www.renalandurologynews.com october 2013
Renal & Urology News 23
Limiting dietary protein can have positive effects in uremic patients.
that protein sources rich in branchedchain amino acids (especially leucine and isoleucine) or their keto-analogues could be more beneficial in patients with PEW by virtue of their anabolic effects. 26 However, these questions will need to be clarified in properly designed and conducted clinical trials before their mainstream application can be advocated. Until then, an individualized approach to these decisions is suggested based on a patient’s catabolic status and other clinical and financial considerations.
Novel dietary interventions Many of the deleterious effects of dietary protein are related to specific components of the diet. This has led to attempts to control such complications by selectively preventing the absorption of one or more dietary components. Theoretically, such an approach could retain the nutritional benefits of proper protein intake while avoiding its undesirable side effects (Table 1). Phosphorus Phosphorus is present in many dietary proteins. It has numerous adverse effects, including direct vascular toxicity and an association with increased mortality and progression of CKD,27 and the application of phosphorus binders in patients with non-dialysis dependent CKD has been associated with lower mortality in observational studies.28 Small clinical trials in patients with CKD29 and in laboratory
animals30 showed an attenuation of CKD progression after dietary restriction of phosphorus. These studies would need to be corroborated by larger clinical trials before phosphorus binders can be recommended towards treatment of progressive CKD or to decrease mortality. Potassium Potassium is also introduced through intestinal absorption (albeit not necessarily with proteins), and abnormally high or low levels have been associated with increased mortality in CKD and ESRD,31,32 and hypokalemia has also been associated with significantly more severe loss of kidney function.32 Dietary interventions can thus be used to avoid both high and low serum potassium levels with a goal towards improving both renal outcomes and survival. Interventions such as dietary modifications, medical potassium supplementation or the use of potassium binders are widely applied in everyday practice due to the accepted arrhythmogenicity of both hypo- and hyperkalemia. It is thus unlikely that randomized controlled trials will ever be conducted to test the clinical utility of such interventions towards other endpoints; thus, their potential benefits in these regards will likely remain theoretical.
Metabolic acidosis Metabolic acidosis is another frequent metabolic abnormality in CKD and ESRD that can be linked to nutrition
and to the amount of protein intake. Its adverse effects are complex and include protein catabolism and PEW,33 worsening uremic bone disease,34 an association with increased mortality in patients with ESRD,35 non-dialysis dependent CKD,36 kidney damage, and increased progression of CKD.37 Bicarbonate supplementation has been shown to be renoprotective in a number of small single center randomized clinical trials,38;39 and alkali-rich diets such as vegetarian diets administered to CKD patients have been shown to decrease proteinuria40 and serum levels of phosphorus, parathyroid hormone, and fibroblast growth factor-23.41 The impact of therapies for metabolic acidosis on clinical outcomes will also have to be tested in larger clinical trials, but the ease of administration, the relative lack of side effects (provided that metabolic alkalosis is prevented), and the low cost of these interventions make it a desirable therapeutic target that can be pursued even while awaiting final evidence about its efficacy.
Other uremic toxins Indoles and phenols are other potential uremic toxins linked directly or indirectly to intestinal absorption. These are products of protein catabolism in the gut that have been shown to cause oxidative stress, inflammation, vascular and renal toxicity, and increased mortality.42 One of the most frequently studied protein catabolic by-products is indoxyl sulfate, which has also been linked to kidney damage and progression of CKD.43 Binder medications that can lower the absorption and the systemic levels of indoxyl syulfate (such as AST-120) have been shown to ameliorate renal interstitial fibrosis, glomerular sclerosis, and proteinuria43 in animal models. Human benefits have been suggested in small randomized controlled trials.44,45 Unfortunately, similar benefits were not corroborated by larger clinical trials such as the EPPIC-1 and EPPIC-2 studies (ClinicalTrial.gov study numbers: NCT00500682 and NCT00501046). Exploratory analyses indicated that certain subgroups of patients (such as those at high risk for progression and those unable to strictly adhere to the medication regimen) may derive a significant renoprotective benefit from
this intervention, but this would have to be corroborated in future studies.
Conclusions The type and amount of ingested protein affects clinical outcomes such as PEW, kidney function, and even survival, and various dietary interventions have emerged as a means to attempt improving these outcomes. Protein restriction may be effective, but its implementation on a large scale in clinical practice is difficult. Other interventions such as protein supplementation, the use of binder medications to affect intestinal absorption of phosphorus or various protein catabolic products, potassium supplementation, or correction of metabolic acidosis are all possible interventions that could be beneficial for different indications. With the exception of protein restriction (including low protein diets and supplemented very low protein diets), the clinical trial evidence for many of these interventions is sparse or nonexistent, so their wide-scale implementation in clinical practice cannot yet be recommended. n References 1. Chauveau P, Combe C, Rigalleau V, et al. Restricted protein is associated with decreased proteinuria: consequences on the progression of renal failure. J Ren Nutr 2007;17:250-257. 2. Klahr S, Levey AS, Beck GJ, 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;330:877-884. 3. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: what have all the results of the MDRD study shown. Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 1999;10:2426-2439. 4. Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev 2009; CD001892 5. Menon V, Kopple JD, Wang X, et al. Effect of a very low-protein diet on outcomes: long-term follow-up of the Modification of Diet in Renal Disease Study. Am J Kidney Dis 2009;53:208-217. 6. 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 2010;103:608-616. 7. Levey AS, Adler S, Caggiula AW, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1996;27:652-663. 8. Motojima M, Hosokawa A, Yamato H, et al. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int 2003;63:1671-1680. 9. Di Iorio BR, Cucciniello E, Martino R, et al. [Acute and persistent antiproteinuric effect of a lowprotein diet in chronic kidney disease.] G Ital Nefrol 2009;26:608-615. 10. Chang JH, Kim DK, Park JT, et al. Influence of ketoanalogs supplementation on the progression of chronic kidney disease patients who had training on lowprotein diet. Nephrology (Carlton ) 2009;14:750-757.
9/24/13 10:50 AM
Clinical news for nephrologists and urologists.