Saulo Klahr

The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease

Background Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases. Methods In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients. Results The mean follow-up was 2.2 years. ...

The modification of diet in renal disease study.

For reasons that are unknown, chronic kidney failure of diverse causes tends to progress to end-stage renal disease. Several hypotheses have been advanced to explain the mechanisms by which renal i...

Metabolism in immunoreactive parathyroid hormone in the dog. The role of the kidney and the effects of chronic renal disease.

The role of the kidney in the metabolism of parathyroid hormone (PTH) was examined in the dog. Studies were performed in awake normal and uremic dogs after administration of bovine parathyroid hormone (b-PTH) or synthetic amino terminal tetratricontapeptide of b-PTH (syn b-PTH 1-34). The renal clearance of immunoreactive PTH was determined from the product of renal plasma flow and the percent extraction of PTH immunoreactivity by the kidney. Blood levels of circulating immunoreactive PTH were determined by radioimmunoassay. The normal dog kidney extracted 20 plus or minus 1% of the immunoreactive b-PTH delivered to it, and renal clearance (RC) of immunoreactivity was 60 ml/min. When RC was compared to an estimate of total metabolic clearance (MCR) of immunoreactivity, it accounted for 61% of the total. Both MCR and RC were markedly decreased in dogs with chronic renal disease. However, the percent extraction of immunoreactive PTH was unchanged in chronic renal disease, and the observed decrease in RC was due to changes in renal plasma flow. The largest portion of the reduction in total MCR was accounted for by the decrease in RC, and there was no compensation for the decrease in RC by extrarenal sites of PTH metabolism.

The Peripheral Metabolism of Parathyroid Hormone

AFTER the radioimmunoassay for parathyroid hormone (PTH) was introduced by Berson et al. in 1963,1 initial enthusiasm for its clinical application was tempered because widely differing results were...

Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-Dominant Polycystic Kidney Disease: The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Cohort

The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

Lovastatin Ameliorates the Development of Glomerulosclerosis and Uremia in Experimental Nephrotic Syndrome

The nephrotic syndrome was induced in uninephrectomized Sprague-Dawley rats using repeated injections of puromycin and protamine sulfate. Preliminary studies demonstrated that the administration of lovastatin (4 mg/kg body weight [BW] subcutaneously [SC] daily) was effective at lowering plasma cholesterol over a 63-day period, although not to normal values. Subsequently, two groups of rats that had been made nephrotic were studied; one group (n = 8) received lovastatin, the other (n = 9) received the vehicle alone. Blood and urine collections were made at days 0, 23, and 60. Clearance studies and renal histology were obtained at day 60. Lovastatin-treated rats had significantly lower cholesterol at day 23 and 60 than vehicle-treated rats (270.5 +/- 39.7 v 501.7 +/- 81.9 and 148.2 +/- 10.7 v 268.2 +/- 40.8 mg/dL, P less than 0.05). Both groups of rats developed equivalent degrees of proteinuria and hypoalbuminemia. At day 60, the lovastatin-treated rats had a lower urea: 18.3 +/- 4.1 v 55.8 +/- 9.6 mmol/L (blood urea nitrogen [BUN] 51.2 +/- 111.5 v 156.2 +/- 27.0 mg/dL, P less than 0.02) and greater unulin clearance (1.83 +/- 0.42 v 0.82 +/- 0.41 mL/min/kg BW, P less than 0.05) than the vehicle-treated rats. Neither group was hypertensive and the blood pressure (BP) was similar in both groups. The percentage of glomeruli showing no changes or minimal histological changes was significantly greater in the lovastatin-treated group (26.5% +/- 5.7% v 8.33% +/- 3.33%, P less than 0.02), and there were more glomeruli with global sclerosis in the vehicle-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired parathyroid hormone metabolism in patients with chronic renal failure.

SECONDARY hyperparathyroidism, with markedly elevated levels of circulating parathyroid hormone, is a universal complication of chronic renal failure.1 , 2 Increased secretion has been accepted as ...

Transforming Growth Factor-β Induces Renal Epithelial Jagged-1 Expression in Fibrotic Disease

For elucidation of the mechanisms by which growth factors and cytokines affect renal epithelial cells, gene array analysis of renal cells cultured in the presence of transforming growth factor-beta1 (TGF-beta1) was performed. Many genes that were not previously considered to be involved in renal cell biologic processes were affected, one of which was jagged-1. The jagged ligand/notch receptor family controls the formation of boundaries between groups of cells and regulates cell fates. On the basis of the array analysis, jagged-1 expression was further evaluated in cultured cells and in C57BL/6 mice with a model of unilateral ureteral obstruction (UUO). Recombinant human TGF-beta1 increased jagged-1 mRNA levels at concentrations between 10(-11) and 10(-10) M. There was a commensurate increase in jagged-1 protein levels, as assessed by Western blotting. The expression of jagged-1 mRNA and protein was observed to be significantly increased in the kidneys of C57BL/6 mice with obstructed ureters, compared with the contralateral kidneys, at 7 and 14 d of UUO. Immunohistochemical analyses demonstrated jagged-1 expression in distal tubules of kidneys from normal mice or contralateral kidneys from mice with UUO. Jagged-1 protein expression was increased in tubules not yet in apparent atrophy in the kidneys with an obstructed ureter. Jagged-1 expression was significantly increased in the kidneys of normal mice treated with TGF-beta1 and was decreased in the kidneys of mice with UUO treated with a TGF-beta receptor II-Fc chimera. These results suggest that jagged-1 is expressed in normal kidneys and that this expression is upregulated during renal disease, in a TGF-beta-dependent manner.

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.