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Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.
We describe the case of a 54-year-old man who first presented with a clinical syndrome manifested by recurrent pulmonary hemorrhage, hematuria, and mild renal insufficiency. Direct immunofluorescence of renal biopsy sections showed linear deposition of IgA-kappa in the glomerular (GBM) and tubular basement membranes. Serum protein immunoelectrophoresis was positive for a monoclonal immunoglobulin A (IgA)-kappa protein. Serum analysis showed circulating IgA anti-GBM antibodies. Treatment with high-dose steroids, cyclophosphamide, and plasma exchange resulted in resolution of the clinical picture. To the best of our knowledge, this is the first report of Goodpasture's disease associated with the presence of a circulating monoclonal IgA-kappa antibody.
Despite several decades of clinical experience, the mortality rate for patients with acute renal failure (ARF) requiring dialysis remains high, and the evaluation of the patients prognosis has been difficult. To date, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system has been used more frequently for prediction in studies of ARF than any other scoring system, but has not been prospectively validated in controlled multicenter studies of this entity. In a multicenter, prospective, controlled trial evaluating the use of biocompatible hemodialysis membranes (BCMs) in patients with ARF, we evaluated the extent to which the APACHE II scoring system, based on the physiological variables in the 24 hours before the onset of dialysis and the presence or absence of oliguria, is predictive of outcome. Analysis of survival and recovery of renal function for the 153 patients treated in this study show that APACHE II scores are predictive both of survival and recovery of renal function, whether analyzed separately by type of dialysis membrane used (BCM or bioincompatible [BICM]) or for both groups combined (all P < 0.01). There was no evidence of a significant center effect or interaction of APACHE II score with dialysis membrane in our study. After adjusting for the APACHE II score, there was a positive effect of the BCM on both probability of survival (P < 0.05) and recovery of renal function (P < 0.01). In patients dialyzed with BCMs, oliguria at onset of dialysis had an adverse effect on both survival and recovery of renal function (both P < 0.01). Receiver operator curves (ROCs) using APACHE II score and the use of BCMs in nonoliguric patients yielded a statistically significant improvement versus the use of APACHE II score alone in the area under the curve (AUC) for survival (0.747 to 0.801; P < 0.05) and recovery of renal function (0.712 to 0.775; P < 0.05). We conclude that the use of the APACHE II score determined at the time of initiation of dialysis for patients with ARF is a statistically significant predictor of patient survival and recovery of renal function. The use of the APACHE II score measured at the time of dialysis initiation, especially when modified by the presence or absence of oliguria, should help in predicting outcome when evaluating interventions for patients with ARF.
The role of the renin-angiotensin system (RAS) in the pathogenesis of cisplatin nephrotoxicity was evaluated in an experimental rat model using a specific, nonpeptide angiotensin II(AII) receptor blocker, losartan. Rats were treated with a single dose of losartan (at 10 mg/kg and 30 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/kg, i.p.). Renal function was assessed 3 and 7 days after cisplatin treatment. A second group of rats received losartan (10 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/kg, i.p.), and losartan (10 mg/kg, i.p.) or saline daily for 6 days after cisplatin treatment. Renal function was assessed on day 7. Neither high- nor low-dose losartan pretreatment prevented development of cisplatin-induced nephrotoxicity. Blood urea nitrogen (BUN) and plasma creatinine values at 7 days were similar to those of animals receiving cisplatin alone (BUN: 17.12 +/- 1.1 and 22.17 +/- 2.2 vs. 20.58 +/- 2.4 mg/dL; creatinine: 1.04 +/- 0.05 and 0.82 +/- 0.09 vs. 0.84 +/- 0.06 mg/dL). A significant reduction in creatinine clearance with cisplatin treatment was seen 3 days after therapy, which was not prevented by pretreatment with losartan (GFR in controls: 2.1 +/- 0.16 mL/min; cisplatin: 0.24 +/- 0.05; cisplatin plus low-dose losartan: 0.05 +/- 0.03 and cisplatin plus high-dose losartan: 0.37 +/- 0.05). All groups of cisplatin-treated rats displayed systemic signs of cisplatin toxicity: reduced food intake and body weight. Rats receiving chronic losartan treatment had more rapid weight gain and lower BUN and plasma creatinine levels on day 7 than rats receiving cisplatin alone (BUN: 24.0 +/- 2.64 vs. 36.4 +/- 0.91 mg/dL; p < 0.05; plasma creatinine: 0.86 +/- 0.06 vs. 1.15 +/- 0.07 mg/dL; p < 0.05). Acute blockade of the AII receptor with losartan does not alter the onset or severity of cisplatin nephrotoxicity. Chronic blockade of the AII receptor may improve the rate of recovery of renal function in cisplatin-treated rats.
The ability of a 13 amino-acid analog of atrial natriuretic peptide (ANP), A68828, to prevent development of cisplatin toxicity was evaluated in a rat model. ANP (1 microgram/kg/min), A68828 (10 micrograms/kg/min), A68828 (50 micrograms/kg/min), or peptide buffer was given as an intravenous infusion over 1 h beginning 15 min prior to an infusion of 5 mg/kg cisplatin. Animals receiving cisplatin plus peptide buffer vehicle developed predictable renal failure, with mean plasma creatinine and blood urea nitrogen concentrations of 1.09 +/- 0.09 mg/dL and 50.13 +/- 5.96 mg/dL, 72 h after treatment. ANP and A68828 (10 micrograms/kg/min) attenuated the increase in these indices of nephrotoxicity (mean plasma creatinine 0.86 +/- .06 mg/dL and 0.76 +/- 0.11 mg/dL, respectively). Surprisingly, the higher dose of A68828 (50 micrograms/kg/min) did not reduce cisplatin nephrotoxicity (72-h plasma creatinine 1.61 +/- 0.34 mg/dL). These results indicate that a short-term infusion of ANP or the analog A68828 can reduce the severity of cisplatin toxicity. At high doses of A68828 the beneficial effects of treatment may be lost.
Both functional and structural damage characterize nephrotoxicity due to cyclosporine (CsA) with accumulating evidence for dissociation of mechanisms that lead to each of these processes. We studied the role of endothelin (Et) and angiotensin II (AII), since each of these peptides can modulate vasoconstriction as well as parenchymal destruction. Salt-depleted rats were treated with daily CsA (15 mg/kg s.c.) for 5 weeks (group 1, CsA, n = 13). Separate groups of CsA-treated rats received either a combined antagonist of both EtA/EtB receptors (group 2, CsA+aEtA/B, 100 mg/kg/day p.o., n = 6) or angiotensin I-converting enzyme inhibitor (group 3, CsA+ACEI, enalapril 200 mg/L drinking water, n = 8). Glomerular filtration rate (GFR) was assessed by creatinine clearance (Ccr) in conscious rats at 3 and 5 weeks. At 3 weeks, serum creatinine was 1.5 +/- 0.1 mg/dl in group 1 rats, 1.2 +/- 0.2 mg/dl in group 2 rats (P < 0.05 vs. CsA), and 2.3 +/- 0.8 mg/dl in group 3 rats. Ccr was 0.87 +/- 0.08 ml/min in group 1. In group 2, GFR was remarkably preserved (1.14 +/- 0.11 ml/min, P < 0.05 vs. group 1). By contrast, GFR in group 3 rats was lower (0.31 +/- 0.08 ml/min) than either aEtA/B-treated or even CsA-treated rats (P < 0.0005 vs. group 1, P < 0.0005 vs. group 2). At 5 weeks, the same pattern emerged; serum creatinine was 2.5 +/- 0.2 mg/dl in group 1, 1.2 +/- 0.1 in group 2 (P < 0.0005 vs. CsA), and 3.4 +/- 0.9 in group 3 (P < 0.025 vs. CsA+aEtA/B). Ccr had decreased dramatically in CsA-treated rats to 0.18 +/- 0.03 ml/min. GFR was preserved in CsA+aEtA/B rats (0.51 +/- 0.03 ml/min, P < 0.0005 vs. group 1), while profound hypofiltration was apparent in CsA+ACEI rats (0.12 +/- 0.03 ml/min, P < 0.0005 vs. group 2). In salt-depleted control animals, GFR was 0.62 +/- 0.02 ml/min. Despite striking functional preservation in response to antagonism of Et receptors, tubular vacuolization/dilatation, as well as arteriolopathy, was not different among the CsA-treated groups. Tubulointerstitial fibrosis was also not different between CsA and CsA+aEtA/B rats (on a 0-4 scale, 1.05 +/- 0.14 vs. 0.87 +/- 0.14, P = NS). In contrast, both tubular vacuolization/dilatation and interstitial fibrosis were significantly greater in all CsA-treated groups compared with salt-depleted controls. However, in the CsA+ACEI group that had the most severe hypofiltration at each time point, tubulointerstitial fibrosis was 0.69 +/- 0.06 (P < 0.05 vs. CsA).(ABSTRACT TRUNCATED AT 400 WORDS)
Many models have been developed to study renal function following injury. Two types of studies have evolved: acute--to define the acute renal injury and chronic--to determine the pattern of recovery. Current models allow either study alone to be performed, but they lack the flexibility to combine the studies. In this study of renal ischemia, a model was designed which solved this problem. The authors constructed a model for performing a unilateral nephrectomy and episiotomy on female dogs. Catheters were placed in the renal vein, vena cava, and aorta, and a renal artery flow cuff was applied. The catheters and wires were buried in a subcutaneous pocket and were exteriorized after a recovery of several weeks. The episiotomy allowed easy intermittent Foley catheterization. With the animals awake and in a harness, parameters of renal function were measured: renal extraction, filtration fraction, fractional excretion, osmolar clearance, and free water clearance. Glomerular filtration rate and renal plasma flow were calculated by inulin and paramino hippurate clearances. The animals were studied in diuretic and antidiuretic states. In addition, renal artery flow was determined by the Doppler flow cuff. All parameters were determined every half hour in the acute setting, then every day in the chronic setting. The model was easily reproducible and functioned well in the authors' renal ischemia studies. Initial experiments with 1 hour of warm ischemia produced a greater than 50 per cent reduction in GFR acutely. Chronic studies showed a GFR with a return toward normal. All model construction purposes and plans were met.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the effect on the progression of glomerular sclerosis of two different experimental maneuvers, peritoneal dialysis and oral adsorbent, which remove circulating substances in different fashions. Munich-Wistar rats with established glomerular sclerosis, verified by renal biopsy analysis at seven weeks after subtotal nephrectomy, were treated for four weeks with either peritoneal dialysis (PD) or oral charcoal adsorbent (AST-120). Treatment was initiated at eight weeks. Rats were paired in treatment and control groups according to the similarity in the degree of sclerosis determined at biopsy with a minimum of 50 glomeruli analyzed. Systolic blood pressure and BUN and creatinine clearance, measured at seven to eight weeks, were not different among groups. In Group 2 rats, PD was performed with 1.5% dextrose for eight one-hour cycles, six days per week, while Group 1 control rats had zero indwelling time of the dialysate. Group 4 rats received AST-120, an oral adsorbent charcoal, mixed 5% by weight with standard rat chow and given ad libitum from 8 to 12 weeks after subtotal nephrectomy, while control Group 3 rats received only rat chow. Whole kidney GFR at 12 weeks was significantly higher in Group 2 PD versus Group 1 control (0.50 +/- 0.08 vs. 0.30 +/- 0.05 ml/min, P less than 0.05). There was no statistical difference for BUN and whole kidney creatinine or inulin clearance in Group 4 AST-120 treated versus Group 3 control rats. Light microscopic studies in autopsy specimens revealed that both PD and AST-120 attenuated progression of glomerular sclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)