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Inulin clearance (CIn) was measured in the presence of varying degrees of renal excision (NX, 0-85% of renal mass by weight), in anesthetized rats fed on high-protein (HP, 30%), median-protein (MP, 10%), or low-protein (LP, 7%) diets, before and during amino acid (AA) infusion or before and after an intragastric protein load. CIn was higher in rats fed HP than in rats fed LP in controls (3.4 vs. 2.1 ml/min) and in rats with NX up to 70% after feeding for 3 wk (1.4 vs. 0.7 ml/min) or 4 days (1.5 vs. 1.1 ml/min). The difference decreased from 0% to 70% NX, and disappeared when NX exceeded 70%. Acute AA infusion and intragastric loads always increased CIn with wide individual variations. The increase was greater in rats fed HP than in rats fed MP and LP (+1.4 vs. 0.8 and 1.1 ml/min for 0% NX), diminished with greater NX (0.7 vs. 0.2 and 0.4 ml/min for 70% NX), and was very small for NX above 70%. However, when expressed as the percent of baseline values, the mean CIn increment after acute stimulation remained constant (30-45%), regardless of renal ablation and of diet. Thus preexisting hyperfiltration resulting from diet or from renal ablation does not suppress the glomerular response to an acute protein load, and acute loads afford no advantages over baseline glomerular filtration rate (GFR) measurements. By contrast, chronic protein feeding increases GFR only when nephron loss is not too severe.

Low-protein diets supplemented with keto-analogues and essential amino acid (KA-EAA) mixtures or with EAA have been widely used to retard renal deterioration without affecting nutrition. These assumptions have recently been challenged in clinical studies and rest on little or no experimental data. The effects of EAA and KA-EAA supplementations have not been compared. We compared three groups of rats with subtotal nephrectomy that were fed (1) a 16% casein reference (R) diet, (2) a 6% casein plus EAA (A) diet, or (3) a 6% casein plus KA-EAA (K) diet with KA as amino acid salts. The three diets had the same energy and mineral contents, and they induced comparable growth. The two supplements had the same nitrogen content. The only difference found until month 3 was higher proteinuria and plasma urea levels in group R rats. Renal biopsies performed at month 3 showed more severe glomerular sclerosis and tubular changes in R rats than in A and K rats. From months 3 through 7, R rats developed higher plasma creatinine levels than did A and K rats (final median values: 167, 106, and 83 mumol/L; p < 0.04), had more proteinuria (232, 56, and 84 mg/day), and showed greater mortality rates. At the time the rats were killed, 2 R, 6 A, and 5 K rats had survived while receiving the diets. Examination of the remnant kidneys, regardless of time of death, showed that renal lesions were significantly worse in R than in A and K rats, with sclerosis affecting more than 50% of the glomeruli in 7 of 13 R, 4 of 14 A, and 4 of 15 K rats, and less than 25% glomeruli in 2 of 13 R, 10 of 14 A, and 10 of 15 K rats (A and K vs R: p < 0.03). In conclusion, restriction of nonessential amino acids compensated by EAA or by KA-EAA mixtures retards renal damage without affecting growth, but no real benefit of KA or EAA has been observed.

The many published studies of experimental chronic renal failure (CRF) include a few findings which are similar to those reported in children with the naturally occurring disease. Experimental CRF has proved a useful model for investigating changes in eating behaviors: lack of appetite for sweet foods and selection of foods with high protein contents was comparable to behaviors exhibited by children. Optimal protein intake was found to be close to the minimum recommended intake for "optimal" growth (different from maximum growth in rats). Excessive protein intake had detrimental effects on renal function and growth with conventional dehydrated feeds, but water intake may have a greater impact than blood urea nitrogen and acidosis. A 50% reduction in protein intake with adequate amounts of essential amino acids ensured normal growth and slowed progression of renal lesions. Replacement of protein by mixtures of ketoanalogs was more likely to be responsible for growth failure; where similar growth rates were achieved, there was no evidence of a beneficial effect on renal lesions. Diets with high sucrose contents were poorly tolerated by CRF rats and were associated with fructose "intolerance" and reduced liver energy stores.

The nutritional effects of low-protein diets are difficult to assess in humans. Normal and uraemic growing rats were therefore fed: a moderately low-protein (12%) reference diet (diet R), two 5% casein diets, one supplemented with essential amino acids (AA) (diet A) and the other with their keto acids (diet K), and a 7% casein diet isonitrogenous with diet K (diet L). Appetite and growth of both uraemic and control rats were identical on diets R and A and were reduced on diets K and L. Stunting was prominent in rats fed diet L and more severe than in those on diet K. Diet K induced marked anorexia in controls. This effect was smaller in uraemic rats, which were all anorectic, regardless of the diet. Plasma essential AA were similar in rats on diets R and A but low in control rats fed diets L and K. In particular, diet K did not improve the branched-chain AA levels although it produced better growth than diet L. Plasma and muscle threonine were surprisingly elevated in rats on the semi-synthetic diets A and K, despite identical or lower consumptions. Regardless of the diet, uraemia resulted in unchanged or increased plasma essential AA, despite reduced appetite and stunting. Uraemia caused a marked rise in some non-essential AA. Muscle essential AA, except for threonine, were essentially unaltered and did not correlate with growth or uraemia.

Several experiments have shown that deterioration of renal parenchyma after reduction of functional mass is affected by the protein content of the diet. The respective role of proteins and that of other nutrients that vary with proteins were never clearly separated. Three groups of 9 uremic rats received diets differing exclusively in protein (casein) content, which was 8% (group 1), 16% (group 2), and 32% (group 3). Energy and minerals were maintained identical. Food intake was similar in groups 1 and 2 and was lower in group 3. Mortality rate remained closely related to protein intake. Of group 3 rats, 78% died within 10 weeks and 100% within 15 weeks. Of group 2 rats, 56% were dead at week 15, and 100% at week 30. Mortality occurred significantly later in group-1 rats fed the lowest protein diet. Histology of remnant kidneys showed severe glomerular and tubular damage, with no or little calcium deposits despite normal phosphorus diet and frequent hyperphosphatemia. These data suggest that protein intake, independent of any other nutrient, influences survival by accelerating the renal damage in rats with reduced kidney mass.

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.

Six infants, 4.5 to 19 months old, whose creatinine clearance was less than 6 ml/min/1.73 m2 received, successively, three low-nitrogen diets. Diet A contained 9.3 g of human milk protein; and diet B, 4.2 g of human milk protein plus synthetic essential amino acids. Diet C was the same as B except that five essential amino acids were replaced by alpha-keto and hydroxy analogs. Serum urea decreased as the infants were transferred from diet A to diets B and C, and the serum urea/creatinine ratio decreased from diet A to diet B and from diet B to diet C. Urea appearance was 14.8 +/- 4.5, 9.1 +/- 4.3, and 6.9 +/- 1.7 mmoles/day, with diets A, B, and C, respectively. Weight gain was also lowest with diet C, as was the difference between nitrogen intake and urea nitrogen appearance, an indicator of nitrogen balance. Plasma free amino acids were not modified by diets A and B, but valine, leucine, and the plasma free essential amino acid pool decreased significantly with diet C.

Several experiments have shown that deterioration of renal parenchyma after reduction of functional mass is affected by the protein content of the diet. The respective role of proteins and that of other nutrients particularly phosphorus which varies with proteins was never clearly separated. Three groups of 9 uremic rats U I, U II, U III, received three diets differing exclusively in their protein content, which was supplied by casein and was respectively 8%, 16% and 32%. Other nutrients were maintained identical, including energy and minerals. Food intake was similar in U I and U II rats and was lower in U III rats. Mortality rate remained closely related to protein intake. Of U III rats, 78% died within 10 weeks and 100% within 15 weeks. Of U II rats, 56% were dead at week 15, and 100% at week 30. Mortality occurred significantly later in U I rats fed the lowest protein diet. Histology of remnant kidneys showed severe glomerular and tubular damage, with no or little calcium deposits despite normal phosphorus diet and frequent hyperphosphoremia. In conclusion, protein intake influences survival by accelerating the renal damage in rats with reduced kidney mass independently of any other nutrient.