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ORIGINALARTICLE
Journal of Cachexia, Sarcopenia and Muscle (2017)
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12264
Low-protein diet for conservative management of
chronic kidney disease: a systematic review and
meta-analysis of controlled trials
1† 1,2† 3,4 1,2,5,6,7*
Connie M. Rhee , Seyed-Foad Ahmadi , Csaba P. Kovesdy &Kamyar Kalantar-Zadeh
1
Harold SimmonsCenterforKidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA,
2 3
USA; DepartmentofMedicine, University of California Irvine Health, Orange, CA, USA; Division of Nephrology, University of Tennessee Health Science Center, Memphis,TN,
4 5 6
USA; Memphis Veterans Affairs Medical Center, Memphis, TN, USA; Tibor Rubin Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA; Department of
7
Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA
Abstract
Background Recent data pose the question whether conservative management of chronic kidney disease (CKD) by means of
a low-protein diet can be a safe and effective means to avoid or defer transition to dialysis therapy without causing protein-
energy wasting or cachexia. We aimed to systematically review and meta-analyse the controlled clinical trials with adequate
participants in each trial, providing rigorous contemporary evidence of the impact of a low-protein diet in the management of
uraemia and its complications in patients with CKD.
Methods Wesearched MEDLINE (PubMed) and other sources for controlled trials on CKD to compare clinical management
of CKD patients under various levels of dietary protein intake or to compare restricted protein intake with other interventions.
Studies with similar patients, interventions, and outcomes were included in the meta-analyses.
Results Weidentified 16 controlled trials of low-protein diet in CKD that met the stringent qualification criteria including
having 30 or more participants. Compared with diets with protein intake of >0.8 g/kg/day, diets with restricted protein intake
(<0.8 g/kg/day) were associated with higher serum bicarbonate levels, lower phosphorus levels, lower azotemia, lower rates
of progression to end-stage renal disease, and a trend towards lower rates of all-cause death. In addition, very-low-protein
diets (protein intake <0.4 g/kg/day) were associated with greater preservation of kidney function and reduction in the rate
of progression to end-stage renal disease. Safety and adherence to a low-protein diet was not inferior to a normal protein diet,
and there was no difference in the rate of malnutrition or protein-energy wasting.
Conclusions In this pooled analysis of moderate-size controlled trials, a low-protein diet appears to enhance the conserva-
tive management of non-dialysis-dependent CKD and may be considered as a potential option for CKD patients who wish to
avoid or defer dialysis initiation and to slow down the progression of CKD, while the risk of protein-energy wasting and
cachexia remains minimal.
Keywords Low-protein diet; Chronic kidney disease; Glomerular filtration rate; End-stage renal disease; All-cause death; Conserva-
tive management; Cachexia; Protein-energy wasting
Received: 16 August 2016; Revised: 8 October 2017; Accepted: 10 October 2017
*Correspondenceto:KamyarKalantar-Zadeh,Harold SimmonsCenterfor Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of
California Irvine Medical Center, 101 The City Drive South, City Tower, Orange, CA 92868-3217, USA. Tel: (714) 456-5142; Fax: (714) 456-6034; Email: kkz@uci.edu
†C. M. R. and S.-F. Ahmadi contributed equally to this work.
Introduction deteriorates over time until it permanently fails. Management
strategies have largely focused on slowing down progression
Chronic kidney disease (CKD) is among the leading causes of to end-stage renal disease (ESRD), at which time, patients are
death worldwide including emerging giant economies such invariablyexpectedtotransitiontorenalreplacementtherapy,
1 2
as India and China. Upon its development, kidney function mostly in the form of maintenance dialysis treatment.
©2017TheAuthors.JournalofCachexia,Sarcopenia and Musclepublished by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
2 C.M. Rhee et al.
Nevertheless, recent data suggest that attempts to delay or well as additional records identified through other sources in-
evenpreventtransitiontodialysistherapymaynotbeinappro- cluding prior reviews. A field expert (K. K.-Z) identified any
3
priate, including a 2009 study that showed that the initiation additional relevant studies. The studies were included if they
of dialysis was associated with a substantial and sustained described data from controlled trials (including randomized,
decline in functional status of the elderly nursing home self-controlled, parallel, and crossover trials) on CKD patients
patients.4 Many patients with kidney disease prefer to opt to (excluding prevalent ESRD patients and those receiving dialy-
exhaustall conservative managementoptionsforCKD,includ- sis treatment) to compare clinical outcomes across various
ingnutritionalstrategies,priortoconsideringdialysistherapy.5 protein intake levels (i.e. protein-free, very-low-protein, low-
Century-oldevidencesuggeststhatlowerdietaryproteinin- protein, moderate-protein, high-protein, very-high-protein,
takemayhelpwithCKDmanagementincludingslowingitspro- or unrestricted protein diets) or to compare a restricted pro-
6–9
gression, improving albuminuria, and controlling uraemia. tein intake with another intervention. An LPD was defined as
However, results from the Modification of Diet in Renal Dis- a diet with a protein content of <0.8 g/kg/day. To ensure
ease study in 1994 were inconclusive with regards to the meaningful sample size in each study given our focus on the
efficacy of a low-protein diet (LPD) in slowing the rate of CKD conservativemanagementofCKD,weselectedonlycontrolled
progression.10 Several meta-analyses that focused on the rate trials that included at least 30 participants to ensure selection
of CKD progression showed favourable but modest effects of of studies with adequate sample size and higher level of ro-
an LPD.11,12 Nevertheless, no single study has examined all bustness15(Figure1).Theaforementionedendeavourwasun-
clinically relevant outcomes, and fewer studies have focused dertaken to both provide a comprehensive roster of relevant
ontheroleofanLPDinmanaginguraemiaorotherCKDcom- randomized controlled trials of LPD for CKD management,
plications such as mineral and bone disorders and metabolic which has become Supporting Information, Table S2 of a re-
acidosiswithoutcausingprotein-energywastingorcachexia.13 cently published NewEnglandJournalofMedicinereviewarti-
Protein-energy wasting characterized by a decline in body cle,titled,‘NutritionalManagementofChronicKidneyDisease’
16
protein mass and energy reserves, including muscle and fat by Kalantar-Zadeh and Fouque, and for an additional meta-
wasting and visceral protein pool contraction, is an underap- analysis project that is presented in this manuscript.
preciated condition in early to moderate stages of CKD and a We extracted and tabulated the main characteristics and
strong predictor of adverse outcomes.14 The applicability of findings of the included studies as well as comments on their
manynutritional interventions and their effects on outcomes methodological quality and clinical significance (Table 1).
in patients with moderate to advanced CKD, including those Also, we evaluated the risk of bias using the Cochrane
with protein-energy wasting or at high risk of its develop- Collaboration’s tool for assessing risk of bias (Table 2). We
ment, has not been well studied. The challenge remains as examined the effects of an LPD or very-low-protein diet
to how to reconcile low dietary protein intake—to avoid or (VLPD) (with or without supplementation with ketoacids or
delay dialysis initiation—with adequate nutrient intake and amino acids) on various outcome measures in CKD patients.
nutritional therapy while insuring favourable nutritional The corresponding authors of the studies with incomplete
13 results were contacted in order to request further data.
status and to avoid or correct protein-energy wasting. The
field lacks an up-to-date systematic review and meta-analysis Studies with clinical homogeneity (e.g. similar patients,
study on the subject with a focus on the conservative interventions, and outcomes) were included in meta-
management of CKD. There is an urgency to revisit all tradi- analyses. Statistical heterogeneity was assessed using the I2
tional and novel options for the non-dialytic management statistic. Summary estimates with a corresponding I2 ≤ 50%
of patients with advanced CKD. Given these considerations were pooled using fixed-effects meta-analysis while those
and given commonalities and distinctions of the old and with a corresponding I2 > 50% were pooled using the
emerging controlled trials over the past two decades follow- random-effects model. In addition, in order to ascertain that
ing the Modification of Diet in Renal Disease study, we aimed our results were not dependent on the selected summary
to conduct a comprehensive systematic review and meta- estimate or meta-analysis model, we completed sensitivity
analysis study examining the effect of an LPD on the clinical analyses. Statistical significance was defined as a 95% confi-
management of patients with CKD. dence interval with no overlap with the null effect value
(risk difference/mean difference = 0). For statistical proce-
dures, we used Stata 12 (StataCorp., College Station,TX, USA).
Materials and methods
K.K.-Z., supported by other coauthors, searched MEDLINE Results
(PubMed) and other relevant sources with no limitation in
study type, language, and geographical area using the search Sixteen randomized controlled trials, reported in 17 articles,
terms including ‘low protein diet’, ‘CKD’, and ‘clinical trial’ as each with at least 30 participants, were included in our
Journal of Cachexia, Sarcopenia and Muscle 2017
DOI: 10.1002/jcsm.12264
Low-protein diet for uraemia 3
Figure 1 Flow diagram of the study selection. See also Supporting Information,Table S2 of the New England Journal of Medicine review article, titled,
16
‘Nutritional Management of Chronic Kidney Disease’ by Kalantar-Zadeh and Fouque.
Records screened Records excluded due to poor relevance to
(n = 287) the study subject (n = 241)
Full-text articles Full-text articles excluded due to reporting
assessed for eligibility ineligible study designs, inadequate sample
(n = 46) size, and/or poor relevance (n = 29)
Studies included in
qualitative synthesis
(n = 17)
Studies included in
quantitative synthesis
aka meta-analysis
(n = 9)
review (Table 1). Based on the interventions and compari- PTH was not significantly different in the two intervention
sons, the included studies were divided into the following groups according to the results by Cianciaruso et al.19 and
groups: (i) those comparing LPD with higher-protein Ihle et al.22 However, Malvy et al.28 completed a longer
10,17–24 10,25–30
diets ; (ii) those comparing VLPD with LPD ; and follow-up (up to 40 months) and revealed a significantly
(iii) those involving other comparisons31,32 (Table 1). As all lower PTH in those who received a lower protein intake
studies were not similar in their recruited patients and/or (mean PTH: 2.71 vs. 5.91 ng/mL; P < 0.001). Similarly, serum
outcome measures, not all studies in each category were calcium was not significantly different as reported by Ihle
meta-analysed (Figures 2 and 3). et al.22 and Rosman et al.23 However, it was significantly
higher in the study by Malvy et al.28 with a longer follow-up
duration (serum calcium: 2.42 vs. 2.25 mmol/L; P < 0.01).
Low-protein diet vs. higher-protein diets Also, Jiang et al.17 showed that in peritoneal dialysis
patients, those who received an LPD had better preservation
For this comparison, LPD was defined as a protein intake of of glomerular filtration rate (GFR) and residual kidney
<0.8 mg/kg/day; therefore, VLPD was also considered a function. In addition, PTH was significantly lower in those
subgroup of LPD. Our pooled results showed that the risk of who received ketoacid-supplemented LPD. However, serum
progression to ESRD was significantly lower in those who phosphorus and calcium were not significantly different
received LPD compared with those who received higher- between the two intervention groups.
protein diets (Figure 2A). In addition, the pooled results
indicated a trend towards lower all-cause death in those
who received LPD (Figure 2B). Very-low-protein diet vs. low-protein diet
We also meta-analysed other metabolic factors, which
showed that 1 year serum bicarbonate was significantly Although the primary aim of this review was to compare LPD
higher in those whoreceived LPD(Figure 2C). However, 1year with higher-protein diets, we also performed meta-analyses
serum phosphorus was comparable in the two groups (Figure of studies comparing VLPD with LPD. The two dietary groups
2D). Wecouldnotmeta-analyseresults representingparathy- were respectively defined as those with protein intakes of
roid hormone (PTH), calcium, and other metabolic factors <0.4and0.4–0.8mg/kg/day.Thepooledresults showed that
because of their clinical and methodological heterogeneity. the progression to ESRD was significantly lower (Figure 3A)
In addition to the results of our meta-analysis, some and 1 year GFR was significantly higher (Figure 3C) in those
results by individual studies were also informative: serum who received VLPD compared with LPD. In addition, the
Journal of Cachexia, Sarcopenia and Muscle 2017
DOI: 10.1002/jcsm.12264
4 C.M. Rhee et al.
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Journal of Cachexia, Sarcopenia and Muscle 2017
DOI: 10.1002/jcsm.12264
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