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Few studies have examined tubular function after subtotal nephrectomy (Nx) and conservative treatments. The effects of 70% and 80% Nx (associated with dietary phosphate restriction in the latter case) on the apical brush border membrane (BBM) enzymes 5'-nucleotidase, gamma glutamyl-transferase and alkaline-phosphatase, and one BBM Na-phosphate cotransporter (NaPi-2) were studied in rats after a six week period. Changes in activity and mRNA abundance of the BBM enzymes and in NaPi-2 protein and mRNA abundance were compared with changes in the distal markers of Na,K-ATPase activity and epidermal growth factor (EGF) production. The activity, but not the mRNA of BBM enzymes, was moderately reduced by the 70% Nx. Both the mRNA and activity of gamma glutamyl-transferase and alkaline-phosphatase were decreased in the 80% Nx, and the NaPi-2 mRNA, protein and Na,K-ATPase activities were also reduced. These effects (except for 5'nucleotidase and Na,K-ATPase) were partly reversed by phosphate restriction. Overproduction of EGF occurred after the 70% Nx, was blunted in the 80% Nx, and then partially restored by phosphate restriction. Aggravation of tubular alteration was associated with enhanced renal hyperplasia (increased DNA mass), reduced GFR and hyperphosphatemia, and high PTH levels, but reduced cAMP excretion. Improvement following phosphate restriction was associated with reduced hyperplasia and lowering of phosphatemia and PTH levels. These data demonstrate that Nx selectively affected BBM function through transcriptional changes that were partially reversed by phosphate restriction. Regulatory factors involved in these changes may include intracellular phosphate content and growth factors, but not the PTH effects that are impaired in chronic renal failure.

Chronic metabolic acidosis (CMA) is a major cause of growth defect, implying disturbances of protein metabolism. Previously, in vivo studies performed in the fasting state showed enhanced whole body protein turnover, whereas in vitro studies showed unchanged muscle protein synthesis. The present study is the first to determine the effects of CMA on muscle protein synthesis and degradation in vivo. Two studies were performed in 60 g male rats fed a 30% casein diet. In study I, one group was sham-operated (C rats), and two groups underwent subtotal nephrectomy. One of them developed acidosis (UA rats) which was corrected in the other by NaHCO3 in the diet (UNA rats). Study II compared sham-operated rats rendered acidotic by NH4Cl in the drinking water (CA rats) and normal pair-fed (CNA) rats. Fractional protein synthesis rate (FSR) was determined in gastrocnemius muscle after injection of 3H-phenylalanine. Fractional protein degradation rate (FDR) was calculated as FSR minus fractional rate of muscle growth (FGR). In study I, UA rats had lower growth and N balance (163 +/- 12 vs. 216 +/- 11 mg N/day; P < 0.001) than UNA rats, despite identical food intake (11 g/day). This was associated with identical FSR (10.4 +/- 0.5 vs. 10.9 +/- 0.5%/day), but enhanced protein degradation (6.30 +/- 0.99 vs. 5.10 +/- 0.71%/day; P < 0.05). Plasma insulin, C peptide, PTH and corticosterone did not differ in UA and UNA rats, whereas plasma IGF-I was markedly reduced (147 +/- 21 vs. 283 +/- 27 ng/ml; P < 0.01) in UA rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin converting enzyme inhibitors (ACEI) are believed to protect remnant kidney, but all previous studies used the ligation model which causes severe hypertension, and very few have compared drugs in rats having similar control of blood pressure (BP). We compared rats with uremia obtained by 70% excision of total renal mass, a model which causes mild, late hypertension. Study I compared the effects of enalapril (E), cicletanine (C) and placebo (P) in uremic (U) rats fed a 0.50% (normal-high) Na diet. Study II compared the effects of E, C, P, and guanfacine (G) in U rats fed a diet restricted to 0.25% Na (normal-low). In study I, UP rats developed progressive hypertension (140, 146, 160 and 166 mm Hg at 3, 6, 9 and 12 weeks), proteinuria (240 mg/day at 9 and 12 weeks) which were not affected by E or C. The occurrence of end-stage renal disease (ESRD) led to the sacrifice of all rats after three months. All three groups had similar severe renal lesions (over 25% sclerosed glomeruli in 5 of 10 UP, 9 of 14 UE, 7 of 14 UC rats, with huge cystic tubular dilatations). In study II, rats could be sacrificed later (6 months) and had evidence of less severe renal disease. All the drugs tested prevented hypertension throughout the study (P less than 0.001), with lowest values in UE rats. E and G, but not C, reduced proteinuria. Renal damage was reduced with E and G, but not with C, despite similar BP in C and G rats. Thus, in contrast with what was obtained in the ligation model, ACEI affected neither the BP nor the renal lesions of rats made uremic by renal excision and fed a 0.50% Na diet. Moderate Na restriction improved the consequences of nephron loss and restored the anti-hypertensive effect of drugs. However, these drugs had a different effect on renal preservation: it was dramatic with E, good with G, and undetectable with C.

The renal effects of carbohydrates (CHO) were studied in two experiments. 1) The effects of CHO-energy restriction was evaluated by comparing uremic growing rats (initial weight: 80 g) fed "ad lib" (L rats) or CHO-restricted (starch and glucose) but receiving identical amounts of all other nutrients (R rats). R rats showed reduced growth, slower increase in plasma creatinine, lower mortality rate, and less histological renal damage than L rats. 2) Two types of CHO restriction, low glucose (R1 rats) or low starch (R2 rats) were compared to "ad lib" feeding (L1 rats) in adult rats (initial weight: 130 g). Growth was identically reduced in R1 and R2 rats. Mean plasma creatinine levels at week four was lower in R1 than in L1 rats. The overall rate mortality was higher for L1 and R2 than in R1 rats (79%, 81%, 53%) but included deaths from other causes than renal failure. Actuarial survival excluding these deaths was 27%, 83% and 10% in L1, R1 and R2 rats, respectively. Diffuse renal lesions were found in 25 of 30 L1, 5 of 15 R1, and 12 of 15 R2 rats (R1 vs. R1 and R2, P less than 0.01). The results show that CHO restriction may preserve the renal parenchyma, and suggest that restriction of "simple" rather than "complex" CHO restriction may be beneficial, a finding which could be of clinical importance if confirmed by further investigations.

High protein diet is known to increase glomerular filtration rate (GFR) and induce kidney hypertrophy. The mechanisms underlying these changes are not understood. Since the mammalian kidney comprises different nephron segments located in well-delineated zones, it is conceivable that the hypertrophy does not affect all kidney zones and all nephron segments uniformly. The present experiments were designed to study the chronic effects of high or low isocaloric protein diets (HP = 32% or LP = 10% casein, respectively) on kidney function and morphology in Sprague-Dawley rats. HP diet induced significant increases in kidney mass, GFR, free water clearance, and maximum urine concentrating ability. Kidney hypertrophy was characterized by: 1. a preferential increase in thickness of the inner stripe of the outer medulla (IS) (+54%, P less than 0.001, while total kidney height, from cortex to papillary tip, increased only by 18%); 2. a marked hypertrophy of the thick ascending limbs (TAL) in the inner stripe (+40% epithelium volume/unit tubular length, P less than 0.05) but not in the outer stripe nor in the cortex; 3. an increase in heterogeneity of glomeruli between superficial (S) and deep (D) nephrons (D/S = 1.47 in HP vs. 1.17 in LP, P less than 0.05). In contrast, normal kidney growth with age and kidney hypertrophy induced by uninephrectomy were not accompanied by preferential enlargement of IS structures. The morphologic changes induced by high protein intake parallel those we previously reported in rats fed a normal diet (25% protein) but in which the operation of the urine concentrating mechanism was chronically stimulated by ADH infusion or by reduction in water intake.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate the role of calorie and protein intake in growth impairment due to chronic renal failure (CRF), a subtotal nephrectomy was performed in weanling Wistar rats. A two-thirds reduction of renal function was obtained, which induced a marked growth retardation. Growth retardation was identical in nephrectomized and in pair-fed controls, and thus appeared to be entirely due to a deficient food intake. Using low protein diets, administration of a supplement with small amounts of essential amino acids (EAA) resulted in accelerated growth associated with a higher calorie intake, a better utilization of ingested calories for growth and a greater fall of blood urea nitrogen concentration.

The effects on growth, renal function, and survival of three isocaloric diets of various protein content (14, 27, and 37 g/100 g in diets I, II, and III, respectively) were compared in uremic rats and in controls. Diet I provided the minimal requirements in all amino acids for gorwing rats. In controls fed ad lib, weight and length gain were better with high protein diets, whereas they were inversely related to the diet protein content in uremic rats. The higher the protein intake, the higher the progressive elevation of BUN and serum creatinine and the mortality rate. Because proteins were supplied by fish flour, their increase was associated with increased mineral content, and the conclusions are restricted to the use of natural proteins: a moderately restricted protein diet securing only the minimal requirements had a beneficial effect on growth and survival of rats with reduced kidney mass. Avoiding any excess in proteins from the early stage of renal disease is suggested.