 on HD and 69 on PD). After adjustment for age, gender, and established CVD and stratification by diabetic status, there was no significant between-treatment difference in 4-yr survival (relative risk [RR], 0.91; 95% confidence interval [CI], 0.79 to 1.06). The risk of de novo CVD did not differ significantly by treatment modality (RR, 1.06; 95% CI, 0.79 to 1.43). The risk of mortality and de novo CVD for new patients with ESRD assigned to HD or PD was similar in Lombardy in the period 1994 through 1997.     

A broad-based metabolic approach to study VLDL apoB100 metabolism in patients with ESRD and patients treated with peritoneal dialysis

BACKGROUND: Dyslipidemia is often observed in patients with end-stage renal disease (ESRD) and is associated with cardiovascular diseases. Peritoneal dialysis treatment may further deteriorate the lipoprotein abnormalities, suggesting that peritoneal dialysis alters lipid metabolism. METHODS: To study the mechanisms involved in these abnormalities in peritoneal dialysis, we measured insulin sensitivity, free fatty acids release, de novo lipogenesis (DNL), very low-density lipoprotein (VLDL) apoB100 kinetics and cholesterol synthesis in vivo in ESRD (N= 6), peritoneal dialysis patients (N= 5), and controls (N= 7) using stable isotopes. RESULTS: Insulin sensitivity, as assessed by an euglycemic hyperinsulinemic clamp, tended to be lower in ESRD and peritoneal dialysis compared to controls [P= 0.08 by analysis of variance (ANOVA)]. Free fatty acid release during the euglycemic hyperinsulinemic clamp tended to be higher in ESRD and peritoneal dialysis compared to controls (P= 0.08 by ANOVA), while DNL and fractional cholesterol synthesis were normal. VLDL-1 apoB100 (P < 0.05) and VLDL-2 apoB100 pool sizes (P < 0.05) were significantly higher in peritoneal dialysis patients compared to controls. The increased VLDL-1 apoB100 pool size was explained by increased VLDL-1 apoB100 synthesis (P < 0.05) in combination with reduced VLDL-1 apoB100 catabolism (P < 0.01), while the increased VLDL-2 apoB100 pool was explained by reduced catabolism (P < 0.01). CONCLUSION: Both VLDL-1 apoB100 and VLDL-2 apoB100 pool sizes are increased in peritoneal dialysis patients, due to disturbances both in synthesis and catabolism. VLDL-1 apoB100 production is, at least partially, explained by increased free fatty acid availability secondary to peripheral insulin resistance, thus identifying insulin resistance as potential therapeutic target in peritoneal dialysis patients.     

Hydroxyapatite crystal deposition causing rapidly destructive arthropathy of the hip joint

Destructive arthropathy of the hip joint can be attributed to various etiologies like rheumatoid arthritis, aseptic necrosis of the femur head, Charcot''s joint, subacute septic arthritis, and tubercular arthritis. A disease that results in much rapid destruction of the hip joint and is not associated with clinical syndrome of above mentioned disease has been reported way back in 1970. However, no evidence-based study has been published to support hydroxyapatite (HA) crystals as a probable cause of rapidly destructive arthropathy of the hip joint. We report a case with microscopic and biochemical confirmation of HA crystal deposition causing destructive arthropathy of the hip joint.     

Beneficial effects of magnesium in chronic renal failure: a foe no longer

Magnesium plays a critical role in cellular physiology in humans, regulating many fundamental functions. In the general population its deficiency is associated with many disorders, the most significant being cardiovascular diseases. The role of magnesium in many aspects of end-stage renal disease (ESRD) may be also very important, although this has not been explored in depth. The most significant of these roles are use of magnesium salts as phosphate binders and its ability to inhibit the development or progression of vascular calcification. Moreover, serum magnesium suppresses parathyroid hormone excretion, whereas high magnesium dialysate may result in intradialytic hemodynamic stability. Data provided by recent studies on these issues have promoted promising renewed interest in the role of magnesium in ESRD and its possible favorable therapeutic application in these patients. Further large studies are needed to establish its efficacy and safety, and, probably, to re-evaluate its appropriate concentration in hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) fluids.     

Desferrioxamine therapy in hemodialysis patients with aluminum-associated bone disease

Aluminum toxicity in dialysis patients is associated with decreased bone turnover and a relative parathyroid hormone (PTH) deficiency. Desferrioxamine (DFO), a chelating agent, has been reported to improve bone histology in aluminum associated, low turnover bone disease in dialysis patients not subjected to parathyroidectomy. Information on the effect of DFO therapy on parathyroid gland function is lacking. In the present study, in addition to changes in bone histology, parathyroid gland function was evaluated in 18 hemodialysis patients with aluminum associated, low turnover bone disease (osteomalacia and aplastic bone disease) before and after one year of DFO treatment (1 to 6 g/week). Parathyroid gland function was assessed by using a calcium free and high calcium (3.5 to 4 mEq/liter) hemodialysis bath.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aluminum-binding protein in dialysis dementia. I. Characterization in plasma by gel chromatography and electrophoresis

A low molecular weight (approx. 8,000 daltons) protein has been found to be the major aluminum-binding protein in plasma of patients with dialysis dementia. Following treatment with desferrioxamine, the concentration of the low molecular weight protein and its aluminum content rise in parallel. The results suggest that aluminum exposure in dialysis dementia may result in the de novo synthesis of an aluminum-binding protein and that desferrioxamine may release aluminum in conjunction with its binding protein from tissue stores.     

UNRESOLVED ISSUES IN DIALYSIS: Dialysis‐Related Amyloidosis: Late Finding or Hidden Epidemic?

Dialysis-related amyloidosis is a complication of end-stage renal disease (ESRD) that results from retention of beta2-microglobulin (beta2M) and its deposition as amyloid fibrils into osteoarticular tissue. The clinical manifestations usually develop after several years of dialysis dependence and include carpal tunnel syndrome, destructive arthropathy, and bone cysts and fractures. High-flux membranes, daily dialysis, and hemofiltration all would be expected to delay the onset of dialysis-related amyloidosis because, to varying degrees, each increases the clearance of beta2M from the plasma. Thus what is currently a late complication of ESRD might become an even later complication as dialysis practices change. The significance of histologically evident but clinically silent beta2M amyloid, detectable not only in osteoarticular tissue but also in blood vessels, is unclear. Accumulating evidence that amyloidogenic proteins have direct and specific effects on cell processes irrespective of the extent of amyloid deposition raises the possibility that early, clinically silent beta2M amyloid deposits have unrecognized importance.     

Maligne Neoplasien und Nierentransplantation

Together with cardiovascular disorders and metabolic changes, malignant diseases are considered as great challenges in clinical transplantation. As far as long-term function of transplanted organs is concerned, an impact of malignancies is obvious. However, it is important to distinguish between neoplastic disease originating from preexisting lesions in the transplanted organs and de novo graft tumors. Further, there is also a high risk of developing malignant disease during the dialysis, likely due to potential harmful metabolic changes associated with this procedure. After curative management of tumors in such patients, an interval of 2 years for surveillance should be adhered to before patients are put back on the waiting list. The overall risk of transmission of a malignant disease with the transplanted graft has been considered to be as low as <0.2%. In this context, and considering the continual shortage of donated organs, there is an international consensus about the use of kidney grafts with a history of small tumors (<2 cm in diameter und low-grade, i.e., G1). However, the lesions should have been removed with subsequent histopathologic characterization before the acceptance of the organ for transplantation. Early diagnosis and management of de novo malignant disease in transplant patients is crucial for the prognosis of graft function and patient survival. Genitourinary malignancies are frequent among de novo malignancies in transplanted patients. Thus, there is a need for clearly structured concepts for screening of transplant patients in order to detect early malignancies. The incidence of malignant disease correlates directly with the extent of immunosuppression in patients with end-stage renal disease (ESRD) on dialysis, as well as after transplantation with life-long immunosuppressant therapy. In addition, also geographic factors seem to play a role in the differential incidence of tumors among different populations. For instance, the highest incidence of malignancies among immunosuppressed patients has been observed in Australia followed by the USA and Europe. This might be due to the high incidence of de novo skin cancer, which has been linked to the extent of UV exposure.     

Glycolate determination detects type I primary hyperoxaluria in dialysis patients

The detection of type I primary hyperoxaluria is based on the finding of exceedingly high oxalate excretion which is associated with increased glycolate excretion. The differential diagnosis of this disease may become a difficult task once end-stage renal disease (ESRD) and anuria have supervened. The various procedures thus far proposed to obviate this circumstance are complex, inaccurate or not reproducible. In this paper we propose the accurate liquid chromatographic determination of glycolate in blood and dialysate as a means to detect type I primary hyperoxaluria in patients on maintenance hemodialysis (RDT). The method is based on the enzymatic conversion of glycolate to glyoxylate coupled with alpha-keto acid derivatization with phenylhydrazine. The resulting phenylhydrazone is then resolved by high-performance liquid chromatograph (HPLC). With this method, plasma glycolate in 12 healthy controls was 7.8 +/- 1.7 mumol/liter, almost twentyfold less than previously reported. Five dialysis patients with high serum oxalate, of whom four with primary hyperoxaluria and one with Crohn's disease and presumed enteric oxalate hyperabsorption, were checked by this method and compared to nine patients with oxalosis-unrelated ESRD. The patients with hyperoxalemia were also evaluated for their response to pyridoxine therapy. The measurement of glycolate in blood drawn prior to and at the end of the dialysis session as well as in the dialysate soundly discriminated the patients with type I hyperoxaluria from all the other dialysis patients. Glycolate measurement was shown to be much more powerful than oxalate in that patients with oxalosis-induced ESRD exhibited an almost two hundred and fiftyfold increase compared to the oxalosis-unrelated patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

De novo membranoproliferative glomerulonephritis III in a renal transplant patient: case report and review of the literature

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare cause of renal failure with a cumulative incidence of 0.3% of all ESRD and 4% of all primary glomerulonephritis for types I and II. Membranoproliferative glomerulonephritis type III is more uncommon and idiopathic de novo MPGN III in a renal transplant patient has not been reported. We present the case of a 57-year old white female patient with a diagnosis of lithium toxicity as cause of end stage renal disease (ESRD) who developed MPGN III in her allograft 6 years after a renal transplant. Despite treatment, she progressed to ESRD within four and a half years from the time of diagnosis.     

Hyperphosphatemia in end-stage renal disease

Hyperphosphatemia occurs universally in end-stage renal disease (ESRD) unless efforts are made to prevent positive phosphate balance. Positive phosphate balance results from the loss of renal elimination of phosphate and continued obligatory intestinal absorption of dietary phosphate. Increased efflux of phosphate from bone because of excess parathyroid hormone-mediated bone resorption can also contribute to increased serum phosphate concentrations in the setting of severe hyperparathyroidism. It is important to treat hyperphosphatemia because it contributes to the pathogenesis of hyperparathyroidism, vascular calcifications, and increased cardiovascular mortality in ESRD patients. Attaining a neutral phosphate balance, which is the key to the management of hyperphosphatemia in ESRD, is a challenge. Control of phosphorus depends on its removal during dialysis and the limitation of gastrointestinal absorption by dietary phosphate restriction and chelation of phosphate. Knowledge of the quantitative aspects of phosphate balance is useful in optimizing our use of phosphate binders, dialysis frequency, and vitamin D sterols. The development of new phosphate binders and efforts to find new ways to inhibit gastrointestinal absorption of phosphate will lead to improvements in the control of serum phosphate levels in ESRD.     

Aluminum-related bone disease in mild and advanced renal failure: evidence for high prevalence and morbidity and studies on etiology and diagnosis

To study aluminum-related bone disease, bone biopsies and serum biochemical measurements were done in 97 patients on maintenance dialysis and in 100 patients with mild to moderate renal failure. Bone histology, histochemical staining for aluminum and determination of bone aluminum content were done. Stainable bone aluminum was found in 50% of dialyzed patients and in 5% of nondialyzed patients. The finding of stainable bone aluminum in dialyzed patients was associated with high morbidity and mortality; it was not only seen in most patients with low turnover osteomalacia, but also in 47% of patients with mixed uremic osteodystrophy and in 1 patient with predominant hyperparathyroid bone disease. Patients with stainable aluminum had lower bone mass and decreased activity of bone-forming and -resorbing cells. Cumulative doses of aluminum-containing phosphate binders were a major risk factor. Aluminum in drinking water represents an additional risk factor. Neither serum biochemical tests nor single infusion of deferoxamine could be employed as diagnostic tools. Bone biopsies were the only means for diagnosis.     

Immunization in End‐Stage Renal Disease: Opportunity to Improve Outcomes

Infection is the second most common cause of death in patients with end‐stage renal disease (ESRD), following cardiovascular causes. Immunization is a fairly simple, but underutilized, strategy for prevention of infectious morbidity and mortality in patients with kidney failure. It is imperative for nephrologists and primary care providers to have an understanding of immunization as an essential component of preventive healthcare measures in this high‐risk population. Patients with ESRD represent a unique population due to their immunosuppressed state, dialysis‐related exposures and suboptimal response to routine vaccines. While the Advisory Committee on Immunization Practices (ACIP) provides guidelines for vaccination of patients with renal disease against Hepatitis B, influenza and pneumococcal disease, the data on immunization against other commonly preventable infectious diseases are lacking. This article reviews the recent evidence on immunization in the ESRD population and synthesizes the related implications for maximizing prevention of infectious diseases in this high‐risk population.