To better define the efficacy of dietary protein restriction, we did separate meta-analyses of studies in diabetic and nondiabetic patients, including patients in the MDRD study. The occurrence of death or end-stage renal disease was used to assess treatment effects in nondiabetic patients. These data are not available in most studies of diabetic nephropathy; thus, in patients with this condition, the efficacy of protein restriction on renal function was determined by changes in glomerular filtration rate, creatinine clearance, or urinary albumin excretion rate.

Methods

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The meta-analyses were done as previously described [4, 5]. We searched the English-language medical literature published from January 1966 through December 1994 for studies examining the effect of low-protein diets in humans with chronic renal disease. Studies were identified through MEDLINE, references in review articles and published studies, and other papers written by the authors of the published trials. We included only full-length published studies in our analysis.

Of 38 studies done in patients with predominantly nondiabetic renal diseases, only 5 [2, 6-9] used a randomized, controlled design; had a mean length of follow-up of more than 1 year; and included information on the number of patients who developed renal failure or died. We did not include two small studies that were included in the analysis by Fouque and coworkers [1] because the results of one have not been published and the other did not include an adequate control group [10]. If a series of papers was published, all data were retrieved from the most recent report. Data on renal failure or death in the MDRD study [2] were provided by the Data Coordinating Center (Beck GJ. Personal communication). Of 17 studies of patients with insulin-dependent diabetes mellitus, we selected 5 that had a mean length of follow-up of more than 9 months and either a randomized, concurrent control design [11-13] or a nonrandomized crossover design [14, 15]. In four studies of patients with albuminuria (baseline albumin excretion rate more than 300 mg/d or urinary total protein excretion rate more than 500 mg/d) [11-13, 15], we used a decline in glomerular filtration rate or creatinine clearance greater than 0.1 mL/min per month (1.2 mL/min per year) as the end point. In one study of patients with normal albumin excretion rates or microalbuminuria (baseline urinary albumin excretion rate less than 300 mg/d) [13], we used an increase of more than 10% from baseline in the albumin excretion rate as the end point. We chose this end point because, in patients with early diabetic nephropathy, the urinary albumin excretion rate is a better renal index than the glomerular filtration rate or the creatinine clearance.

The overall effect was calculated by using both the random-effects model described by DerSimonian and Laird [16] and a fixed-effects model [17]. Because the results from both analyses were similar, we present only the results produced by using the random-effects model. Data were extracted independently by two of us, and differences were resolved in a conference. The total number of patients in each study were retrieved, and the proportions of the patients whose renal function progressed were calculated. The data are presented as risk ratios with 95% CIs [16]. Heterogeneity in relative risk among studies was assessed by using the chi-square test. Differences between the low-protein diet group and the usual-protein diet group in pooled mean arterial blood pressure and glycosylated hemoglobin level were calculated as previously described [5].

Results

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Nondiabetic Renal Diseases

Five randomized, controlled studies including a total of 1413 patients with predominantly nondiabetic renal diseases were selected for analysis according to the criteria listed above. The mean duration of follow-up in each study ranged from 18 months to more than 36 months, and the dropout rate ranged from 1.8% to 38.3%. The prescribed protein intake in the low-protein diet group ranged from 0.4 g/kg of body weight per day to 0.6 g/kg of body weight per day. Except in the study by Ihle and colleagues [7], mean baseline renal function was consistent with moderate renal insufficiency. The primary outcome measure in all studies was the rate of decline in renal function (increase in serum creatinine level or decline in creatinine clearance or glomerular filtration rate). The conclusions drawn from these studies were inconsistent (Table 1).

Because of the slow rate of progression of renal disease and the relatively short duration of follow-up, few patients in each study developed renal failure or died. However, pooled results showed that dietary protein restriction significantly reduced the risk for renal failure or death (relative risk, 0.67 [CI, 0.50 to 0.89]; P = 0.007) compared with the usual protein diet (Figure 1). Despite differences among the five studies Table 1, no significant differences were seen in the relative risk for renal failure or death (chi-square test, P > 0.2). The difference between the low-protein and usual-protein diet groups in pooled mean arterial blood pressure was only –2.9 mm Hg (CI, –10.4 mm Hg to 4.9 mm Hg). Thus, the beneficial effect of the low-protein diet did not appear to be the result of an effect on blood pressure.

View larger version (14K): [in this window] [in a new window]   Figure 1. Effect of dietary protein restriction on progression of nondiabetic renal diseases. Data presented as risk ratios with 95% CIs on log scale.

Diabetic Nephropathy

Five studies including a total of 108 patients with insulin-dependent diabetes mellitus were selected for analysis (Table 2). The mean duration of follow-up in each study ranged from 9 to 33 months, and the dropout rate ranged from 0% to 41%. The prescribed protein intake in the low-protein diet group ranged from 0.50 g/kg of body weight per day to 0.85 g/kg of body weight per day. With the exception of the study by Dullaart and associates [13], the mean protein excretion rate at baseline was consistent with albuminuria in all studies. Outcome measures for these studies were the change in albumin level or total protein excretion rate and the decline in glomerular filtration rate or creatinine clearance. All five studies concluded that the low-protein diet had a beneficial effect on one or both outcome measures. Of the 108 patients, only 9 were treated with angiotensin-converting enzyme inhibitors. Six of the 9 were in low-protein diet groups [12, 15], and 3 of the 9 were in usual-protein diet groups [12].

Pooled results showed that dietary protein restriction significantly reduced the risk for decline in glomerular filtration rate or creatinine clearance or increase in urinary albumin excretion rate (relative risk, 0.56 [CI, 0.40 to 0.77]; P < 0.001) (Figure 2). The studies did not differ significantly in relative risk (chi-square test, P > 0.2). Between diet groups, the difference in pooled mean arterial blood pressure was –2.6 mm Hg (CI, –6.1 mm Hg to 1.0 mm Hg), and the difference in glycosylated hemoglobin level was 0.03% (CI, –0.58% to 0.65%). Thus, the apparent beneficial effect of dietary protein restriction on diabetic renal disease did not seem to be the result of an effect on blood pressure or glycemic control.

View larger version (14K): [in this window] [in a new window]   Figure 2. Effect of dietary protein restriction on progression of diabetic renal disease. Data presented as risk ratios with 95% CIs on log scale.

Discussion

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Our analyses show that dietary protein restriction slows the progression of both diabetic and nondiabetic renal diseases. For nondiabetic renal diseases, our analysis included only randomized, concurrent controlled studies, including data from the recently completed MDRD study [2]. We found that dietary protein restriction significantly reduced the risk for renal failure or death; this confirms and extends the results of Fouque and coworkers [1]. The beneficial effect on the incidence of renal failure or death was consistent across clinical studies and did not result from differences in blood pressure. Contradictory conclusions in these studies appear to be caused by two factors: 1) differences among outcome measures (rate of increase in serum creatinine level or rate of decline in creatinine clearance or glomerular filtration rate) [18]; and 2) insufficient sample size to detect a beneficial effect on the incidence of renal failure or death.

Our results may appear to conflict with those of the MDRD study [2]. In patients assigned to the low-protein diet in that study, the mean decline in glomerular filtration rate was 1.6 mL/min faster during the first 4 months of follow-up but was 28% slower thereafter compared with the rate in patients assigned to the usual-protein diet. These findings are reminiscent of results in laboratory animals: A low-protein diet initially reduces the single-nephron glomerular filtration rate but subsequently slows the progression of renal disease [19]. However, after 3 years of follow-up in the MDRD study, the projected decline from baseline in glomerular filtration rate was only 10% less (P > 0.2) in patients assigned to the low-protein diet group than in patients assigned to the usual-protein group. The authors therefore concluded that a longer follow-up would have been needed to show a beneficial effect of the low-protein diet on the decline in glomerular filtration rate from baseline to the end of the study. During the MDRD study, relatively few patients died or developed renal failure. According to our calculation, the relative risk for renal failure or death in the low-protein diet group in the MDRD study was 0.65 (CI, 0.38 to 1.10; P = 0.10), a trend toward a beneficial effect that is consistent with the overall results of our meta-analysis. We calculated that a study would need to include 1000 or more patients to detect a 33% risk reduction by dietary protein restriction [20]. Neither the MDRD study nor the other studies included this many patients.

In principle, a low-protein diet might reduce the risk for renal failure either by slowing the progression of renal disease (delaying the occurrence of renal failure) or by ameliorating uremic symptoms (delaying the recognition of renal failure). That low-protein diets alleviate uremic symptoms is well known. Recently, secondary analyses from the MDRD study have shown a strong correlation between achieved protein intake and both the rate of decline in glomerular filtration rate and the incidence of renal failure or death in patients with advanced renal disease [21]. Thus, both mechanisms probably contribute to the beneficial effect of the low-protein diet.

The studies we analyzed used an intention-to-treat analysis plan; that is, patients were included in their assigned diet group regardless of their actual protein intake. Nonadherence to the prescribed low-protein diet by some patients would result in an underestimate of the diet's true beneficial effect. In these studies, achieved mean protein intake in the low-protein diet group ranged from approximately 0.7 g/kg of body weight per day to 0.8 g/kg of body weight per day, exceeding prescribed protein intake. Nonetheless, the achieved mean protein intake in the low-protein diet group was significantly lower than that in the usual-protein diet group in each study, indicating that patients can reduce protein intake. Our results indicate that such reductions, even though they do not reach the prescribed goal, effectively slow the progression of renal disease.

The studies we analyzed included patients with diverse renal diseases and with glomerular filtration rates less than 55 L/min · 1.73 m². Because the serum creatinine level alone is an imprecise index of renal function [3, 18], in practice, glomerular filtration rate or creatinine clearance can be estimated by using serum creatinine levels and formulas or tables that also consider age, sex, and body size. Different renal diseases may, in theory, respond differently to dietary protein restriction. These studies did not contain sufficient information to determine whether the effects of the low-protein diet are different in various renal diseases. Patients with urinary protein excretion greater than 10 g/d were not included in most of the studies included in our analysis, and such patients may be at greater risk for malnutrition, which is the major potential adverse effect of a low-protein diet. We did not assess the risk for malnutrition because nutritional status was not reported in all studies. However, most studies suggest that a prescribed protein intake of 0.6 g/kg of body weight per day, with approximately 65% as high biological value protein and caloric intake sufficient to maintain body weight, is safe in patients with chronic renal disease [22].

Diabetic renal disease can be characterized by different stages of renal abnormalities, depending on the duration of diabetes. In type I diabetes mellitus, the earliest abnormality is microalbuminuria, which is followed by albuminuria and then by a decline in glomerular filtration rate. Consequently, we used 1) an increase in albumin excretion rate to assess progression of renal disease in studies that included patients with normal albumin excretion rates or microalbuminuria and 2) decline in glomerular filtration rate in studies that included patients with albuminuria. After combining the data from these studies, we found that the low-protein diet had a consistent benefit in patients with insulin-dependent diabetes mellitus. These studies included small numbers of patients and varied in design; thus, we view these results as a strong indication, but not conclusive proof, that the low-protein diet is beneficial. In addition, the results are consistent with our observations in patients with nondiabetic renal disease.

Other studies have shown that the progression of diabetic renal disease can be slowed by blood pressure control [23], intensive glycemic control [5, 24], and angiotensin-converting enzyme inhibition [25, 26]. In our analysis, blood pressure control and glycemic control did not differ between the low-protein and usual-protein diet groups. In addition, our results are unlikely to have been confounded by the use of angiotensin-converting enzyme inhibitors because only two of the five studies included patients treated with these drugs and because the number of these patients was small. Further studies are needed to confirm the beneficial effect of dietary protein restriction in the nephropathy of type I diabetes mellitus and to determine the efficacy of dietary protein restriction in patients receiving intensive glycemic control and angiotensin-converting enzyme inhibitors. Moreover, the effect of dietary protein restriction in type II diabetes mellitus remains to be studied.

In summary, pooling the results of 10 studies in two meta-analyses showed that dietary protein restriction significantly delays the progression of both diabetic and nondiabetic renal disease. Our results in nondiabetic renal disease are based on a decreased risk for renal failure or death in five randomized, controlled trials of 1413 patients and are robust. They provide sufficient justification to recommend dietary protein restriction for well-informed patients with chronic renal disease and renal insufficiency. We suggest a prescribed protein intake of 0.6 g/kg of body weight per day with adequate high biological value protein and caloric intake. However, practitioners must be wary of the possible harmful effects of dietary protein restriction on the nutritional status of patients with chronic renal disease. Patients should be followed carefully by a physician in conjunction with a skilled dietitian to assess protein and energy intake and nutritional status.

Our results in diabetic renal disease are also based on five studies, but these studies included fewer patients and used more varied study designs and surrogate end points. In our view, these results are not as strong a justification for the use of dietary restriction protein in routine clinical practice. Nevertheless, on the basis of clinical judgment, dietary protein restriction should be recommended to selected diabetic patients, such as those who have progressive proteinuria despite good glycemic control and the use of angiotensin-converting enzyme inhibitors. If dietary protein intake is reduced to 0.6 g/kg of body weight per day in diabetic patients with nephropathy, the calories lost should be replaced by calories from complex carbohydrates.

Dr. Levey: Division of Nephrology, Department of Medicine, New England Medical Center, 750 Washington Street, Boston, MA 02111.

Dr. Lau: Division of Clinical Care Research, New England Medical Center, 750 Washington Street, Boston, MA 02111.

Dr. Wang: Departments of Medicine and Biological Chemistry, Medical Science I, C240, University of California, Irvine, CA 92717.