REVIEW

Benets in Nutritional Interventions in Patients With CKD Stage 3-4

Philippe Chauveau, MD, and Michel Aparicio, MD, PhD
The efcacy and safety of protein-restricted diets in chronic kidney disease (CKD) is still a matter of debate. However, several studies have clearly demonstrated the benecial effects of such diets on the outcome of patients with stage 3-4 CKD. This point has been conrmed by 4 recent studies. In 2009, a meta-analysis showed that protein restriction signicantly delayed the time to renal death with a substantial economic benet for the health service. Although toxicity of urea has since long been considered as negligible, an experimental model in rats has shown a direct role of urea in the development of oxidative stress and insulin resistance, which are among the leading mechanisms of cardiovascular complications in CKD. These latter results conrm an interest in studying reduction in blood urea levels as observed in patients kept on a low-protein diet (LPD) or on a supplemented very-low protein diet (SVLPD). A reduction in proteinuria, which is associated to a LPD, has the following prognostic value: the more important the reduction in proteinuria, slower is the decline in renal function. This effect, which is additive to the one of an angiotensin-converting enzyme inhibitor (ACEI), is higher with SVLPD than with conventional LPD. Safety of a reduced protein intake has been conrmed by the study on the long-term outcomes (11 years) of patients already on SVLPD. The difference between these results and those from the extended follow-up of the modication of diet in renal disease (MDRD) study, in which no recommendations were made after the completion of the trial, conrms the importance of a close nutritional survey of patients with CKD who are put on a protein-restricted diet. 2011 by the National Kidney Foundation, Inc. All rights reserved.

ORE THAN 100 YEARS after the initial publication on the prescription of dietary protein restriction in patients with chronic kidney disease (CKD), this topic remains a matter of debate and controversy, as shown by a recent editorial of Alp Ikizler entitled dietary restriction in CKD: the debate continues.1 Several cases involving meta-analysis have clearly shown that protein restriction prescribed to stable patients with CKD resulted in a signicant delay in renal death without any detrimental effect, as long as patients were being carefully followed up.2 Many nephrologists are still reluctant to prescribe such a diet on account of a potential impairment of nutritional status; however,
Department of Nephrology, Centre Hospitalier Universitaire and University Bordeaux II, Bordeaux, France. Address reprint requests to Philippe Chauveau, Department of Nephrology, Centre Hospitalier Universitaire and University Bordeaux II, Bordeaux, France. E-mail: ph.chauveau@gmail.com 2011 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.11.005

such complications do not seem to have ever been conrmed in the literature. In 2007, Fouque and Aparicio reported the eleven reasons to control the protein intake in patients with CKD.3 In the present review, we report recent studies and new guidance concerning the positive effects of the restriction of protein intake in patients with CKD.

Delay in Renal Replacement Therapy

Studies in the 5/6 nephrectomized rats model have constantly demonstrated that, in comparison with high or normal protein intake, low-protein diet (LPD) and supplemented very-low protein diet (SVLPD) have benecial effects on decrease in renal function.4 The results of clinical studies in human beings are controversial. Most of them included few patients in open studies. The effect of LPD on the rate of decrease of glomerular ltration is also controversial and varies according to the measurement of renal function, that is, slope of decline of plasma creatinine or isotopic
Journal of Renal Nutrition, Vol 21, No 1 (January), 2011: pp 2022

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methods. When the criterion used is renal death or time to renal replacement therapy (RRT), most studies showed a positive effect of protein restriction. In a meta-analysis, which included more than 1,400 patients from 7 controlled studies, Fouque and Aparicio observed that a reduction of 0.2 g protein/kg/day was associated with a reduced renal death of 49%.3 In 2009, another meta-analysis included more than 2,000 patients, and the relative risk of renal death was 0.68 in favor of a reduction in protein intake.5 In 2007, Brunori et al. demonstrated in a randomized study that, for patients aged .70 years, SVLPD delayed the initiation of dialysis without any negative consequence on morbidity and mortality, the mean delay in the SVLPD group was 10.7 months.6 On the basis of this study, an economic evaluation showed that the rst year economic benet for the health service per patient was V21,800.7 In comparison with LPD, SVLPD seems to have an additive effect; Chang et al. studied 120 patients who were trained for 6 months on a LPD (0.6 g/kg/day) and then switched to a SVLPD. Glomerular ltration rate (GFR) decline (estimated using the modication of diet in renal disease [MDRD] formula) during the SVLPD period was signicantly lower in patients with and without diabetes.8

explain these data ndings, the authors propose that urea can alter the function of cytosolic, nuclear, and mitochondrial proteins that are involved in the regulation of mitochondrial ROS production. According to them, reduction of serum urea to its lowest achievable level in addition to a judicious use of antioxidant supplements should be proposed to patients with CKD to stem the production of ROS and their deleterious consequences.

LPD and Proteinuria

One of the less controversial issues concerning LPD in CKD is that in proteinuric patients with or without diabetes, restriction in protein intake is associated with reduction of proteinuria. According to the series, the mean reduction in proteinuria ranges from 20% to 37%. Patients with reduction higher than 50% exhibit a higher reduction of GFR decline. LPD confers an additive effect with an ACE inhibitor or ARB.11 It has been recently demonstrated by Bellizzi et al. that SVLPD had a higher effect on proteinuria as compared with LPD alone.12

Nutritional Safety and Long-term Outcomes

It had been suggested that reduction in protein intake could be associated with an increased risk of malnutrition and that LPD and SVLPD could have detrimental effects before RRT and could also have an effect on morbidity and mortality after patients were put on RRT. This remains true in patients without counseling or on standard nutritional survey. Approximately 50% of patients, who started RRT in the United States between 2005 and 2007, exhibited low serum albumin level. In contrast, among all LPD or SVLPD clinical studies, very few cases of malnutrition have been reported. Nine months after completion of the MDRD study, the mean albuminemia level was 42 g/L, whereas in the Bordeaux cohort of 239 patients, only 2 stopped for malnutrition13 and the mean albuminemia level at the start of RRT was 39 g/L. After the initiation of RRT, patients who were previously on SVLPD rapidly increased their protein intake and maintained an adequate calories intake at least during the rst year. In 2009, we examined the long-term outcomes of patients who were included between 1985 and 2000. The survival rate of dialysis patients was comparable with those of the

Insulin Resistance and Oxidative Stress

The increased level of oxidative stress and insulin resistance (IR), which are common in patients with CKD, seem to play a crucial role in the pathogenesis of several complications, particularly atherosclerosis, which is the leading cause of death in uremic patients.9 These abnormalities are observed in dialyzed patients as well as in patients with mild or moderate CKD. A recent article10 suggested that an increased level of urea, which has since long been considered to have negligible toxicity, could be the link between these 2 abnormalities. In a mouse model of CKD induced by 5/6 nephrectomy, DApolito et al. reported increased reactive oxygen species (ROS) production, IR, and increased expression of IR-associated adipokines in visceral adipose tissue. Urea infusion in normal animals induced abnormalities similar to that observed in uremic animals. The impairment of insulin sensitivity was corrected by antioxidant therapy, thereby leading the authors to conclude that IR resulted from urea-induced ROS. To

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renal diseases: a meta-analysis. Ann Intern Med 124:627-632, 1996 3. Fouque D, Aparicio M: Eleven reasons to control the protein intake of patients with chronic kidney disease. Nat Clin Pract Nephrol 3:383-392, 2007 4. Gao X, Wu J, Dong Z, et al: A low-protein diet supplemented with ketoacids plays a more protective role against oxidative stress of rat kidney tissue with 5/6 nephrectomy than a low-protein diet alone. Br J Nutr 103:608-616, 2010 5. Fouque D, Laville M: Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev 3: CD001892, 2009. 6. Brunori G, Viola BF, Parrinello G, et al: Efcacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis 49:569-580, 2007 7. Scalone L, Borghetti F, Brunori G, et al: Cost-benet analysis of supplemented very low-protein diet versus dialysis in elderly CKD5 patients. Nephrol Dial Transplant 25:907-913, 2010 8. Chang JH, Kim DK, Park JT, et al: Inuence of ketoanalogs supplementation on the progression in chronic kidney disease patients who had training on low-protein diet. Nephrology (Carlton) 14:750-757, 2009 9. Rigalleau V, Gin H: Carbohydrate metabolism in uraemia. Curr Opin Clin Nutr Metab Care 8:463-469, 2005 10. DApolito M, Du X, Zong H, et al: Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest 120:203-213, 2010 11. Chauveau P, Combe C, Rigalleau V, et al: Restricted protein diet is associated with decrease in proteinuria: consequences on the progression of renal failure. J Ren Nutr 17: 250-257, 2007 12. Bellizzi V, Di Ioro BR, De Nicola L, et al: Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease. Kidney Int 71:245-251, 2007 13. Chauveau P, Couzi L, Vendrely B, et al: Long-term outcome on renal replacement therapy in patients who previously received a keto acid-supplemented very-low-protein diet. Am J Clin Nutr 90:969-974, 2009 14. Menon V, Kopple JD, Wang X, et al: Effect of a very lowprotein diet on outcomes: long-term follow-up of the Modication of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 53:208-217, 2009

age-matched patients of the French national registry. The outcome of patients who underwent grafting could be favorably compared with that of the entire cohort of patients who underwent grafting in Bordeaux during the same period.13 These results are in contradiction with those of an extended follow-up of the MDRD study by Menon et al. conducted in 2009,14 in which no recommendations were made after the completion of the trial and no information on medical management and clinical course was available. This conrms that close nutritional survey during the diet, education of the patient and his family, close nutritional counseling when the patient starts RRT, and motivation of the medical staff throughout the patients history from CKD to dialysis and transplantation represent the cornerstone of success of a program of dietary prescription in patients with CKD.

Conclusion
LPD or SVLPD are associated with many benecial effects in patients with CKD stages 3-4. To avoid malnutrition, the nephrology unit should be able to provide nutritional support and education. In these ideal conditions of agreement between the patients and the staff, after an educational program, nutritional therapy with LPD is considered to be nutritionally safe.

References
1. Ikizler TA: Dietary protein restriction in CKD: the debate continues. Am J Kidney Dis 53:189-191, 2009 2. Pedrini MT, Levey AS, Lau J, et al: The effect of dietary protein restriction on the progression of diabetic and nondiabetic