An MTHFR variant, homocysteine, and cardiovascular comorbidity in renal disease.

BACKGROUND: It is unclear whether total serum homocysteine (tHcy) and the C677T mutation of methylenetetrahydrofolate reductase (MTHFR) are associated with cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). METHODS: A cross-sectional sample of 459 patients with ESRD on chronic dialysis was assessed to determine whether tHcy and the C677T mutation are associated with CVD prevalence in multiple logistic regression. As CVD mortality is high, we examined the relationship between homozygosity and duration of dialysis. RESULTS: Mean tHcy was higher in patients without a history of CVD (35.2 micromol/L vs. 30.4 micromol/L, P = 0.02). In multivariate models, CVD was negatively associated with tHcy and positively associated with TT genotype, male gender, and body mass index. Mean tHcy levels were higher among those with the TT genotype compared with those with the CC genotype when adjusted for age, folate, creatinine, and albumin (37.9 micromol/L vs. 31.9 micromol/L, P = 0.005). Among whites, the prevalence of the TT genotype was higher in those having undergone less than one year of dialysis (P = 0.002). CONCLUSIONS: The C677T genotype of MTHFR is associated with CVD in ESRD and may be a more meaningful marker than tHcy for abnormal homocysteine metabolism in ESRD. Prospective data from ongoing clinical trials are needed to improve our understanding of these findings. Screening for this polymorphism may help guide prevention measures.

Podocyte loss and progressive glomerular injury in type II diabetes.

Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.

The long-term course of cyclosporine-associated chronic nephropathy.

We evaluated a chronic renal injury in 37 cardiac transplant recipients treated for 12 to 24 months with cyclosporine (CsA). Twenty-four cardiac transplant recipients treated with azathioprine for more than 24 months served as controls. Despite equivalent cardiac performance, GFR in those treated with CsA was depressed, 47 +/- 3 versus 94 +/- 4 ml/min/1.73 m2 (P less than 0.001). CsA therapy was also associated with significant elevation of renal vascular resistance (RVR), proteinuria, arterial hypertension, and impaired intrarenal conversion of inactive prorenin to active renin. Histopathological changes associated with CsA included an obliterative arteriolopathy with deposition of proteinaceous material in necrotic arteriolar walls, and associated tubulointerstitial damage. A minority of glomeruli exhibited either ischemic collapse or sclerosis. Area perimeter analysis revealed enlargement of the remaining glomeruli with significant expansion of the mesangium. Longitudinal examination over a 48 month period (N = 15) during which CsA was reduced in dosage or withdrawn revealed persistent hypofiltration, increasingly elevated RVR and heavier proteinuria. Further histopathological deterioration was observed when renal tissue was sampled a second time in six patients, and three members of the experimental group developed end-stage renal disease. We conclude that continuous CsA therapy for more than 12 months causes a chronic injury to renal microvessels that is rarely reversible and potentially progressive.

Continuous ambulatory peritoneal dialysis. Technique of catheter insertion and management of associated surgical complications.

Fifty-seven patients initiated continuous ambulatory peritoneal dialysis. All patients were generally pleased with this form of dialysis and particularly enjoyed the greater mobility and decreased dietary restriction. Complications associated with continuous ambulatory peritoneal dialysis include peritonitis, pericatheter infection, catheter malfunction, dialysate leak, and hernias of the abdominal wall.

The long-term clinical course of systemic lupus erythematosus in end-stage renal disease.

In an attempt to define the long-term clinical course of systemic lupus erythematosus followed by end-stage renal disease, we studied 28 patients with lupus nephritis at Stanford University between January 1969 and December 1980. The clinical and serologic manifestations of both renal and nonrenal disease improved with long-term hemodialysis despite the withdrawal of immunosuppressive drugs in almost all the patients. Rehabilitation was excellent, and a return to normal physical activity was generally the rule. The mortality rate was low (6 of the 28 patients died), but death occurred primarily in patients receiving high doses of prednisone. Recovery from renal failure and discontinuation of dialysis were not rare (eight patients recovered) despite the reduction in immunosuppressive drugs. Renal transplantation was also well tolerated. We found the long-term clinical course of these patients to be comparable to that of patients with end-stage renal disease associated with disorders other than systemic lupus erythematosus.

Interrelationships of sodium transport and carbon dioxide production by the toad bladder: response to changes in mucosal sodium concentration, to vasopressin and to availability of metabolic substrate.

Active sodium transport and CO2 production were measured simultaneously in toad bladders mounted in membrane chambers. The rate of sodium transport was varied by changing the concentration of sodium in the mucosal bath (substitution with choline), by adding vasopressin, by adding metabolic substrates and by adding malonate, and the ratio of the change of sodium transport and CO2 production was determined Mean values for deltaNa/deltaCO2 (equiv/mole) were: Na in equilibrium choline 18.3 +/- 1.1; vasopressin 15.5 +/- 2.8; and pyruvate (corrected for the increment in "nontransport" CO2) 15.4 +/- 3.5. Based on previously determined values for the respiratory quotient (R.Q.), calculated mean values for deltaNa/deltaO2 ranged between 15.5 and 18.5 equiv/mole. It appears that basal metabolism does not contribute to metabolism supporting sodium transport when the rate of sodium transport is varied. "Transport" metabolism appears much more responsive to changes in the availability of endogenous and exogenous substrates than does "nontransport" metabolism. We conclude that "transport" and "nontransport" metabolism are functionally separated in the toad bladder.

Clearance of gentamicin during hemodialysis: comparison of four artificial kidneys.

The effects of four types of artificial kidney on dialyzer clearance rates and serum pharmacokinetics of gentamicin were compared. In 19 patients undergoing chronic hemodialysis, the mean (+/-SE) interdialysis half-life of gentamicin in serum was 49.3 +/- 3.5 hr, whereas during dialysis this value was reduced to 10.0 +/- 0.7 hr. The mean half-life of gentamicin in serum at conventional flow rates for the Hollow Fiber Kidney, Kiil, Gambro, and Coil dialyzers was 11.3, 10.9, 8.2, and 7.4 hr, respectively, and the mean values for clearance of gentamicin were 26,28,42, and 48 ml per min, respectively. For all dialyzers, rates of clearance of gentamicin increased linearly with plasma flow rate over the flow range studied. The Gambro and Coil dialyzers had significantly higher rates of clearance of gentamicin from serum (P less than 0.05) than the Hollow Fiber Kidney and Kiil dialyzers over a wide range of clinically useful plasma flow rates (119-300 ml per min), whereas the Kiil dialyzer cleared gentamicin more effectively (P less than 0.05) than the Hollow Fiber Kidney dialyzer over a more limited interval (117-177 ml per min). Therapeutic recommendations for patients undergoing hemodialysis were made in light of current findings.

Acute renal cortical necrosis. Variable course and changing prognosis.

Three cases of acute bilateral renal cortical necrosis, each with a different clinical course, are discussed. One patient spontaneously recovered renal function after prolonged oliguria. This case should be added to the small number of similar case reports in the literature. The second patient recovered adequate renal function temporarily, but eventually required chronic hemodialysis and renal transplantation. There was pathological evidence of progression from focal to massive cortical necrosis. The third patient never regained renal function, but is well after dialysis and transplantation. The influence of modern theories of pathogenesis of the disease, and increased availability of dialysis, are discussed in relation to the initial prognostic assessment of the patient with cortical necrosis.