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Background: Although still controversial, several studies in humans have suggested That dietary protein restriction may slow the rate of progression of chronic renal failure. Thus, the influence of dietary protein on renal function and progression of renal failure has been the subject of numerous studies in several animal models of chronic renal failure, including rodents, dogs, and baboons. Because of the high incidence of chronic renal failure in aged cats, and the high dietary protein requirements of cats, we studied the effects of dietary protein intake on renal function, proteinuria, and renal morphology in cats with reduced renal mass., Experimental Design: Partial (5/6) nephrectomy was performed in 14 young adult female cats. Sham surgical procedures were performed in eight control cats. Control cats and cats with 5/6 nephrectomy were randomly assigned to diets containing either 27.6% (low) or 51.7% (high) protein and studied for 1 year., Results: Renal mass reduction by 5/6 decreased glomerular filtration rate by 2/3 and significantly increased proteinuria. Cats with remnant kidneys had significantly higher systolic and mean blood pressures than control cats. Increased dietary protein/calorie intake significantly increased glomerular filtration rate and proteinuria in all cats. Glomerular filtration rates remained stable in all cats over the year of study. However, high protein/calorie intake resulted in significant renal morphologic injury in remnant kidney cats that was prevented by dietary protein/calorie restriction. Light and electron microscopic glomerular changes in remnant kidney cats fed the high protein diet were similar to changes previously reported in rats and dogs with remnant kidneys., Conclusions: Dietary protein/calorie restriction limits proteinuria and glomerular injury in cats with remnant kidneys in a fashion similar to that reported in rats. However, the remnant kidney model in the cat appeared to be associated with a slower rate of progression compared with kidney model in the cat appeared to be associated with a slower rate of progression compared with rats.

Dietary protein provokes renal growth and synthesis of renin. Because angiotensin II (AII) has growth-promoting properties, we tested the possibility that protein-induced renal growth depends on angiotensin II. Normal adult male rats placed on a high-protein diet (50%) developed significant renal and glomerular growth over 6 days compared with rats on a low-protein diet (6%). However, neither angiotensin converting enzyme inhibition with enalapril nor angiotensin receptor antagonism with losartan influenced the degree of whole-kidney, cortical tubular, or glomerular growth. Thus, angiotensin II is not a necessary factor in dietary protein-induced renal growth in normal adult rats.

High dietary protein increases renin mRNA and likely contributes to the increased plasma renin activity (PRA) in the normal rat. In experimental renal ablation, dietary protein influences renal growth and injury. This study was undertaken to examine the effect of dietary protein on the renin-angiotensin system after reduction of renal mass. Male Sprague-Dawley rats were subjected to 1 1/3 nephrectomy (1 1/3 NX) and maintained for 7 days on a low-protein (6%) diet, at which time they were stratified according to serum creatinine to either continue on the low-protein diet or were switched to a high-protein (40%) diet. Two weeks after stratification renal renin mRNA was higher on the 40% compared with the 6% protein diet, angiotensinogen mRNA was lower in the high-protein group, and no change occurred in renal actin mRNA. The magnitude of this dietary protein-induced increase in renin mRNA with high-protein diet was greater in the 1 1/3 NX group compared with that observed in sham-operated rats (320 vs. 60%). PRA and tissue renin activity were also elevated on the high-protein diet after 1 1/3 NX. When three levels of dietary protein intake were examined after 1 1/3 NX, the high-protein (40%) diet was associated with increased renal renin mRNA compared with both the intermediate-protein (20%) and low-protein (6%) diets. In conclusion, a high-protein diet induced activation of the renin-angiotensin system. This activation may explain some of the detrimental effects of dietary protein on the course of chronic renal failure.

Dietary protein restriction reduces proteinuria and slows the progression of renal failure in a variety of renal diseases in native kidneys. Such beneficial effects may be mediated by the multiple renal effects of dietary protein including those on glomerular capillary hemodynamics and the renin-angiotensin system. The role of dietary protein restriction in the management of chronic renal transplant rejection is, however, unclear. This study was therefore undertaken to examine the effects of dietary protein restriction in patients with chronic rejection. Fourteen patients with biopsy proven chronic rejection, who had been on a self-selected home diet of 1.0 +/- 0.1 g protein/kg/day, were randomly assigned, using a crossover design to two 11-day periods, one on a low protein diet (0.55 g/kg/day) and the other on a high protein diet (2 g/kg/day). The effect of these diets on renal hemodynamics, proteinuria, plasma renin activity, and nutritional status was examined. The low protein diet was associated with a significant improvement in glomerular permselectivity in all patients as evidenced by a significant fall in the fractional clearance of albumin and IgG and reduction in 24-hour urinary excretion of total protein, albumin and IgG without any change in blood pressure, glomerular filtration rate, or renal plasma flow. Compared to the proteinuria at the beginning of each diet, a high protein diet did not increase but a low protein diet significantly decreased the proteinuria. The low protein diet was also associated with a significant reduction in plasma renin activity, suggesting that part of the beneficial effect of protein restriction was related to the suppression of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary protein restriction improves the course of renal disease in the remnant kidney model. Dietary protein restriction can also reduce plasma renin activity in several circumstances. We examined the interaction between dietary protein and the renin-angiotensin system in subtotally nephrectomized rats (1-2/3 nephrectomy). No difference was seen in tissue renin activity in rats ingesting a high (30%) versus a low (6%) protein diet. To determine the pathophysiological role of angiotensin II in subtotally nephrectomized rats, we examined the acute renal response to an intrarenal infusion of the angiotensin II antagonist Sar1 Gly8-angiotensin II (10 micrograms/kg/min). Only those subtotally nephrectomized animals ingesting a high protein diet exhibited a consistent improvement in glomerular permselectivity, as manifested by a 24% fall in the fractional clearance of albumin (basal 16.19 +/- 3.65 x 10(-4) vs. Sar1 Gly8-AII 12.26 +/- 3.21 x 10(-4); P less than 0.02) and a 19% fall in the fractional clearance of IgG (basal 3.75 +/- 0.67 x 10(-4) vs. Sar1 Gly8-AII 3.03 +/- 0.48 x 10(-4); P less than 0.02). No consistent change occurred in glomerular permselectivity in the rats on the low protein diet or rats infused with vehicle only. No change in mean arterial pressure or whole-kidney hemodynamics were seen with angiotensin II blockade. Decrements in SNGFR and glomerular capillary pressure occurred with angiotensin blockade in the animals ingesting the high protein diet, suggesting hemodynamic factors as a mechanism for the improvement in permselective defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive hormonal response to two levels of dietary protein intake was studied in seven healthy adult volunteers. The subjects were randomly placed on a 2-g.kg-1.day-1 (high) or 0.55-g.kg-1.day-1 (low) diet using a crossover design and were studied on the morning of the 5th day and again after 24 h of indomethacin treatment. Plasma renin activity (PRA), aldosterone, vasopressin, and urinary excretion of 6-ketoprostaglandin F1 alpha (PGF1 alpha) were significantly higher on the high-protein diet despite constancy of body weight, blood pressure, pulse, urinary sodium and potassium excretion, and plasma amino acid levels. After treatment with cyclooxygenase inhibitor indomethacin, 6-keto-PGF1 alpha excretion was equalized, but the elevated PRA and aldosterone levels persisted on the high-protein diet, suggesting that PRA and aldosterone elevations do not depend entirely on prostanoid release. We conclude that chronic augmentation of dietary protein intake is accompanied by alterations of vasoactive hormones, which persist for up to 10 h postprandially and are independent of elevated plasma amino acid levels. Such hormonal alterations may mediate some of the dietary protein-mediated changes in renal hemodynamics.

Plasma renin activity varies with the level of dietary protein, being higher on a high protein diet. To explore the molecular mechanisms underlying this relationship we first examined the effect of dietary protein on renin and angiotensinogen gene expression at the level of steady state mRNA in male Sprague-Dawley rats. Renal renin mRNA was higher on a 50% (high) compared to a 6% (low) protein diet both 3 d (9.4 +/- 1.1 vs. 5.3 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) and 21 d (6.8 +/- 1.0 vs. 3.5 +/- 0.4 pg/micrograms of total RNA; P less than 0.02) after dietary change. No change occurred in either renal or liver angiotensinogen mRNA. When three levels of dietary protein were examined, renal renin mRNA was elevated on a 50% and lowered on a 6% protein diet compared to a more standard 20% protein diet. Kidney weights and renal protein, RNA, and RNA/DNA increased with the level of dietary protein reflecting protein-induced renal hypertrophy. Uninephrectomy resulted in no change in renin mRNA compared to sham operation (3.7 +/- 0.1 vs. 3.4 +/- 0.1 pg/micrograms RNA; P = NS) despite renal growth in the uninephrectomy group implicating dietary protein and not hypertrophy as the major factor for stimulating renin mRNA. In conclusion, the level of dietary protein is a novel and specific stimulus for changes in renal renin mRNA. The increased plasma renin activity on a high protein diet is due at least in part to increased renin synthesis.

Dietary protein restriction imposed before renal injury is established in the remnant kidney model in the rat reduces glomerular hypertension and hyperperfusion and renal injury. We demonstrate that dietary protein restriction (6% vs. 20%) imposed on a background of established renal injury in the remnant model leads to a greater preservation of renal function as measured by glomerular filtration rate and fractional clearances of albumin and IgG, despite the persistence of systemic hypertension. In similarly prepared rats, dietary protein restriction (6% vs. 20%) led to a lower glomerular capillary hydraulic pressure, a higher ultrafiltration coefficient, and similar single nephron filtration rates. In addition, less impairment of glomerular permselectivity was demonstrable after protein restriction. Our data demonstrate that the preservation of renal function with dietary protein restriction after established glomerular injury follows upon reduction of glomerular capillary hydraulic pressure, despite constancy of single nephron filtration rate and plasma flow and persistence of arterial hypertension.

The effects of dietary protein on glomerular and hormonal function were studied in twelve adults with a variety of glomerular diseases. They were randomly assigned, using a crossover design, to two 11-day periods, one on a high-protein diet (2 g.kg-1.day-1) and the other on a low-protein diet (0.55 g.kg-1.day-1). Improvement in glomerular permselectivity on the low-protein diet was manifested by a decreased 24-h urinary excretion of total protein, albumin, and IgG by 33, 40, and 25%, respectively (all P less than 0.02); a fall in the fractional clearance of albumin (10.1 +/- 6.3 X 10(-3) to 5.8 +/- 3.3 X 10(-3)), and IgG (6.9 +/- 5.1 X 10(-3) to 3.5 +/- 2.3 X 10(-3)) (both P less than 0.02); and a decreased fractional clearance of neutral dextrans of molecular radii 48-56 A (P less than 0.05), when measured on the final day of each dietary period. The high-protein diet was accompanied by a higher plasma renin activity (6.9 +/- 1.6 vs. 3.5 +/- 0.8 ng angiotensin I.ml-1.h-1) (P less than 0.02), and increased excretion of prostaglandin E and 6-ketoprostaglandin F1 alpha. We conclude that a low-protein diet rapidly improves the size-selective defect in glomerular permselectivity.

The chronic effects of dietary protein on renal structure and function were studied in rats with normal and reduced renal mass. Control rats with two kidneys were compared with unilaterally nephrectomized rats, and with one and one-third nephrectomized rats obtained by unilateral nephrectomy and infarction of one-third of the remaining kidney. Rats at each level of renal mass were maintained on chow containing either 6% or 40% protein content. Separate cohorts of rats were studied four and eight months after ablation and institution of these dietary regimens. At both time intervals and at all levels of renal mass, rats fed the high protein diet had higher average values for GFR than comparable animals fed the low protein chow. Within each of the dietary regimens the animals with loss of renal mass developed greater prevalences of sclerotic glomeruli by eight months. Furthermore, at each level of initial renal mass, rats eating the high protein diet had a greater prevalence of sclerotic glomeruli than those on the low protein diet. Similarly, rats on the high protein diet had greater rates of protein excretion than those on the low protein diet at each degree of ablation. The prevalence of sclerosed glomeruli increased between four and eight months in each group. Thus, the extent of renal injury as manifested by proteinuria and glomerular sclerosis was directly related to the degree of initial loss of renal mass, and dietary protein restriction retarded these manifestations of injury across a wide range of initial renal mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular filtration rate (GFR) increases after a meat meal in several species. The mechanism of this phenomenon is unknown and the excretory and metabolic responses largely unexplored. We examined in humans the nature of the hemodynamic response to a meat meal, the role of salt and water load in this response, and the associated renal excretory responses. Ten normal volunteers were studied after eating an average of 3.5 g/kg body wt of lean cooked beef steak and, on a separate day, after ingesting an amount of sodium and water equivalent to that in the steak. Average GFR increased by 28% for the entire 3 h after the meat meal compared with the same time period after the control salt solution (90 +/- 8 vs. 114 +/- 6 ml X min-1 X 1.73 M-2, mean +/- SE, P less than 0.05) and by 15% compared with the base-line periods, although this difference was not of statistical significance. However, not all subjects demonstrated an increase, and in those eight who did the degree was variable from 5 to 46% for the 3-h mean above the basal value. During the hour of peak GFR, the increment was associated with a nearly proportional increase in renal plasma flow and renal blood flow (all P less than 0.05). The increase in renal blood flow was entirely due to a significant fall in renal vascular resistance. The vasodilation was not accompanied by any change in prostaglandin E excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of dietary protein on the renin-angiotensin system was studied in rats. Rats were fed isocaloric, 50% (high protein, HP), or 6% (low protein, LP) protein diets with identical electrolyte content for 10 days. Food intake and electrolyte excretion were equivalent on the two diets. Plasma renin activity (PRA) was higher in HP (10.0 +/- 2.5 vs. 3.5 +/- 0.5 ng ANG I . ml-1 . h-1, P less than 0.02) as was plasma aldosterone. However, in conscious rats mean arterial pressure (MAP) was not different between groups. The pressor response to graded doses of angiotensin II (ANG II) was diminished by 30-60% with HP (all doses, P less than 0.05). ANG II binding by mesenteric artery smooth muscle particles did not differ between HP and LP. Chronic administration of captopril did not normalize the pressor response in HP. Urinary prostaglandin (PG) E and 6-keto-PGF1 alpha excretion was markedly increased by the HP diet. Acute inhibition of prostaglandin synthesis with meclofenamate restored the pressor response to ANG II in HP to that in LP. In summary, a HP diet increased PRA, plasma aldosterone, urinary PGE, and 6-keto-PGF1 alpha and decreased pressor responsiveness to ANG II. Resistance to ANG II was not reversed by chronic converting enzyme inhibition but was abolished by inhibition of prostaglandin synthesis.

The response of erythropoietin to dietary protein was examined in nine subjects with a variety of glomerular diseases. They were randomly assigned by using a crossover design to two 11-day periods, one on a high-protein diet (2 gm/kg/day) and the other on a low-protein diet (0.55 gm/kg/day). The high-protein diet was associated with increased urinary erythropoietin excretion (4.28 +/- 0.84 U/24 hr vs 1.28 +/- 0.16 U/24/hr; p less than 0.05), increased serum erythropoietin concentration (22 +/- 2 mU/ml vs 10 +/- 2 mU/ml; p less than 0.05), and increased reticulocyte count (3.0 +/- 0.8 vs 1.6 +/- 0.4; p less than 0.05), demonstrating that erythropoietin production by the diseased kidney was still responsive to dietary protein manipulation. To examine whether changes in erythrocyte survival could be responsible for the differences in erythropoietin production, red cell survival was measured in two groups of subtotally nephrectomized rats, one group ingesting a high-protein diet (30%) and the other a low-protein diet (6%). No difference in erythrocyte survival rate was found. Reticulocyte counts were, however, elevated on the high-protein diet. We conclude that in the diseased kidney, a high-protein diet, perhaps by increasing renal O2 consumption, directly stimulates erythropoietin production.