Low protein diets delay end-stage renal disease in non-diabetic adults with chronic renal failure

Denis Fouque,1,2, Ping Wang2,3, Maurice Laville1,2 and Jean-Pierre Boissel2

1 Department of Nephrology, 2 Cochrane Renal Group, Hôpital Edouard Herriot, Lyon, France and 3 University of California, Irvine, CA, USA



   Abstract
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 Abstract
 Introduction
 Methods
 Criteria for considering studies...
 References
 
Background. The objective of this study was to determine the efficacy of low protein diets in delaying the need to start maintenance dialysis based on an analysis of published literature.

Methods. The search strategy involved a Medline and Embase search from January 1966 through to June 1999, congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987) and direct contacts with investigators. The selection criteria included randomized trials comparing two different levels of protein intake in adult patients suffering from moderate to severe renal failure, followed for at least 1 year. Patients with diabetic nephropathy were excluded. Seven trials were selected from 40 studies since 1975. A total of 1494 patients were analysed: 753 had received reduced protein intake and 741 a higher protein intake. The numbers of ‘renal deaths’ (defined as the need for starting dialysis, the death of a patient or kidney transplant during the trial) were collected.

Results. 242 renal deaths were recorded, 101 in the low protein diet and 141 in the higher protein diet group, giving an odds ratio of 0.61 with a 95% confidence interval of 0.46 to 0.83 (P=0.006).

Conclusion. Reducing protein intake in patients with chronic renal failure reduces the occurrence of renal death by about 40% as compared with larger or unrestricted protein intake. The optimal level of protein intake cannot be confirmed from these studies.

Keywords: Cochrane Collaboration; chronic renal failure; end-stage renal failure; low protein diet; meta-analysis; nutrition; systematic review



   Introduction
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 Abstract
 Introduction
 Methods
 Criteria for considering studies...
 References
 
During the past years, numerous experimental and clinical studies have addressed the question of reducing protein intake to retard or even halt the development of non-specific glomerular or interstitial lesions, and hence, the progression of patients towards end-stage renal disease. Despite the large number of studies on dietary interventions that were performed a few decades ago, it is still unclear if patients should limit their protein intake and if so, to what extent nutritional behaviour should be changed during chronic renal failure. Most of the clinical studies were designed to test the efficacy of reducing protein intake on surrogate renal function outcomes, such as serum creatinine increase or creatinine clearance decrease over time. Unfortunately, changing protein intake will modify all creatinine markers and, therefore, no valid conclusions can be drawn from these studies. Although a few trials used what are considered as gold standard renal function assessments such as glomerular filtration rate (GFR), the results from these studies have been conflicting. Moreover, GFR is not a clinical outcome.



   Methods
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 Abstract
 Introduction
 Methods
 Criteria for considering studies...
 References
 
The objective of this review was to determine the efficacy of low protein diets in preventing the natural progression of chronic renal failure towards end-stage renal disease and therefore delaying the need for starting maintenance dialysis. For this purpose, we defined the ‘renal death’ outcome, i.e. the number of deaths or number of patients who will start dialysis or will receive a kidney transplant during the observation period according to their protein intake level.



   Criteria for considering studies for this review
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 Abstract
 Introduction
 Methods
 Criteria for considering studies...
 References
 
Types of studies
Trials in which participants have been randomly allocated to receive either their usual intake of protein or were ask to limit their protein intake for at least 12 months. Crossover studies were considered if the starting intervention period was randomly allocated.

Types of participants
All patients were suffering from moderate to severe chronic renal failure, as estimated by either serum creatinine, creatinine clearance or a GFR measurement. Because of the difficulty in controlling confounding factors, trials including diabetic patients or children with renal failure were excluded from analysis.

Types of interventions
Standard protein intake (0.8 g/kg/day) or greater versus a moderate (0.6 g/kg/day) to severe protein restriction (0.3 g/kg/day) regardless of supplementation with essential amino acids or ketoacids.

Types of outcome measures
Renal death was defined as:

death during follow-up, due to any cause;

need to start haemodialysis or peritoneal dialysis during follow-up;

kidney transplant during the study.

Search strategy for identification of studies
The search for studies was performed by one of the authors (DF) using to the Cochrane Renal Group search strategy. The Renal Group Trials Register was searched by Sandrine Dury, Trials Search Coordinator. Medline and Embase were searched from January 1966 through June 1999. Congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987) were hand-searched. Authors of published work were contacted to ask if they were aware of any unpublished studies.

Methods of the review
Two reviewers (DF, JPB) independently selected trials for inclusion in the review. Disagreements were resolved by discussion. For each trial, the number of patients originally allocated to each treatment group was noted and an ‘intention to treat’ analysis was performed. Data were obtained directly from investigators when not available in the published report. Data collected for each trial included study inclusion and exclusion criteria, patient details (age, gender), type of diet prescribed (level of proposed protein intake, nature of proteins, supplementation in energy or amino acids), and time to the start of dialysis, if available. The nature of renal disease was recorded to verify that the distribution of prognostic factors was balanced between the groups. No quality assessment of the studies was performed. Details of the randomization processes were obtained directly from the investigators. Heterogeneity between trials was tested using appropriate statistical analyses.

Description of studies
Seven randomized studies were identified and retained for this review (Table 1Go), with 1494 patients, 753 in the restricted protein intake groups and 741 in the unrestricted or higher protein intake groups. The number of patients in each study varied from 19 [1] to 585 [3]. The collection of events was done after the longest observation time obtained in each study. Data obtained during follow-up after completion of studies, if present, were not considered for analysis.


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Table 1. Characteristics of included studies

 
Randomization was performed using: (i) envelopes after stratification by age, gender and renal function [2]; (ii) after stratification by renal function and blood pressure levels, (iii) by centre and study and by block permutation [3]; (iv) after allocating envelopes without stratification [1,4,5], (v) by random number table and a telephone call [6] (vi) and by random number table [7].

The level of renal insufficiency was moderate [3,6] [2; study A1–B] or severe [1,4,7] [3; study 2] [2; study A2–C). Mean age of patients was: 48 years (range 15–73) [2], 62 (32–79) [1], 49 (18–65) [6], 55 (15–75) [7], 44 (15–70) [5] and 52 years [3].

The type of kidney disease was available for all studies. Glomerulopathies of included patients represented 36% [2], 26% [1], 29% [6], 28% [7], 47% [4], 23% [5] and 25% [3]. Polycystic kidney disease was present in 6% of patients [2], 21% [1], 16% [6], 30% [7], 18% [4], 17% [5] and 24% [3]. Interstitial nephritis was present in 24% of patients [2], 16% [1], 34% [6], 14% [7], 26% [4], 17% [5] but was not reported in one study [3]. Importantly, these nephropathies were equally distributed between groups within studies.

Gender (Male/Female) was as follows: 0.54 [2], 0.37 [1], 0.54 [6], 0.58 [7], 0.67 [4], 0.63 [5] and 0.60 [3], reflecting well the higher male prevalence of renal disease. Again, no difference between treated and control groups was observed.

All other studies were excluded from analysis (Table 2Go).


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Table 2. Studies excluded from the meta-analysis and reasons for exclusion

 

Methodological quality of included studies
There was no blinded follow-up of treatment, because of the nature of the nutritional intervention. All selected studies appeared to use adequate randomization processes.

Statistical methods
We conducted an ‘intention to treat’ analysis, and used standard statistical analyses (odds ratio, percentage difference, Peto, Mantel-Haenszel) [8]. As they all gave similar P values for the difference between control and treated groups, we only provide here the results from the analysis of the logarithm of odds ratio. Number needed to treat (NNT) was calculated for each trial as the inverse of the difference in absolute risks between treated and control groups [9]. The absolute risk in the treated group of a given trial was obtained by multiplying the overall odds ratio by the absolute risk in the control group of the corresponding trial. All data were adjusted for a 1-year period, in order to compare treatment efficiency in trials of different durations.

Results
From more than 40 clinical trials published between 1975 and 1999, there were only seven randomized controlled trials in non-diabetic adult patients. They were all published as full length articles, including the last study from France, published in 1999 [7].

The overall unadjusted incidence of renal death in the control groups was 19%, and ranged from 9% [3] to 78% [1]. All but one study [5] showed a trend for a beneficial effect of a restricted protein intake compared with an unrestricted intake, and one study showed a statistically significant difference [4]. There was no heterogeneity between studies ({chi}2 heterogeneity test 4.62, degrees of freedom=6, P=0.59). The overall effect was found to be highly significant, with 101 renal deaths observed with restricted protein intake compared with 141 events in the unrestricted protein intake. There was a 39% relative risk reduction in renal death (P=0.006, odds ratio) in favour of a restricted protein intake. Of importance, due to randomization, there was a similar percentage in categories of renal disease (glomerulopathy, interstitial nephritis, nephroangiosclerosis, polycystic disease) in both restricted and unrestricted protein intake groups. A subgroup analysis of the ‘start of dialysis’ event was also highly significant, with an odds ratio of 0.56 in favour of a restricted protein intake, P<0.01.

The number of patients needed to be treated (NNT) during 1 year to avoid one renal death ranged from four [1], eight [7], 11 [4], 11 [5], 14 [2], 37 [6] and 56 [3]. To estimate the overall benefit of a restricted protein intake longer than 1 year, these results should be divided by the number of years during which the low protein diet is prescribed.

There was some heterogeneity between diets. This reflects the absence of homogenous experimental hypotheses and the historical background of these treatments. Theoretically, the mean difference in protein intake between higher and restricted protein intake groups was approximately 0.35 g/kg/day in all studies except 0.2 g/kg/day in studies by Jungers [1] and Williams [5] and 0.7 g/kg/day in Klahr [3]. However, based on urinary collection of protein waste products, the actual reduction in protein intake between groups in each study was less than expected and close to 0.2 g/kg/day [6], 0.25 g/kg/day [4,5], 0.3 g/kg/day [2] and 0.35 g/kg/day [3,10]. These values should be considered to be the true therapeutic intervention estimated by the present review.

Although we report a limited number of trials, a publication bias may be discussed as there is a trend for a funnel plot on the graphical representation (Fig. 1Go [11]).



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Fig. 1. Reduction in the odds of renal death in seven prospective randomized studies of protein restriction in chronic renal insufficiency. A square denotes the odds ratio (treatment/control) for each trial and the diamond for the overall results. 95% CIs are represented by the horizontal lines. Overall ‘common’ odds ratio=0.61 (95% CI: 0.46, 0.83), P=0.006. Test for heterogeneity between studies: {chi}2=4.84; degrees of freedom=6, P=0.56.

 

Discussion
Updating two previous meta-analyses [12,13], this systematic review shows that reducing the protein intake of patients with chronic renal failure significantly reduces the number of patients entering end-stage renal disease by about 40% (P=0.006). In addition to a positive trial [4], a favourable but not significant trend was already present in five of the seven studies (individual odds ratio <1; Fig. 1Go), but on limited size or inadequate duration. In response to a more appropriate number of patients obtained through the meta-analysis, the overall result was strongly positive and thus confirmed the beneficial effect of low protein diets in a cohort of almost 1500 patients.

For many decades, reducing protein intake has been proposed for patients suffering from kidney disease for metabolic purpose. Urea production, and hence, serum urea can be reduced by a low protein diet. More recently, it was suggested that, from experimental studies, a low protein intake may prevent the natural progression of chronic renal insufficiency towards end-stage renal disease, thus delaying the start of maintenance dialysis treatment [14]. However, inadequate markers or protocols may have masked the effects of low protein diets [15]. Reducing protein intake modifies creatinine concentrations and since this was used as a intermediary outcome in many reports published since 1975, it is not possible to use these data to reliably assess the effects of low protein diets. To avoid problems raised by the use of intermediary outcomes, we chose a robust clinical end-point, renal death. This end-point was easily observed for all patients, i.e. the date of first dialysis session, kidney transplant or the death of a patient during the study. Because in some studies patients were transplanted before starting dialysis, we also counted them as renal death. These results were obtained accurately from each paper or by direct contact with the investigators.

A number of comments should be made [16,17]. First, although the populations studied were clinically heterogeneous in age, gender, type of nephropathy, level of protein restriction, the effects of treatments were not statistically different since the heterogeneity test was not significant (P=0.59). Secondly, although the amounts of protein intake were quite different between studies (Table 1Go), the fact that a common effect was found indicates that the gradient in protein intake is the therapeutic factor. In fact, due to a well-described spontaneous increase in protein intake during a diet [18], it was not surprising that the true protein intake gradient between groups was less than expected. Thus, the effect of the diet might have been even more pronounced if the diet was better observed.

Thirdly, because the decision to start dialysis is often based on serum urea levels (but not only), and because low protein diets decrease these urea levels, it can be expected that patients with a reduced protein intake will have a more reduced serum urea. Hence they will start dialysis later than patients with higher protein intake. Therefore, it cannot be derived from our review that low protein diets reduce the progression of renal disease. Only studies measuring GFR and reporting a decrease in renal function over time may give this information. In the present report, two studies used these markers: [4] showed a beneficial effect and [3] did report a nearly significant beneficial effect (P=0.07). Interestingly, Kasiske and colleagues [19] performed a meta-analysis on the renal function deterioration (not on the renal death) and showed a moderate but significant protection by low protein diets (0.5 ml/min/year smaller loss for restricted protein intake than for higher protein intake). Even if this represents a protective renal effect of low protein diets, it is moderate and not responsible for the greater reduction in renal death we have observed in the present review. Thus, it is probably a combination of renal protection and better metabolic control offered by the low protein diets that may explain the benefit we report here. However, from a patient's point of view, there is no doubt that ‘renal death’ is a very clinical indicator of renal disease worsening.

The number needed to treat is a tool recently introduced to better compare the strength of a treatment between studies and to homogenize these effects when absolute event risks are quite different between studies [9]. In the present review, NNT during 1 year for each study varied from four to 56. These variations mainly depend on the basal risk for renal death at inclusion and correspond to the impairment in renal function, since the absolute risk of renal death during the study is greater when renal function is more impaired [1,7]. However, the amplitude of NNTs among trials is not very large (from four to 56) and thus appears to be very acceptable in primo-secondary prevention for a treatment that is not expensive and whose potential side-effects can be avoided by routine dietician survey. Moreover, these results compare favourably with the well-accepted mortality reduction obtained by statins in the 4S trial (NNT=30) or WOSCOPS study (NNT=111) [20].

The funnel plot represents the individual odds ratio corresponding to the study patients number [11]. Figure 1Go shows that the odds ratios from the three largest studies [2,3,6] are closer to the common odds ratio (i.e. 0.61), whereas the smaller trials [1,4,7] provide a smaller odds ratio (between 0.29 and 0.38) suggesting a stronger trend for a beneficial effect of a reduced protein intake. The fact that only one small size trial provided an odds ratio greater than 0.61 [5] suggests that a publication bias might have occurred. Indeed, if investigators did find negative or less robust conclusions on small effectives (e.g. 20–100 patients), they might have censored themselves and were eventually reluctant to report their findings. Also, medical journals might have refused to publish negative trials due to inadequate size. On the basis of the limited number of trials in the present review, funnel plot analysis may, however, not be very robust, and should be re-analysed when future trials are available.

Conclusion
Patients with moderate chronic renal failure should be proposed a nutritional intervention, which includes a reduction in protein intake. The optimal level of protein intake cannot be deduced from the present review. The fact that the actual patient protein intake was greater than prescribed in all studies suggests that a skilled and regular dietitian survey should be proposed (NKF-DOQI Guideline #23 [21]). Moreover, it has been demonstrated that patients with CRF left without dietetic survey will express a progressive decline in protein and energy intakes, potentially contributing to the decline in nutritional markers [18]. In contrast, feasability of low protein diets has been shown in large studies with convincing results [22], highlighting the fact that interested teams can motivate patients to the point of excellent compliance and optimal nutritional benefit, a goal that should be reached for most patients in all renal units. Thus, based on physician enthusiasm and dietitian survey, the patient may eventually make his personal treatment choice. Factors other than diet therapy have demonstrated a renal protective effect and have been shown to delay end-stage renal disease [23]. These include angiotensin-converting enzyme inhibitors, blood pressure control, and optimal glucose monitoring in diabetic patients. Even if it is more difficult to modify dietary habits than taking blood pressure treatment, a restricted protein intake should be proposed to the patients, in addition to other current and future renoprotective treatments.



   Acknowledgments
 
We thank the authors of each included trial for providing additional data and are particularly indebted to Michel Cucherat, MD, PhD, and Margaret Haugh, PhD, Centre Cochrane Français, for statistical and methodological assistance.



   Notes
 
Correspondence and offprint requests to: Denis Fouque, MD, PhD, Department of Nephrology, Hôpital Edouard Herriot, F-69437 Lyon cedex 03, France. Back



   References
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 Abstract
 Introduction
 Methods
 Criteria for considering studies...
 References
 

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Received for publication: 30.11.99
Revision received 11. 7.00.