Hostetter TH, Meyer TW, Rennke HG, Brenner BM
Kidney Int 1986 Oct;30(4):509-517

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.

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Provoost AP, De Keijzer MH, Molenaar JC Department of Pediatric Surgery, Erasmus University, Rotterdam, The Netherlands.
J Urol 1990 Aug;144(2 Pt 2):567-573

Changes in renal function were followed lifelong in male rats with only 1 kidney either intact or damaged by ureteral obstruction or ischemia. After surgery the rats were given a low (12%) or a high (36%) protein diet. After a period with a stable glomerular filtration rate, which was longer on the low protein diet, there was a linear decline in rats with an intact single kidney. The rate of decline was highest on the high protein diet, resulting in a shorter survival time. A decrease in urine osmolality and an increase in protein excretion preceded the decrease in filtration rate, while it was followed by an increase in blood pressure. The glomerular filtration rate of the rats with a single damaged kidney initially recovered to 75 to 80% of that of rats with an intact single kidney on the same diet. There was a linear decrease in the glomerular filtration rate, with the highest rate of decrease on the high protein diet. The mean survival time was less than that of rats with a single intact kidney. Proteinuria preceded the decrease in filtration rate, while hypertension was observed later. We conclude that in rats with a solitary kidney renal failure eventually develops. A low protein diet postpones and attenuates this development but it does not prevent it.

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Robertson JL, Goldschmidt M, Kronfeld DS, Tomaszewski JE, Hill GS, Bovee KC
Kidney Int 1986 Feb;29(2):511-519

It has been proposed that ingestion of large amounts of dietary protein leads to sustained renal hyperperfusion and progressive glomerulosclerosis in rats. This hypothesis was tested in dogs, with 75% reduction in renal mass, maintained for 4 years on either 56, 27, or 19% dietary protein. Twelve of 21 dogs survived 4 years, and death due to renal failure was not correlated to diet. Dogs fed 56 and 27% protein had increased GFR and CPAH before and after reduction of renal mass compared to the 19% group. A pattern of deterioration of renal function, including proteinuria, was not found in any diet group. Nine of 11 dogs, fed 56, 27, or 19% protein had minimal glomerular lesions, including mesangial proliferation, GBM irregularities, adhesions, and sclerosis. Two other dogs, fed 56% protein, had more severe glomerular lesions. No significant ultrastructural differences were found in glomeruli among the three diet groups. These results do not support the hypothesis that high protein feeding had a significant adverse effect on either renal function of morphology in dogs with 75% nephrectomy.

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Adams LG, Polzin DJ, Osborne CA, O'Brien TD, Hostetter TH Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul.
Lab Invest 1994 Mar;70(3):347-357

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.

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Wiegmann TB, Zlomke AM, MacDougall ML, Kipp DE Kidney and Urology Research Center, Kansas City, KS.
Am J Kidney Dis 1990 Feb;15(2):147-154

The effect on renal function (creatinine clearance [Ccreat] and inulin clearance [Cinulin]) of changes in chronic dietary protein intake was studied in seven healthy male subjects. Serial 24-hour urine collections were used to determine creatinine excretion (UcreatV) and Ccreat. Subjects were examined after ad libitum (ad lib) food intake and after 2-week periods of high protein diet ([HPD] 1.6 g/kg body weight [BW] per day) and low protein diet ([LPD] 0.5 g/kg BW per day). Inulin clearance (Cinulin) was determined at the end of each 2-week diet period. UcreatV increased from 1,838.8 +/- 97.2 mumol/kg (20.8 +/- 1.1 mg/kg) BW to 2,068.6 +/- 106.1 mumol/kg (23.4 +/- 1.2 mg/kg) BW daily during HPD and decreased significantly to 1,555.9 +/- 167.9 mumol/kg BW per day (17.6 +/- 1.9 mg/kg BW per day) with beginning of LPD. Ccreat rose from 1.54 +/- 0.09 mL/s 1.73 m2 (92.5 +/- 5.5 mL/s.1.73 m2 (104.7 +/- 4.9 mL/min/1.73 m2) during HPD and decreased to 1.23 +/- 0.04 mL/s.1.73 m2 (74.0 +/- 2.2 mL/min/1.73 m2) with initiation of LPD. There was no difference between Cinulin after HPD (1.42 +/- 0.12 mL/s.1.73 m2; 84.9 +/- 7.2 mL/min/1.73 m2) and after LPD (1.36 +/- 0.05 mL/s.1.73 m2; 81.4 +/- 2.9 mL/min/1.73 m2). This study confirms the effect of protein intake on Ccreat and UcreatV, but fails to show an effect of changes in chronic protein intake on glomerular filtration rate (GFR). Ccreat during dietary protein restriction to 0.5 g/kg/d is similar to Cinulin and may be a useful measure of GFR under circumstances where more specific inulin or isotope studies are not available.

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Blum M, Averbuch M, Wolman Y, Aviram A Department of Nephrology, Rokach Hospital, Tel Aviv, Israel.
Arch Intern Med 1989 Jan;149(1):211-212

The effect of dietary protein on kidney function expressed by creatinine clearance was studied in healthy subjects following a "normal" unrestricted protein diet and compared with a group of vegetarians maintained on a long-term low-protein diet. Both groups had similar kidney function and displayed the same rate of progressive deterioration in renal function with age. These results suggest that, in contrast with the important therapeutic effect of low-protein intake on the progressive deterioration of kidney function in diseased kidneys, such a diet does not significantly affect kidney function with "normal aging" in healthy subjects.

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Brandle E, Sieberth HG, Hautmann RE Department of Urology, University of Ulm, Germany.
Eur J Clin Nutr 1996 Nov;50(11):734-740

OBJECTIVE: Relatively little is known about the influence of chronic oral protein intake on the kidney function. In most studies only the effect of a short-term change in protein intake [6-28 days] or the effect of an acute protein load on the glomerular filtration rate was studied. The purpose of this study was to investigate the effect of chronic oral protein intake on endogenous creatinine clearance and on the albumin excretion rate. DESIGN AND SUBJECTS: In a prospective study 88 healthy volunteers with normal renal function (32 vegetarians, 12 body-builders with no supplementary protein concentrates, 28 body-builders with supplementary protein concentrates and 16 subjects with no special diet) were examined. In order to investigate the effect of chronic oral protein intake, the participants were on their diet for at least 4 months. RESULTS: Endogenous creatinine clearance as a measure for glomerular filtration rate varied between 32 ml/min and 197 ml/min or 34 and 186 ml/min x 1.73 m2, respectively. Nitrogen excretion rate was used as a measure for the daily protein intake, since it is known to correlate linearly with the daily protein intake. Nitrogen excretion rates ranged between 2.66 g/d and 33.93 g/d reflecting a daily protein consumption between 17 and 212 g/d or 0.29 g/kg bw/d and 2.6 g/kg bw/day, respectively. Between nitrogen excretion rate and endogenous creatinine clearance a non linear, highly significant correlation was found showing a saturation with a maximum endogenous creatinine clearance of 181.7 ml/min (dose response curve). A similar correlation was observed between urea excretion rate and endogenous creatinine clearance. Using a model for multiple regression analysis the dependence of the albumin excretion rate on nitrogen excretion rate and endogenous creatinine clearance was examined. Only a significant correlation was found between albumin excretion rate and endogenous creatinine clearance, while the correlation between albumin excretion rate and nitrogen excretion rate was not significant. CONCLUSION: This investigation shows that chronic oral protein intake of widely varying amounts of protein is a crucial control variable for the glomerular filtration rate in subjects with healthy kidneys. It is suggested that these changes reflect in part structural changes of the glomerulus and tubules due to chronic protein intake.

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Manz F, Remer T, Decher-Spliethoff E, Hohler M, Kersting M, Kunz C, Lausen B. Forschungsinstitut fur Kinderernahrung, Dortmund.
Ernahrungswiss 1995 Mar;34(1):10-15

Bodybuilders often prefer a high protein diet to achieve maximum skeletal muscle hypertrophy. In this study the effect of a high protein diet on renal acid load and renal handling of proton excretion was studied comparing dietary intake and urinary ionograms in 37 male bodybuilders and 20 young male adults. Energy intake (+ 7%), protein intake (128 vs 88 g/d/1.73 m2), and renal net acid excretion (95 vs 64 mmol/d/1.73 m2) were higher in the bodybuilders than in the controls, however, urine-pH was only slightly lower (5.83 vs 6.12). In the bodybuilders renal ammonium excretion was higher at any given value of urine pH than in the controls. In a regression analysis protein intake proved to be an independent factor modulating the ratio between urine-pH and renal ammonium excretion. The concomitant increase of renal net acid excretion and maximum renal acid excretion capacity in periods of high protein intake appears to be a highly effective response of the kidney to a specific food intake leaving a large renal surplus capacity for an additional renal acid load.

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Reyes AA, Klahr S Department of Medicine, Washington University School of Medicine at Jewish Hospital of St. Louis, Missouri 63110.
Proc Soc Exp Biol Med 1994 Jun;206(2):157-161

Ingestion of a high-protein diet or intravenous administration of amino acids is associated with an increase in glomerular filtration rate (GFR). It can also lead to renal hypertrophy, and, if sustained, may cause glomerular sclerosis. L-Arginine administration ameliorates the progression of renal disease in rats with subtotal nephrectomy and prevents the increase in GFR observed in rats with experimental diabetes. The present study examines the potential effect(s) of L-arginine administration (1%) in the drinking water on the renal hypertrophy that occurs in rats fed a high-protein diet for 1 month. Four groups of female Sprague-Dawley rats, six in each group, were studied (95 +/- 1 g). Groups 1 and 2 were fed a low-protein diet (12% casein, 0.504% L-arginine); Group 1 was given tap water, whereas Group 2 was given tap water supplemented with L-arginine. Groups 3 and 4 were fed a high-protein diet (40% casein, 1.68% L-arginine); Group 3 was given tap water, whereas Group 4 was given tap water supplemented with L-arginine. The rats had free access to food and water during the study period. The kidney weight and the kidney to body weight ratio of rats of Group 3 were significantly greater than in the other groups of rats. Renal hypertrophy was prevented in the rats of Group 4. The excretion of orotic acid in the urine, an index of L-arginine deficiency, was significantly greater in rats of Group 3 than in rats of Group 4. Thus, the renal hypertrophy that occurs in rats fed a high-protein diet was decreased in rats given L-arginine supplementation in the drinking water. This effect was associated with less excretion of orotic acid in the urine in rats given L-arginine. A relative deficiency of L-arginine may occur during high-protein feeding that may shunt nitrogen metabolism from the urea cycle to the orotic acid pathway.

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Shigematsu T, Caverzasio J, Bonjour JP Department of Medicine, University Hospital of Geneva, Switzerland.
Kidney Int 1993 Jul;44(1):173-181

The influence of PTH in the progression of renal failure induced by a high protein diet was investigated in either sham operated (SHAM) or parathyroidectomized (PTX) and subtotally nephrectomized (NX) rats. NX-SHAM rats were pair-fed either a high (HPr, 40% casein) or a normal (NPr, 20% casein) protein diet and NX-PTX rats a HPr diet. The results indicate that PTX markedly improved the survival rate and prevented the deterioration of renal function induced by the HPr diet. The number of rats alive after 33 weeks was 0 of 11, 6 of 10, and 9 of 10 in NX-SHAM-HPr, NX-PTX-HPr and NX-SHAM-NPr, respectively. The increases in plasma urea and creatinine were consistently delayed or prevented in NX-PTX as compared to NX-SHAM rats fed the HPr diet. The increment in the mass and calcium content of the kidney remnant induced by HPr was prevented by parathyroidectomy. In addition, PTX completely prevented the rise in the circulating level of cholesterol observed in response to HPr. Normalization of plasma calcium in NX-PTX rats with 1,25-dihydroxyvitamin D3 restored the increment in the renal mass and calcium content and reduced the protective effect of PTX on the progression of renal failure induced by high protein diet. In conclusion, in the subtotal nephrectomized rat model of chronic renal failure, the progression of kidney damage induced by a high protein diet can be prevented by removal of the parathyroid glands. This observation suggests that PTH could be implicated in the mechanism whereby a high protein regimen accelerates the course of chronic renal failure.

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Hadj-Aissa A, Bankir L, Fraysse M, Bichet DG, Laville M, Zech P, Pozet N Service d'Exploration Fonctionnelle Renale, Hopital E. Herriot, Lyon, France.
Kidney Int 1992 Nov;42(5):1207-1216

Recent studies have suggested that the renal effects of high protein intake could be mediated, at least in part, by vasopressin and/or an increase in the urinary concentrating activity. The present study investigated the influence of the level of hydration, and hence of the activity of the concentrating process, on the renal response to an acute oral protein load. Clearance studies were performed before (Control) and during three hours after a protein meal (1.5 g/kg body wt protein as cooked meat) in ten healthy volunteers. This study was performed twice at a two to three week interval under either constant low (LowH) or high (HighH) hydration. In spite of the marked difference in initial diuresis (3.1 +/- 0.3 in LowH vs. 13.9 +/- 0.7 ml/min in HighH) and urine osmolality (501 +/- 42 in LowH vs. 99 +/- 3 mOsm/kg H2O in HighH), a similar relative decrease in urine flow rate was observed following the meal in both conditions. TcH2O increased progressively by 70% in LowH whereas CH2O decreased by 40% in HighH. Plasma vasopressin showed a progressive increase with time in LowH (from 1.10 +/- 0.26 in control, to 1.98 +/- 0.35 pg/ml at the third hour after the PM, P < 0.05) but not in HighH (0.53 +/- 0.09 to 0.70 +/- 0.17 pg/ml). Glomerular filtration rate (inulin clearance) increased significantly on the second post-prandial hour under LowH but not under HighH. Excretions rates of Na, Cl, K, and urea increased after the meal, however, not to the same extent nor with the same time course in the two conditions. Significant positive correlations were observed between GFR and TcH2O, urine osmolality, or the ratio of urine-to-plasma urea concentrations in LowH. These results suggest that the protein-induced hyperfiltration is partially blunted by a high water intake, and hence is dependent, directly or indirectly, on the urine concentrating activity.

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No authors listed.
J Am Soc Nephrol 1996 Dec;7(12):2616-2626

The Modification of Diet in Renal Disease (MDRD) Study consisted of two randomized controlled trials to determine the effects of dietary protein restriction and strict blood pressure control. In 255 patients with advanced renal disease (baseline GFR, 13 to 24 mL/min per 1.73 m2; Study B), secondary analyses demonstrated a correlation between achieved protein intake and rate of decline in GFR, consistent with a beneficial effect of a low-protein diet. In 585 patients with moderate renal disease (baseline GFR, 25 to 55 mL/min per 1.73 m2; Study A), the primary analysis of the effect of the low-protein diet was inconclusive because of a nonlinear GFR decline and limited duration of follow-up. A meta-analysis of recent controlled trials, including MDRD Study A, demonstrated a beneficial effect of a low-protein diet on the incidence of renal failure. The objective of these secondary analyses is to explore further the effect of dietary protein restriction in Study A. In these analyses, a total of 585 patients were randomly assigned to follow either a low-protein diet (0.58 g/kg per day) or a usual-protein diet (1.3 g/kg day). Outcomes included the rate of GFR decline, incidence of renal failure or death, and change in urine protein excretion. Analyses included comparisons of randomized groups and correlations of outcomes with achieved protein intake. The comparisons of randomized groups revealed a faster GFR decline during the first 4 months after assignment to the low-protein diet but no difference in the variability in GFR decline between the diet groups, indicating a uniform short-term effect of the low-protein diet on GFR, probably as a result of hemodynamic adjustments. After 4 months, the mean decline in GFR in the low-protein diet group was slower, and the variability of the rate of decline was smaller, than in the usual-protein diet group (ratio of standard deviations, 0.73; 95% confidence interval, 0.55 to 0.91; P < 0.01). This suggests a greater beneficial effect of the low-protein diet in patients with a more rapid GFR decline. The net effect of the low-protein diet on GFR decline over 3 yr was no significant change in mean GFR decline, but reduced variability of the decline (ratio of standard deviations, 0.76; 95% confidence interval, 0.60 to 0.92; P < 0.01). Correlational analyses revealed trends similar to the comparisons of randomized groups. During the first 4 months, patients with a greater decline in protein intake (irrespective of diet group) had a greater decline in GFR; thereafter, patients with a lower protein intake had a slower GFR decline. Over 3 yr, there was no significant correlation between GFR decline and achieved protein intake. The correlation of protein intake with GFR decline after 4 months was less strong than observed in Study B. The relative risk of death or renal failure was 0.65 (95% confidence interval, 0.38 to 1.10; P = 0.10) in patients assigned to the low-protein diet group compared with the usual-protein diet group, which is similar to that observed in the meta-analysis. During follow-up, the increase in urine protein excretion was delayed in the low-protein diet group (P = 0.008) and in patients with lower achieved protein intake (P = 0.005). In summary, the absence of a significant difference between the diet groups in the mean change in GFR from baseline to 3 yr precludes a definitive conclusion of a beneficial effect of the diet intervention based solely on MDRD Study A. However, these secondary analyses are consistent with a beneficial effect of the low-protein diet to slow the GFR decline in patients with the most rapidly declining GFR and to reduce urine protein excretion. These results, together with the results of the recent meta-analysis (including MDRD Study A), provide some support for the hypothesis that dietary protein restriction slows the progression of moderate renal disease.

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Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE. National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Am J Kidney Dis 1996 May;27(5):652-663

Patients with advanced renal disease randomized to the very low-protein diet group in the Modification of Diet in Renal Disease (MDRD) Study had a marginally (P = 0.066) slower mean glomerular filtration rate (GFR) decline compared with patients randomized to the low-protein diet group. The objective of these secondary analyses was to determine the relationship between achieved, in addition to prescribed, dietary protein intake and the progression of advanced renal disease. A randomized controlled trial was conducted in patients with chronic renal diseases of diverse etiology. The average follow-up was 2.2 years. Fifteen university hospital outpatient nephrology practices participated in the study, which comprised 255 patients aged 18 to 70 years with a baseline GFR 13 to 24 mL/min/1.73 m2 who participated in MDRD Study B. Patients with diabetes requiring insulin were excluded. The patients were given a low-protein (0.58 g/kg/d) or very low-protein (0.28 g/kg/d) diet supplemented with keto acids-amino acids (0.28 g/kg/d). Outcomes were measured by comparisons of protein intake from food or from food and supplement between randomized groups, and correlations of protein intake with rate of decline in GFR and time to renal failure or death. Comparison of the randomized groups showed that total protein intake from food and supplement was lower (P < 0.001) among patients randomized to the very low-protein diet (0.66 g/kg/d) compared with protein intake from food only in patients randomized to the low-protein diet (0.73 g/kg/d). In correlational analyses, we combined patients assigned to both diets and controlled for baseline factors associated with a faster progression of renal disease. A 0.2 g/kg/d lower achieved total protein intake (including food and supplement) was associated with a 1.15 mL/min/yr slower mean decline in GFR (P = 0.011), equivalent to 29% of the mean GFR decline. After adjusting for achieved total protein intake, no independent effect of prescription of the keto acid-amino acid supplement to slow the GFR decline could be detected. If the GFR decline is extrapolated until renal failure, a patient with a 29% reduction in the rate of GFR decline would experience a 41% prolongation in the time to renal failure. Additional analyses confirmed a longer time to renal failure in patients with lower total protein intake. In conclusion, these secondary analyses of the MDRD Study suggest that a lower protein intake, but not the keto acid-amino acid supplement, retards the progression of advanced renal disease. In patients with GFR less than 25 mL/min/1.73 m2, we suggest a prescribed dietary protein intake of 0.6 g/kg/d.

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Kimmel PL, Lew SQ, Bosch JP. Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
Nephrol Dial Transplant 1996;11 Suppl 9:85-88

Due to the paucity of long-term observational data, it is still unclear whether the decreased glomerular filtration rate (GFR) noted in older humans is a results of true changes in renal function over time. The fact that a carefully characterized subpopulation of subjects showed no decrease in GFR over time suggests that the 'physiological decrease' in GFR noted in the elderly is not inevitable. In studies in our patient population, there was a significant correlation between creatinine clearance and nutritional protein intake in elderly patients without renal disease. In our studies, elderly subjects without renal disease who ingested > 1 g/kg day of protein had creatinine clearances in the range of 90-100 ml/min/1.73 m2, while those with lower protein intakes had lower creatinine clearances. Our studies suggest that GFR is not a fixed function, and that its value may change both over short periods and over decades in humans, with these changes being associated with changes in nutritional protein intake. Low levels of GFR are not necessarily equivalent to a diagnosis of renal disease. Diet must be considered in the assessment of renal function in elderly patients before a diagnosis of renal insufficiency can be made. Decreased GFR is not an inevitable consequence of ageing in humans.

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Bosch JP. Division of Renal Diseases and Hypertension, George Washington University, Washington, DC 20037, USA.
Semin Nephrol 1995 Sep;15(5):381-385

The hyperfiltration theory challenged the view that glomerular filtration rate is a fixed function as well as that there is a good correlation between GFR and renal parenchymal damage. Glomerular filtration rate is a dynamic parameter that is diet-dependent and can be altered by hemodynamic maneuvers. Therefore, it is not a good indicator of renal lesion. The renal reserve is an indicator of the workload per nephron and may be a useful parameter to assess the progression of renal disease in the presence of dietary or pharmacological intervention.

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Buckalew VM Jr. Department of Internal Medicine, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC 27157-1053.
South Med J 1994 Oct;87(10):1034-1037

The hypothesis that dietary protein restriction slows the rate of progression of chronic renal disease has been tested in four large clinical trials, the largest and most elegant of which was the Modification of Diet in Renal Disease (MDRD) study conducted recently in the United States. During these trials the majority of patients with nondiabetic renal disease had slow progression, and no overall benefit from dietary intervention was demonstrated in three of four studies. However, MDRD is the first trial to suggest that protein restriction has a two-stage effect on renal function. During the first 4 months, glomerular filtration rate (GFR) fell more rapidly in patients with protein restriction than in patients with normal protein intake, probably because of a hemodynamic effect on the renal microcirculation. After this 4-month period, the rate of decline in GFR was slower in patients on the low protein diet. This suggests but does not prove that low protein diet may slow progression of renal disease in the long run. MDRD also showed that strict control of hypertension slows progression in patients with heavy proteinuria.

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Pecis M, de Azevedo MJ, Gross JL. Endocrine Unit, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil.
Diabetes Care 1994 Jul;17(7):665-672

OBJECTIVE--To compare the effect of a normal protein diet (test diet) in which chicken and fish were substituted for red meat with a low-protein diet (LPD) on glomerular filtration rate (GFR) in normoalbuminuric insulin-dependent-diabetes mellitus (IDDM) patients. RESEARCH DESIGN AND METHODS--A crossover randomized clinical trial was performed in 15 normoalbuminuric IDDM patients, 9 normofiltering, and 6 hyperfiltering patients. They followed three diets for a 3-week period each: a usual diet (UD), an LPD (0.5 g.kg-1.day-1 of proteins, 7% calories as protein, 33% as fat, and 60% as carbohydrates), and a normoproteic isocaloric test diet in which white meat (chicken and fish) was substituted for red meat of the UD. At the end of each diet, a clinical evaluation and measurements of GFR (51Cr-ethylenediaminetetraacetate (EDTA) single injection technique), urinary albumin excretion (UAE), and plasma amino acids were performed. Dietary compliance was assessed by a 24-h urinary urea and weekly interviews with the dietitian. RESULTS--In all diabetic patients, GFR after the LPD (114.9 +/- 16.5 ml.min-1 x 1.73 m-2) and after the test diet (122.7 +/- 16.7 ml.min-1 x 1.73 m-2) was significantly lower than after the UD (132.0 +/- 27.7 ml.min-1 x 1.73 m-2) (P = 0.001). Similar results were found in the hyperfiltering group: after UD = 161.1 +/- 15.4 ml.min-1 x 1.73 m-2, after LPD = 129.8 +/- 9.0 ml.min-1 x 1.73 m-2, and after the test diet = 136.5 +/- 3.1 ml.min-1 x 1.73 m-2, (P < 0.001). In the normofiltering group, no significant changes in GFR were observed after the three diets. Metabolic control, nutritional indexes, blood pressure (BP), and UAE did not change after the three diets in all patients. CONCLUSIONS--A normoproteic diet with chicken and fish as the only meat protein source decreases the GFR in the hyperfiltering normoalbuminuric IDDM patients. The GFR reduction after this diet is similar to that observed after an LPD.

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Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
N Engl J Med 1994 Mar 31;330(13):877-884

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. In study 1, the projected mean decline in the glomerular filtration rate at three years did not differ significantly between the diet groups or between the blood-pressure groups. As compared with the usual-protein group and the usual-blood-pressure group, the low-protein group and the low-blood-pressure group had a more rapid decline in the glomerular filtration rate during the first four months after randomization and a slower decline thereafter. In study 2, the very-low-protein group had a marginally slower decline in the glomerular filtration rate than did the low-protein group (P = 0.07). There was no delay in the time to the occurrence of end-stage renal disease or death. In both studies, patients in the low-blood-pressure group who had more pronounced proteinuria at base line had a significantly slower rate of decline in the glomerular filtration rate. CONCLUSIONS. Among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease.

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Pomerleau J, Verdy M, Garrel DR, Nadeau MH. Department of Nutrition, University of Montreal, Canada.
Diabetologia 1993 Sep;36(9):829-834

Recent clinical investigations have suggested that dietary protein intake may modulate the progression of diabetic nephropathy and influence glycaemic control in Type 2 (non-insulin-dependent) diabetes mellitus. Twelve normotensive Type 2 diabetic patients with microalbuminuria took part in a randomized cross-over trial of a 3-week high protein diet (2.0 g/kg.desirable weight per day) and a 3-week moderate protein diet (0.8 g/kg desirable weight per day) to test the simultaneous effect of protein intake modulation on glycaemic control and renal function. Both diets were isoenergetic and the moderate protein diet was supplemented with calcium and phosphate. Renal function and glycaemic control were evaluated at the beginning and at the end of each diet. The moderate protein diet reduced the urinary albumin excretion rate, glomerular filtration rate, creatinine clearance, and proteinuria without adversely affecting glycaemic control; fasting glycaemia and the ratio of fructosamine to proteins were significantly reduced. The high protein diet induced similar improvements in glycaemic control but small changes in renal function.

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Kist-van Holthe tot Echten JE, Nauta J, Hop WC, de Jong MC, Reitsma-Bierens WC, Ploos van Amstel SL, van Acker KJ, Noordzij CM, Wolff ED. Department of Paediatrics, Sophia Children's Hospital/University Hospital Rotterdam, The Netherlands.
Arch Dis Child 1993 Mar;68(3):371-375

The aim of the study was to investigate the effect of a protein restricted diet on renal function and growth of children with chronic renal failure. In a multicentre prospective study 56 children (aged 2-18 years) with chronic renal failure were randomly assigned to the protein restricted (0.8-1.1 g/kg/day) or the control group. All children were followed up by the same paediatrician and dietitian. After a follow up period of three years there was no significant difference in glomerular filtration rate between children on a protein restricted diet and children of the control group. There was no significant difference in weight with respect to height and height SD score between the protein restricted and the control group. Compliance with the protein restricted diet, as indicated by the prospective diet diaries and the serum urea:creatinine ratio, was good. This study shows that children with chronic renal failure do not benefit from a protein restricted diet.

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