Produção Nacional
Revisado por pares
Nutrition and chronic kidney disease
2011; Elsevier BV; Volume: 80; Issue: 4 Linguagem: Inglês
10.1038/ki.2011.118
ISSN1523-1755
AutoresDenis Fouque, Sandra Pelletier, Denise Mafra, Philippe Chauveau,
Tópico(s)Iron Metabolism and Disorders
ResumoThe incidence of malnutrition disorders in chronic kidney disease (CKD) appears unchanged over time, whereas patient-care and dialysis techniques continue to progress. Despite some evidence for cost-effective treatments, there are numerous caveats to applying these research findings on a daily care basis. There is a sustained generation of data confirming metabolic improvement when patients control their protein intake, even at early stages of CKD. A recent protein–energy wasting nomenclature allows a simpler approach to the diagnosis and causes of malnutrition. During maintenance dialysis, optimal protein and energy intakes have been recently challenged, and there is no longer an indication to control hyperphosphatemia through diet restriction. Recent measurements of energy expenditure in dialysis patients confirm very low physical activity, which affects energy requirements. Finally, inflammation, a common state during CKD, acts on both nutrient intake and catabolism, but is not a contraindication to a nutritional intervention, as patients do respond and improve their survival as well as do noninflamed patients. The incidence of malnutrition disorders in chronic kidney disease (CKD) appears unchanged over time, whereas patient-care and dialysis techniques continue to progress. Despite some evidence for cost-effective treatments, there are numerous caveats to applying these research findings on a daily care basis. There is a sustained generation of data confirming metabolic improvement when patients control their protein intake, even at early stages of CKD. A recent protein–energy wasting nomenclature allows a simpler approach to the diagnosis and causes of malnutrition. During maintenance dialysis, optimal protein and energy intakes have been recently challenged, and there is no longer an indication to control hyperphosphatemia through diet restriction. Recent measurements of energy expenditure in dialysis patients confirm very low physical activity, which affects energy requirements. Finally, inflammation, a common state during CKD, acts on both nutrient intake and catabolism, but is not a contraindication to a nutritional intervention, as patients do respond and improve their survival as well as do noninflamed patients. After the first hemodialysis sessions in the early sixties,1.Scribner B.J. Buri R. Caner J.E. et al.The treatment of chronic uremia by means of intermittent hemodialysis: a preliminary report.Trans ASAIO. 1960; 6: 114-122Google Scholar Dr Scribner rapidly pointed out key questions that emerged after these first treatments: how to better control blood pressure, how to manage chronic anemia, and which nutrients should be recommended to these patients. Fifty years later in 2010, the two first issues have been largely solved. By contrast, there is still much to do to fight protein–energy wasting as present epidemiological studies report between 30 and 50% of patients with signs of malnutrition.2.Aparicio M. Cano N. Chauveau P. et al.Nutritional status of haemodialysis patients: a French national cooperative study. French Study Group for Nutrition in Dialysis.Nephrol Dial Transplant. 1999; 14: 1679-1686Crossref PubMed Scopus (162) Google Scholar, 3.Kobayashi I. Ishimura E. Kato Y. et al.Geriatric Nutritional Risk Index, a simplified nutritional screening index, is a significant predictor of mortality in chronic dialysis patients.Nephrol Dial Transplant. 2010; 25: 3361-3365Crossref PubMed Scopus (31) Google Scholar, 4.Pifer T.B. McCullough K.P. Port F.K. et al.Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS.Kidney Int. 2002; 62: 2238-2245Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 5.Chauveau P. Combe C. Laville M. et al.Factors influencing survival in hemodialysis patients aged older than 75 years: 2.5-year outcome study.Am J Kidney Dis. 2001; 37: 997-1003Abstract Full Text PDF PubMed Google Scholar What are the signs or protein–energy wasting? Are these symptoms already present before dialysis? Is this possible to correct these abnormalities and how? In this review, we will try to answer some of these important points. There is now evidence that patients with chronic kidney disease (CKD) should control their protein intake to reach optimal body protective values.6.Fouque D. Aparicio M. Eleven reasons to control the protein intake of patients with chronic kidney disease.Nat Clin Pract Nephrol. 2007; 3: 383-392Crossref PubMed Scopus (51) Google Scholar After an extensive review of the literature, most of the scientific societies worldwide recommend a daily allowance of 0.6–0.8 g protein/kg/day for CKD patients with or without diabetes.7.KDOQI KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 8.Toigo G. Aparicio M. Attman P.O. et al.Expert Working Group report on nutrition in adult patients with renal insufficiency (part 1 of 2).Clin Nutr. 2000; 19: 197-207Abstract Full Text PDF PubMed Scopus (54) Google Scholar, 9.Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation.Am J Kidney Dis. 2000; 35: S1-S140Abstract Full Text Full Text PDF PubMed Google Scholar, 10.Wright M. Jones C. Clinical Practices Guidelines: nutrition in CKD.UK Renal Association. 2010www.renal.org/guidelinesGoogle Scholar, 11.ANAES Moyens thérapeutiques pour ralentir la progression de l’insuffisance rénale chronique chez l’adulte.ANAES. 2004http://www.has-sante.fr/portail/plugins/ModuleXitiKLEE/types/FileDocument/doXiti.jsp?id=c_268116Google Scholar Clinical trials confirmed by meta-analyses on large numbers (e.g., more than 2000 patients) show that it is effective and safe to reduce protein intake from the western-type diet, which contains about 1.3–1.4 g protein/kg/day to a nutritionally and metabolically optimal intake of 0.6–0.8 g protein/kg/day.12.Fouque D. Laville M. Low protein diets for chronic kidney disease in non diabetic adults.Cochrane Database Syst Rev. 2009: CD001892-1254Crossref Scopus (0) Google Scholar,13.Bernhard J. Beaufrere B. Laville M. et al.Adaptive response to a low-protein diet in predialysis chronic renal failure patients.J Am Soc Nephrol. 2001; 12: 1249-1254PubMed Google Scholar This is particularly important in patients with proteinuria, including those with diabetic nephropathy, as any increase in protein intake will increase proteinuria, which per se, is a risk factor for CKD progression.14.Levey A.S. Greene T. Beck G.J. et al.Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group.J Am Soc Nephrol. 1999; 10: 2426-2439PubMed Google Scholar,15.Brantsma A.H. Atthobari J. Bakker S.J. et al.What predicts progression and regression of urinary albumin excretion in the nondiabetic population?.J Am Soc Nephrol. 2007; 18: 637-645Crossref PubMed Scopus (28) Google Scholar Furthermore, reducing protein intake decreases proteinuria as efficiently as angiotensin-converting enzyme inhibitors,16.Aparicio M. Bouchet J.L. Gin H. et al.Effect of a low-protein diet on urinary albumin excretion in uremic patients.Nephron. 1988; 50: 288-291Crossref PubMed Google Scholar,17.Maroni B.J. Staffeld C. Young V.R. et al.Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet.J Clin Invest. 1997; 99: 2479-2487Crossref PubMed Google Scholar improves serum lipid profile,18.Bernard S. Fouque D. Laville M. et al.Effects of low-protein diet supplemented with ketoacids on plasma lipids in adult chronic renal failure.Miner Electrolyte Metab. 1996; 22: 143-146PubMed Google Scholar and has an additional effect on proteinuria reduction to that of angiotensin-converting enzyme inhibitors.19.Gansevoort R.T. de Zeeuw D. de Jong P.E. Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease.Nephrol Dial Transplant. 1995; 10: 497-504PubMed Google Scholar Thus, based solely on proteinuria, there is a strong rationale to control protein intake. Limiting protein intake is associated with an instant decrease in wasted products and uremic toxins, blood urea nitrogen levels, and acid load. Metabolic consequences of restricted protein diet have been extensively reviewed:6.Fouque D. Aparicio M. Eleven reasons to control the protein intake of patients with chronic kidney disease.Nat Clin Pract Nephrol. 2007; 3: 383-392Crossref PubMed Scopus (51) Google Scholar reduction in oxidative stress, amelioration of insulin resistance, better control of metabolic bone disorders in response to a reduced phosphate load, and subsequent improvement in anemia control.20.Bellizzi V. Di Iorio B.R. De Nicola L. et al.Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease.Kidney Int. 2007; 71: 245-251Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 21.Di Iorio B.R. Minutolo R. De Nicola L. et al.Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure.Kidney Int. 2003; 64: 1822-1828Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 22.Rigalleau V. Blanchetier V. Combe C. et al.A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients.Am J Clin Nutr. 1997; 65: 1512-1516PubMed Google Scholar, 23.Combe C. Morel D. de Precigout V. et al.Long-term control of hyperparathyroidism in advanced renal failure by low-phosphorus low-protein diet supplemented with calcium (without changes in plasma calcitriol).Nephron. 1995; 70: 287-295Crossref PubMed Google Scholar As CKD is associated with protein–energy wasting,24.Fouque D. Kalantar-Zadeh K. Kopple J. et al.A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.Kidney Int. 2008; 73: 391-398Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar the nutritional safety of such a protein reduction has been questioned.25.Ikizler T.A. Dietary protein restriction in CKD: the debate continues.Am J Kidney Dis. 2009; 53: 189-191Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Muscle wasting is associated with CKD and increases dependency, mortality, and morbidity in this population.26.Workeneh B.T. Mitch W.E. Review of muscle wasting associated with chronic kidney disease.Am J Clin Nutr. 2010; 91: 1128S-1132SCrossref PubMed Scopus (86) Google Scholar From a basic point of view, one should find a direct relationship between reduced protein intake and muscle wasting. Unfortunately, this approach is not clinically relevant: muscle wasting in chronic diseases is mainly due to an imbalance between protein synthesis and degradation, and is further worsened by inactivity.27.Evans W.J. Skeletal muscle loss: cachexia, sarcopenia, and inactivity.Am J Clin Nutr. 2010; 91: 1123S-11127Crossref PubMed Scopus (171) Google Scholar In addition, acidosis and activation of the ubiquitin–proteasome pathway associated with inflammation and insulin resistance represent the main factors of muscle wasting.26.Workeneh B.T. Mitch W.E. Review of muscle wasting associated with chronic kidney disease.Am J Clin Nutr. 2010; 91: 1128S-1132SCrossref PubMed Scopus (86) Google Scholar,28.Kalantar-Zadeh K. Mehrotra R. Fouque D. et al.Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure.Semin Dial. 2004; 17: 455-465Crossref PubMed Scopus (84) Google Scholar Reducing protein intake has been shown to improve all these catabolic conditions. Indeed, a better control of metabolic acidosis due to a lower acid load leads to a normalization of the adaptive responses to dietary protein restriction, as it has been clearly demonstrated in animals models, CKD, and dialysis patients,29.Mitch W.E. Metabolic acidosis stimulates protein metabolism in uremia.Miner Electrolyte Metab. 1996; 22: 62-65PubMed Google Scholar, 30.Goodship T.H. Mitch W.E. Hoerr R.A. et al.Adaptation to low-protein diets in renal failure: leucine turnover and nitrogen balance.J Am Soc Nephrol. 1990; 1: 66-75PubMed Google Scholar, 31.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (252) Google Scholar and seems beneficial on the progression of CKD.31.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (252) Google Scholar Insulin resistance is associated with muscle protein breakdown in end-stage renal disease patients32.Siew E.D. Pupim L.B. Majchrzak K.M. et al.Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients.Kidney Int. 2007; 71: 146-152Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and rapidly improves after 3 months of low-protein diet (LPD).22.Rigalleau V. Blanchetier V. Combe C. et al.A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients.Am J Clin Nutr. 1997; 65: 1512-1516PubMed Google Scholar Recent experimental data suggest that an increase in blood urea nitrogen induces reactive oxygen species production and enhances insulin resistance.33.D’Apolito M. Du X. Zong H. et al.Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure.J Clin Invest. 2010; 120: 203-213Crossref PubMed Scopus (63) Google Scholar Oxidative stress and upregulation of oxidative metabolism are among the main factors responsible for sarcopenia in chronic disease and in aging. Recent data suggest that oxidative stress is associated with severe disturbances of muscle function even without muscle atrophy.34.Kuwahara H. Horie T. Ishikawa S. et al.Oxidative stress in skeletal muscle causes severe disturbance of exercise activity without muscle atrophy.Free Radic Biol Med. 2010; 48: 1252-1262Crossref PubMed Scopus (43) Google Scholar Moreover, oxidative stress is probably one of the main factors that aggravate glomerulosclerosis and fibrosis during CKD. A low-protein intake confers a protection against oxidative stress in experimental studies.35.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: 608Crossref PubMed Scopus (12) Google Scholar,36.Peuchant E. Delmas-Beauvieux M.C. Dubourg L. et al.Antioxidant effects of a supplemented very low protein diet in chronic renal failure.Free Radic Biol Med. 1997; 22: 313-320Crossref PubMed Scopus (48) Google Scholar Finally in CKD patients treated with LPD or supplemented very low-protein diet (SVLPD), long-term studies on body composition did not find any adverse effect of such diets on muscle or lean body mass.37.Chauveau P. Vendrely B. El Haggan W. et al.Body composition of patients on a very low-protein diet: a two-year survey with DEXA.J Ren Nutr. 2003; 13: 282-287Abstract Full Text Full Text PDF PubMed Google Scholar, 38.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. 2007; 17: 250-257Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 39.Vendrely B. Chauveau P. Barthe N. et al.Nutrition in hemodialysis patients previously on a supplemented very low protein diet.Kidney Int. 2003; 63: 1491-1498Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Quality of protein intake (and not only quantity) should also be addressed. First, despite debate and controversies, clinical studies in patients receiving LPD (0.6–0.8 g/kg/day) or SVLPD (0.3–0.6 g/kg/day, supplemented with amino acids or keto-analogs) are nutritionally safe. No case of malnutrition occurred, in response to an adequate metabolic adaptation.13.Bernhard J. Beaufrere B. Laville M. et al.Adaptive response to a low-protein diet in predialysis chronic renal failure patients.J Am Soc Nephrol. 2001; 12: 1249-1254PubMed Google Scholar,17.Maroni B.J. Staffeld C. Young V.R. et al.Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet.J Clin Invest. 1997; 99: 2479-2487Crossref PubMed Google Scholar In the Modification of Diet in Renal Disease study, 9 months after completion of the study, the mean serum albumin was 42 g/l, and in the 239 patients of the Bordeaux cohort, only two patients stopped an SVLPD diet for reason of malnutrition, whereas the mean cohort serum albumin at start of renal replacement therapy was 39 g/l.40.Menon V. Kopple J.D. 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 (MDRD) study.Am J Kidney Dis. 2009; 53: 208-217Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,41.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. 2009; 90: 969-974Crossref PubMed Scopus (27) Google Scholar Most patients who start renal replacement therapy without prior dietary follow-up do present symptoms of malnutrition, for example, loss of body weight, altered anthropometry, and laboratory nutritional parameters.42.Kaysen G.A. Johansen K.L. Cheng S.C. et al.Trends and outcomes associated with serum albumin concentration among incident dialysis patients in the United States.J Ren Nutr. 2008; 18: 323-331Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The occurrence of a previous nutritional care plan appears to be the main protective factor against this progressive wasting. First, nutritional support and patient information are key factors to ensure motivation and adherence to the diet. This fact has been clearly demonstrated by Campbell et al.,43.Campbell K.L. Ash S. Davies P.S. et al.Randomized controlled trial of nutritional counseling on body composition and dietary intake in severe CKD.Am J Kidney Dis. 2008; 51: 748-758Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar using body composition analysis and subjective global assessment. Second, in clinical studies, an LPD is usually composed of 50% protein of high biological value (such as meat, fish, or egg). In the case of SVLPD, no malnutrition occurred and long-term survey during or after the start of renal replacement therapy did not show a greater relative risk of death.41.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. 2009; 90: 969-974Crossref PubMed Scopus (27) Google Scholar Third, animal experiments and studies in elderly patients renewed attention on protein quality and the importance of essential amino acids intake. Indeed, in the elderly, a protein intake higher than 0.8 g/kg/day is recommended to avoid sarcopenia due to a relative resistance of muscle to the anabolic effect of an amino-acid load.44.Wolfe R.R. Miller S.L. Miller K.B. Optimal protein intake in the elderly.Clin Nutr. 2008; 27: 675-684Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar However, this resistance could be inhibited using amino-acid mixtures, particularly those enriched in branched-chain amino acids, that is, leucine, isoleucine, and valine.45.Kim J.S. Wilson J.M. Lee S.R. Dietary implications on mechanisms of sarcopenia: roles of protein, amino acids and antioxidants.J Nutr Biochem. 2010; 21: 1-13Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar An indirect evidence of the effect of amino acids on CKD-associated sarcopenia is reflected by the observation that, in dialysis patients, resistance training effect on muscle metabolism is enhanced when combined with intradialytic parenteral nutrition.46.Pupim L.B. Flakoll P.J. Levenhagen D.K. et al.Exercise augments the acute anabolic effects of intradialytic parenteral nutrition in chronic hemodialysis patients.Am J Physiol Endocrinol Metab. 2004; 286: E589-E597Crossref PubMed Scopus (53) Google Scholar In elderly, sarcopenia is partly explained by enhanced oxidative stress. In nephrectomized rat, increased oxidative stress caused by protein malnutrition impairs the glomerular filtration barrier and a supplementation with ketoacids reduced kidney and oxidative stress injury.35.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: 608Crossref PubMed Scopus (12) Google Scholar Finally, clinical studies using LPD or SVLPD bear a great attention on energy intake. Specific dietary survey is provided to ensure a sufficient amount of calories, for example, ∼35 kcal/kg/day. This is not always the case in most renal units where time of dietitian is lacking. In conclusion, the beneficial effects of reducing protein intake to optimal values are obscured by the lack of physician confidence, dietitian time, and patient education. Although immediately costly and sometimes tricky to set up, nutritional support should be provided for the patient's sake and is clearly cost-effective over the long term.47.Locatelli F. Del Vecchio L. How long can dialysis be postponed by low protein diet and ACE inhibitors?.Nephrol Dial Transplant. 1999; 14: 1360-1364Crossref PubMed Scopus (30) Google Scholar One of the major side effects of kidney disease is the subtle development of anorexia and the concurrent reduction of protein–energy intake, already present at stage III of CKD48.Kopple J.D. Greene T. Chumlea W.C. et al.Relationship between nutritional status and the glomerular filtration rate: results from the MDRD study.Kidney Int. 2000; 57: 1688-1703Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar and during dialysis.49.Kalantar-Zadeh K. Block G. McAllister C.J. et al.Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients.Am J Clin Nutr. 2004; 80: 299-307PubMed Google Scholar, 50.Carrero J.J. Qureshi A.R. Axelsson J. et al.Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite.Am J Clin Nutr. 2007; 85: 695-701PubMed Google Scholar, 51.Carrero J.J. Mechanisms of altered regulation of food intake in chronic kidney disease.J Ren Nutr. 2011; 21: 7-11Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar A number of orexigenic or anorexigenic hormone dysregulations (leptin, ghrelin, peptide YY, and obestatin) have been proposed to explain anorexia in healthy adults and patients.52.Korner J. Leibel R.L. To eat or not to eat–how the gut talks to the brain.N Engl J Med. 2003; 349: 926-928Crossref PubMed Scopus (144) Google Scholar, 53.Mafra D. Jolivot A. Chauveau P. et al.Are ghrelin and leptin involved in food intake and body mass index in maintenance hemodialysis?.J Ren Nutr. 2010; 20: 151-157Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 54.Mak R.H. Cheung W. Adipokines and gut hormones in end-stage renal disease.Perit Dial Int. 2007; 27: S298-S302PubMed Google Scholar Administering recombinant ghrelin during 7 days has been showed to increase meal energy intake by ∼25% in malnourished hemodialysis patients.55.Ashby D.R. Ford H.E. Wynne K.J. et al.Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment.Kidney Int. 2009; 76: 199-206Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Interestingly, Cheung et al. suggested a dysfunction of hypothalamic appetite-regulating sensors, such as the melanocortin-4 receptor.56.Cheung W. Yu P.X. Little B.M. et al.Role of leptin and melanocortin signaling in uremia-associated cachexia.J Clin Invest. 2005; 115: 1659-1665Crossref PubMed Scopus (160) Google Scholar,57.Cheung W.W. Kuo H.J. Markison S. et al.Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice.J Am Soc Nephrol. 2007; 18: 2517-2524Crossref PubMed Scopus (42) Google Scholar Chronic renal failure mice knockout for this receptor ate normally, whereas their wild-type melanocortin-4 receptor counterparts severely reduced their food intake as a response to kidney failure.56.Cheung W. Yu P.X. Little B.M. et al.Role of leptin and melanocortin signaling in uremia-associated cachexia.J Clin Invest. 2005; 115: 1659-1665Crossref PubMed Scopus (160) Google Scholar When a melanocortin-4 receptor antagonist (such as NBI-12i) was administered to uremic mice, they gained lean and fat mass while lowering their energy expenditure, resulting in a net nutritional improvement. These findings may represent an interesting field to explore in order to improve patients appetite and food intake. Growth hormone has also been associated with improved food efficiency in CKD. Indeed, Mehls et al.58.Mehls O. Ritz E. Hunziker E.B. et al.Improvement of growth and food utilization by human recombinant growth hormone in uremia.Kidney Int. 1988; 33: 45-52Abstract Full Text PDF PubMed Google Scholar reported that uremic rats receiving recombinant growth hormone gained more weight per gram food intake than uremic rats receiving vehicle. Combining growth hormone and insulin-like growth factor-1 improved food utilization and anabolic response in experimental59.Hazel S.J. Gillespie C.M. Moore R.J. et al.Enhanced body growth in uremic rats treated with IGF-I and growth hormone in combination.Kidney Int. 1994; 46: 58-68Abstract Full Text PDF PubMed Google Scholar and clinical CKD.60.Guebre-Egziabher F. Juillard L. Boirie Y. et al.Short-term administration of a combination of recombinant growth hormone and insulin-like growth factor-I induces anabolism in maintenance hemodialysis.J Clin Endocrinol Metab. 2009; 94: 2299-2305Crossref PubMed Scopus (13) Google Scholar Muscle wasting is a predominant feature of CKD and is particularly present in long-term maintenance dialysis patients. Low muscle mass is associated with increased mortality.61.Noori N. Kopple J.D. Kovesdy C.P. et al.Mid-arm muscle circumference and quality of life and survival in maintenance hemodialysis patients.Clin J Am Soc Nephrol. 2010; 5: 2258-2268Crossref PubMed Scopus (86) Google Scholar Muscle wasting results partly from reduced physical activity (see section below) but also because of resistance to anabolic factors. The impaired action of growth hormone and/or insulin-like growth factor-1 has been studied in detail during maintenance dialysis in children and adults as well.62.Mak R.H. Cheung W.W. Roberts Jr, C.T. The growth hormone-insulin-like growth factor-I axis in chronic kidney disease.Growth Horm IGF Res. 2008; 18: 17-25Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 63.Fouque D. Peng S.C. Kopple J.D. Pharmacokinetics of recombinant human insulin-like growth factor-1 in dialysis patients.Kidney Int. 1995; 47: 869-875Abstract Full Text PDF PubMed Google Scholar, 64.Fouque D. Insulin-like growth factor 1 resistance in chronic renal failure.Miner Electrolyte Metab. 1996; 22: 133-137PubMed Google Scholar Short-term therapeutic interventions have been successful in improving body composition,65.Feldt-Rasmussen B. Lange M. Sulowicz W. et al.Growth hormone treatment during hemodialysis in a randomized trial improves nutrition, quality of life, and cardiovascular risk.J Am Soc Nephrol. 2007; 18: 2161-2171Crossref PubMed Scopus (75) Google Scholar,66.Fouque D. Peng S.C. Shamir E. et al.Recombinant human insulin-like growth factor-1 induces an anabolic response in malnourished CAPD patients.Kidney Int. 2000; 57: 646-654Abstract Full Text Full Text PDF PubMed Google Scholar however side effects request long-term studies that are not yet available. As there is a testosterone deficit, which is associated with superimposed mortality in men,67.Carrero J.J. Qureshi A.R. Parini P. et al.Low serum testosterone increases mortality risk among male dialysis patients.J Am Soc Nephrol. 2009; 20: 613-620Crossref PubMed Scopus (88) Google Scholar it may be interesting to test short courses of androgen support in case of severe cachexia and muscle wasting,68.Fouque D. Vennegoor M. ter Wee P. et al.EBPG guideline on nutrition.Nephrol Dial Transplant. 2007; 22: ii45-ii87Crossref PubMed Scopus (230) Google Scholar in association with physical training. Indeed, most anabolic factors will not be efficient if they are not associated with a rehabilitation program. In order to clarify the definition of kidney-associated protein–energy wasting, the International Society for Renal Nutrition and Metabolism released in 2008 a nomenclature paper focused on the causes, consequences, and diagnostic criteria of impaired nutritional status in CKD patients.24.Fouque D. Kalantar-Zadeh K. Kopple J. et al.A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.Kidney Int. 2008; 73: 391-398Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar Four groups of parameters were examined (Table 1): serum chemistry, body composition, muscle mass, and dietary intake. For each parameter, a threshold was given based on the most recent epidemiological studies in CKD patients. Protein–energy wasting is then identified if at least one parameter is found below recommendation in three of the four marker groups,24.Fouque D. Kalantar-Zadeh K. Kopple J. et al.A proposed nomenclature and diagn
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