Osmolar regulation of endothelin signaling in rat renal medullary interstitial cells.

We tested the hypothesis that endothelin (ET) responsiveness in the renal medulla is modulated by ambient osmolarity. Cultured renal medullary interstitial cells (RMICs) were incubated from 3 to 24 h in isosmolar culture medium (300 mOsm/kg H2O) or media rendered hyperosmolar (600 mOsm/kg H2O) by the addition of urea. Under hyperosmolar conditions, the peak of ET-evoked Ca2+ transient was blunted by 45-58% (P < 0.02) and PGE2 accumulation decreased from 16- to 2-fold above basal values (P < 0.001). To explore whether hyperosmolar conditions blunt intracellular signaling via modulation of receptor number or expression, kinetics of ET binding and Northern blot analysis of ETA receptor mRNA was performed. Under hyperosmolar conditions, ETA receptor density was reduced by 84% versus isosmolar conditions (238 +/- 12 vs. 1450 +/- 184 fmol/mg) (P < 0.01). In contrast to the ligand binding studies, ETA receptor mRNA was increased by 58% (P < 0.05) in cells grown under hyperosmolar versus isosmolar media. These observations indicate that in the hyperosmolar setting, ET-evoked intracellular signaling is blunted in RMICs due to ET receptor downregulation. Since ETA receptor mRNA is increased under hyperosmolar conditions, we conclude that ET receptor downregulation is the consequence of either decreased translation of message, increased degradation of receptor peptide, or increased internalization of specific receptor sites.

Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance.

The aim of this study was to determine whether angiotensin receptor subtypes play a role in angiotensin clearance from plasma. Angiotensin metabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes, and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearance rate by > 50% at low-dose infusion, suggesting that type 1 angiotensin II receptors are involved in angiotensin II clearance from plasma. At higher angiotensin infusion rates, the-metabolic clearance rate of angiotensin was unaffected. To dissect the contribution of renin-generated angiotensin, additional experiments were performed in nephrectomized rats. In anephric rats, angiotensin clearance was unaffected by type 1 angiotensin II receptor inhibition. In contrast, the type 2 angiotensin II receptor ligand PD123319 in intact rats caused a > 50% increase in metabolic clearance rate of angiotensin at higher infusion rates (P < .05). In anephric rats, the type 2 angiotensin II receptor ligand alone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T1/2 for angiotensin disappearance. These data argue against a role for type 1 or 2 angiotensin II receptors as clearance receptors. Increased clearance of angiotensin by type 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 ligands may alter angiotensin effects.

The impact of co-morbid risk factors at the start of dialysis upon the survival of ESRD patients.

By using a computerized database, we have catalogued the presence of 29 co-morbid risk factors in 683 patients with end-stage renal disease who started dialysis from 1970 through 1989, with follow-up through 1992. The authors hypothesized that current end-stage renal disease patients have more serious co-morbid risk factors impacting upon their mortality rate. Quantitation of dialysis patient co-morbidity, as a measure of patient illness, is lacking in the general nephrology literature. Seven co-morbid risk factors have been reserved for new dialysis patients: hypertension, low albumin, cerebral vascular disease, peripheral vascular disease, pre-existing cardiac disease, abnormal EKG/old myocardial infarction, and congestive heart failure. Except for low serum albumin, the proportion of patients with the six other co-morbid risk factors has increased significantly over this 20-year period (p < 0.0001, chi-square test for hypertension, peripheral vascular disease, pre-existing cardiac disease, abnormal EKG/old myocardial infarction, and congestive heart failure, and p < 0.006 for cerebral vascular disease). In addition, the co-morbid risk factors of hypertension, low serum albumin, and pre-existing cardiac disease at the start of dialysis were strongly prognostic of survival. The Cox proportional hazards regression model identified these three risks, among other factors, that were significantly associated with a decreased survival, with risk ratios ranging from 1.40-1.66. These results support the authors' hypothesis that incoming end-stage renal disease patients, who recently start dialysis, are sicker than in the earlier years of the authors' program. If the authors' patients reflect the national end-stage renal disease population, the presence of co-morbid risk factors may, in part, explain the continuing high mortality of dialysis patients.

Angiotensin responsiveness in hyperfiltering and nonhyperfiltering diabetic rats.

Renal and systemic responses to angiotensin II were studied in hyperglycemic diabetic rats (streptozotocin, 60 mg/kg, i.v.) and vehicle-injected controls at 24 h, 1 wk, 2 mo, or at 6 to 12 mo. In normal rats, the GFR was less than 0.80 mL/min per 100 g body wt (0.57 +/- 0.02 mL/min per 100 g body wt; range: 0.40 to 0.79 mL/min per 100 g body wt; N = 45). Hyperfiltration (GFR > or = 0.80 mL/min per 100 g body wt) was observed in all diabetic rats studied at 1 wk (GFR, 1.03 +/- 0.07 mL/min per 100 g body wt; N = 5; P < 0.001 versus control). However, at earlier and later times, GFR was elevated in only 8 of 18 of the diabetic rats (44%), with an overall prevalence of 56% (13 of 23). Mean arterial pressure, plasma glucose, urine volume, and filtration fraction were not different in hyperfiltering diabetic rats compared with nonhyperfiltering diabetic rats or normal controls. Angiotensin II (12.5 ng/kg per minute i.v.) had no effect on GFR in normal rats or nonhyperfiltering diabetic rats, but it normalized GFR in hyperfiltering diabetic rats (0.74 +/- 0.05 mL/min per 100 g body wt). In contrast with the renal effects of angiotensin II, blood pressure responses were similar in hyperfiltering and nonhyperfiltering diabetic rats. The findings that angiotensin II infusion caused a greater fall in GFR in hyperfiltering diabetic rats than in nonhyperfiltering diabetic rats, but that blood pressure responses were similar, suggests a localized abnormality in angiotensin responsiveness in the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Minimal change nephropathy associated with sclerosing mesenteritis.

A 65-year-old man with sclerosing mesenteritis developed the nephrotic syndrome. Percutaneous renal biopsy revealed classical histologic findings of minimal change nephropathy with a mild interstitial nephritis. Immunomodulation with prednisone led to a rapid and complete remission of the proteinuria but did not alter the course of the underlying sclerosing mesenteritis. The association of lymphomatous and nonlymphomatous neoplasms with minimal change nephropathy has been well-described. Our review of the literature indicates a parallel association of malignant lymphoma with sclerosing mesenteritis and a variety of disorders that constitute a spectrum of disease. The occurrence of this histopathologic form of renal injury and therapeutic response in the setting of a known lymphoreticular disorder suggests a role for a generalized alteration in cell-mediated immunity and not a tumor-induced elaboration of a factor(s) that directly damages the glomerular filtration barrier.

Comparison of methods for measuring albumin in peritoneal dialysis and hemodialysis patients.

Serum albumin levels have been used extensively as an indicator of morbidity in patients with end-stage renal disease. Recent evidence suggests that albumin levels vary considerably in hemodialysis patients depending on the laboratory method used, but formulas for comparing albumin values by different methods have not been developed. We prospectively evaluated the effects of measuring albumin by three different methods on paired plasma and serum from 23 patients on continuous ambulatory peritoneal dialysis (CAPD) and 53 patients on chronic maintenance hemodialysis. Plasma and serum gave virtually identical results independent of method used. In CAPD patients, bromcresol green and nephelometry gave nearly identical albumin measurements through the entire range of plasma levels. In contrast, bromcresol purple gave values that were 9.9 percent +/- 1.3 percent lower (P < 0.05). Hemodialysis patients showed a similar pattern with close agreement between bromcresol green and nephelometry, but bromcresol purple gave lower albumin levels by 19.1 percent +/- 1.2 percent (P < 0.05). The discrepancy in albumin in CAPD patients was significantly less than in the hemodialysis patients (P < 0.05), suggesting that there were fewer interfering substances in the blood of CAPD patients than in hemodialysis patients. Linear regression analysis was used to develop simple formulas for comparing albumin values obtained by the different methods in CAPD and hemodialysis patients. These studies show that values for albumin in blood vary significantly by method of analysis in CAPD and hemodialysis patients. By the use of these formulas, it becomes possible to compare albumin values between centers using different methods for the purpose of quality management.

Home hemodialysis: patient outcomes during a 24-year period of time from 1970 through 1993.

In the United States, from 1983 to 1993, home hemodialysis use has decreased from 6% to 1.3% of the dialysis population, whereas continuous ambulatory peritoneal dialysis (CAPD) has increased to 20%. Most home hemodialysis programs have withered away because of current patient mix, increase in CAPD, proliferation of outpatient centers, disinterest in nephrologists, and fear of self-cannulation by patients. From 1970 through 1993, 896 patients began dialysis at North Shore and were followed up through 1994. During this period, 687 patients were on in-center hemodialysis, 95 on CAPD, 74 on home hemodialysis, and 40 on in-center peritoneal dialysis. The home hemodialysis patients were younger, with a median age of 44 versus 59 years for in-center hemodialysis patients, and had less comorbidity. The home hemodialysis group had fewer diabetic patients and no renal vascular patients. The 5-year and median survival estimates were significantly better for the home hemodialysis patients versus other dialysis modalities. More home hemodialysis patients received transplants. Compared with the other dialysis modalities, home hemodialysis patients showed significantly improved survival rates. When matched by age, sex, and end-stage renal disease (ESRD) diagnosis to corresponding in-center hemodialysis, the home hemodialysis patients still had significantly better survival rates, but the home hemodialysis patients had less comorbidity. In conclusion, home hemodialysis patients survive longer and have better rehabilitation than other dialysis patients. Reasons for better survival in addition to a younger age and more favorable ESRD diagnosis may include less comorbidity, more patient involvement, and longer dialysis time. Because of these better outcomes, home hemodialysis should be offered to more ESRD patients.