End-stage renal disease is a major cause of death

Transcription

1 The Effect of Dietary Protein Restriction on the Progression of Diabetic and Nondiabetic Renal Diseases: A Meta-Analysis Michael T. Pedrini, MD; Andrew S. Levey, MD; Joseph Lau, MD; Thomas C. Chalmers, MDt; and Ping H. Wang, MD Background: Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restriction is beneficial. Purpose: To use meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the recently completed Modification of Diet in Renal Disease Study. Data Sources: The English-language medical literature published from January 1966 through December 1994 was searched for studies examining the effect of low-protein diets in humans with chronic renal disease. A total of 1413 patients in five studies of nondiabetic renal disease (mean length of follow-up, 18 to 36 months) and 108 patients in five studies of type I diabetes mellitus (mean length of follow-up, 9 to 35 months) were included. Study Selection: Randomized, controlled studies were selected for nondiabetic renal disease; randomized, controlled studies or time-controlled studies with nonrandomized crossover design were selected for diabetic nephropathy. Data Extraction: Data in tables, figures, or text were independently extracted by two of the authors. Data Synthesis: The relative risk for progression of renal disease in patients receiving a low-protein diet compared with patients receiving a usual-protein diet was calculated by using a random-effects model. In five studies of nondiabetic renal disease, a low-protein diet significantly reduced the risk for renal failure or death (relative risk, 0.67 [95% CI, 0.50 to 0.89]). In five studies of insulin-dependent diabetes mellitus, a low-protein diet significantly slowed the increase in urinary albumin level or the decline in glomerular filtration rate or creatinine clearance (relative risk, 0.56 [CI, 0.40 to 0.77]). Tests for heterogeneity showed no significant differences in relative risk among studies of either diabetic or nondiabetic renal disease. No significant differences were seen between diet groups in pooled mean arterial blood pressure (diabetic and nondiabetic patients) or glycosylated hemoglobin level (diabetic patients only). Conclusion: Dietary protein restriction effectively slows the progression of both diabetic and nondiabetic renal diseases. Ann Intern Med. 1996;124: From the University of California, Irvine, California, and New England Medical Center, Boston, Massachusetts. For current author addresses, see end of text. t Deceased. End-stage renal disease is a major cause of death and disability in the United States. Many clinical studies have focused on interventions, including dietary protein restriction in both diabetic and nondiabetic renal diseases, that may prevent or delay the progression of chronic renal disease to renal failure. Unfortunately, the results of these studies have not consistently shown that protein restriction is beneficial; this is partly because of differences in study design, sample size, and methods used to assess the progression of renal disease. A meta-analysis by Fouque and colleagues (1), which included six studies of 890 patients, most of whom had nondiabetic renal diseases, showed that dietary protein restriction reduced the risk for renal failure or death. However, the Modification of Diet in Renal Disease (MDRD) study (2), a large, multicenter, randomized trial that was done recently in patients with nondiabetic renal disease and that used serial measurements of glomerular filtration rate, had inconclusive results. Fewer studies have been done in patients with diabetic renal disease. Thus far, no consensus has been reached on the efficacy of dietary protein restriction in slowing the progression of either diabetic or nondiabetic renal diseases (3). 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 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 au American College of Physicians 627

2 Table 1. Characteristics of Studies of Nondiabetic Renal Disease Included in the Meta-Analysis* Study (Reference) Year Patients Men Mean Age Mean Length of Follow-Up Prescribed Protein Intake in Low-Protein Diet Approximate Mean Level of Renal Function Per Ccr GFR Outcome Measures Conclusion n % y mo g/kg of body weight per d mg/dl ml/min Ihle et al. (7) Rosman et al. (6) Locatelli et al. (8) Williams etal. (9) Klahretal. (2) * * t >18 >36 > GFR decline Per increase Per increase Ccr increase GFR decline Beneficial effect Beneficial effect No difference No difference Possible beneficial effect * Ccr = creatinine clearance; GFR = glomerular filtration rate; Per = serum creatinine, t Based on 228 patients in a previous report (Rosman et al. Lancet. 1984;2:1291-6). * Based on 65 patients at baseline. thors of the published trials. We included only fulllength 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 > 300 mg/d or urinary total protein excretion rate > 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 < 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 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 followup, 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, April 1996 Annals of Internal Medicine Volume 124 Number 7

3 Figure 1. Effect of dietary protein restriction on progression of nondiabetic renal diseases. Data presented as risk ratios with 95% CIs on log scale to 0.89]; P = 0.007) compared with the usualprotein 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, 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. 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 lowprotein 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 Table 2. Characteristics of Studies of Diabetic Renal Disease Included in the Meta-Analysis* Study (Reference) Year Patients Men Mean Mean Length of Prescribed Approximate Outcome Conclusion Age Follow-up Protein Intake Mean Level of Measures in Low-Protein Renal Function Diet AER GFR n % y mo g/kg of body mg/d ml/min weight per d Ciavarellaetal. (11) t AER Beneficial effect GFR declinet No difference Barsottietal. (14) ,17* t AER Beneficial effect GFR declinet Beneficial effect Walker etal. (15) ,33* AER Beneficial effect GFR decline Beneficial effect Zelleretal. (12) AER No difference GFR decline Beneficial effect Dullaart etal. (13) AER Beneficial effect GFR decline No difference * AER = albumin excretion rate; GFR = glomerular filtration rate, t Creatinine clearance. * Crossover design. Total protein excretion rate. 1 April 1996 Annals of Internal Medicine Volume 124 Number 7 629

4 Figure 2. Effect of dietary protein restriction on progression of diabetic renal disease. Data presented as risk ratios with 95% CIs on log scale. 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. Discussion 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 lowprotein 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 April 1996 Annals of Internal Medicine Volume 124 Number 7

5 disease (21). Thus, both mechanisms probably contribute to the beneficial effect of the low-protein diet. The studies we analyzed used an intention-totreat analysis plan; that is, patients were included in their assigned diet group regardless of their actual protein intake. Nonadherence to the prescribed lowprotein 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 m 2. 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 insulindependent 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 lowprotein 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 1 April 1996 Annals of Internal Medicine Volume 124 Number 7 631

6 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. Acknowledgments: The authors thank Dr. G.J. Beck, Dr. J. Walker, G. Viberti, and Dr. A. Ciavarella for providing data from their studies. Requests for Reprints: Ping H. Wang, MD, Department of Medicine, Medical Science I, C240, University of California, Irvine, CA Current Author Addresses: Dr. Pedrini: Department of Internal Medicine, Innsbruck General Hospital, Anichstrasse 35, A-6020 Innsbruck/Tyrol, Austria. Dr. Levey: Division of Nephrology, Department of Medicine, New England Medical Center, 750 Washington Street, Boston, MA Dr. Lau: Division of Clinical Care Research, New England Medical Center, 750 Washington Street, Boston, MA Dr. Wang: Departments of Medicine and Biological Chemistry, Medical Science I, C240, University of California, Irvine, CA References 1. Fouque Df Laville M, Boissel JP# Chifflet R, Labeeuw, M. Zech PY. Controlled low protein diets in chronic renal insufficiency: meta-analysis. BMJ. 1992;304: Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330: Striker G. Report on a workshop to develop management recommendations for the prevention of progression in chronic renal disease. J Am Soc Nephrol. 1996;5: Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med. 1992;327: Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive bloodglucose control on late complications of type I diabetes. Lancet. 1993;341: Rosman JB, Langer K, Brandl M, Piers-Becht TP, van der Hem GK, ter Wee PM, et al. Protein-restricted diet in chronic renal failure: a four year follow-up shows limited indications. Kidney Int Suppl. 1989;27:S Ihle BU, Becker GJ, Whitworth JA, Charlwood RA, Kincaid-Smith PS. The effect of protein restriction on the progression of renal insufficiency. N Engl J Med. 1989;321: Locatelli F, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A. Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Lancet. 1991;337: Williams PS, Stevens ME, Fass G, Irons L, Bone JM. Failure of dietary protein and phosphate restriction to retard the rate of progression of chronic renal failure: a prospective, randomized, controlled trial. Q J Med. 1991;81: Jungers P, Chauveau P, Ployard F, Lebkiri B, Ciacioni C, Man NK. Comparison of ketoacids and low protein diet on advanced chronic renal failure progression. Kidney Int Suppl. 1987;22: Ciavarella A, Di Mizio G, Stefoni S, Borgnino LC, Vannini P. Reduced albuminuria after dietary protein restriction in insulin-dependent diabetic patients with clinical nephropathy. Diabetes Care. 1987;10: Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med. 1991;324: Dullaart RP, Beusekamp BJ, Meijer S, van Doormaal JJ, Sluiter WJ. Long-term effects of protein-restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension. Diabetes Care. 1993;16: Barsotti G, Ciardella F, Morelli E, Cupisti A, Mantovanelli A, Giovannetti S. Nutritional treatment of renal failure in type I diabetic nephropathy. Clin Nephrol. 1988;29: Walker JD, Bending JJ, Dodds RA, Mattock MB, Murrells TJ, Keen H, et al. Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet. 1989;2: DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials. 1986;7: Robins J, Greenland S, Breslow NE. A general estimator for the variance of the Mantel-Haenszel odds ratio. Am J Epidemiol. 1986; Levey AS. Measurement of renal function in chronic renal disease. Kidney Int. 1990;38: Brenner BM. Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int. 1983;23: Donner A. Approaches to sample size estimation in the design of clinical trials a review. Stat Med. 1984;3: Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis. 1996; [In press]. 22. Mitch WE. Dietary protein restriction in patients with chronic renal failure. Kidney Int. 1991;40: Parving HH, Andersen AR, Hommel E, Smidt U. Effects of long-term antihypertensive treatment on kidney function in diabetic nephropathy. Hypertension. 1985;7(6 Pt 2): The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329: Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA. 1994;271: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329: April 1996 Annals of Internal Medicine Volume 124 Number 7