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Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism T. Alp Ikizler 1 , Noel J. Cano 2 , Harold Franch 3 , Denis Fouque 4 , Jonathan Himmelfarb 5 , Kamyar Kalantar-Zadeh 6 , Martin K. Kuhlmann 7 , Peter Stenvinkel 8 , Pieter TerWee 9 , Daniel Teta 10 , Angela Yee-Moon Wang 11 and Christoph Wanner 12 1 Division of Neph
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  Prevention and treatment of protein energy wastingin chronic kidney disease patients: a consensusstatement by the International Society of RenalNutrition and Metabolism  T. Alp Ikizler 1 , Noel J. Cano 2 , Harold Franch 3 , Denis Fouque 4 , Jonathan Himmelfarb 5 ,Kamyar Kalantar-Zadeh 6 , Martin K. Kuhlmann 7 , Peter Stenvinkel 8 , Pieter TerWee 9 , Daniel Teta 10 ,Angela Yee-Moon Wang 11 and Christoph Wanner 12 1 Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA;  2 CHU Clermont-Ferrand, Service de Nutrition, CRNH Auvergne, Clermont-Ferrand, France;  3 Division of Nephrology, Department of Medicine,Emory University, Atlanta, Georgia, USA;  4 Department of Nephrology, Hospital E.HERRIOT, Lyon, France;  5 Division of Nephrology,Department of Medicine, University of Washington, Seattle, Washington, USA;  6 Division of Nephrology, Department of Medicine, University of California Irvine, Orange, California, USA;  7  Division of Nephrology, Department of Medicine, Vivantes Klinikum im Friedrichshain,Berlin Germany;  8 Department of Renal Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden;  9  Department of Nephrology, Vrije University Medical Center, Amsterdam, The Netherlands;  10 Department of Medicine, Service of Nephrology, University Hospital (CHUV), Lausanne, Switzerland;  11 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, People’sRepublic of China and   12 Department of Medicine, Division of Nephrology, University of Wuerzburg, Wuerzburg, Germany  Protein energy wasting (PEW) is common in patients withchronic kidney disease (CKD) and is associated withadverse clinical outcomes, especially in individuals receivingmaintenance dialysis therapy. A multitude of factors canaffect the nutritional and metabolic status of CKD patientsrequiring a combination of therapeutic maneuvers to preventor reverse protein and energy depletion. These includeoptimizing dietary nutrient intake, appropriate treatment of metabolic disturbances such as metabolic acidosis, systemicinflammation, and hormonal deficiencies, and prescribingoptimized dialytic regimens. In patients where oral dietaryintake from regular meals cannot maintain adequatenutritional status, nutritional supplementation, administeredorally, enterally, or parenterally, is shown to be effective inreplenishing protein and energy stores. In clinical practice,the advantages of oral nutritional supplements includeproven efficacy, safety, and compliance. Anabolic strategiessuch as anabolic steroids, growth hormone, and exercise, incombination with nutritional supplementation or alone, havebeen shown to improve protein stores and representpotential additional approaches for the treatment of PEW.Appetite stimulants, anti-inflammatory interventions, andnewer anabolic agents are emerging as novel therapies.While numerous epidemiological data suggest that animprovement in biomarkers of nutritional status is associatedwith improved survival, there are no large randomizedclinical trials that have tested the effectiveness of nutritionalinterventions on mortality and morbidity. Kidney International   (2013)  84,  1096–1107; doi:10.1038/ki.2013.147;published online 22 May 2013KEYWORDS: dialysis; malnutrition; metabolism; nutrition; supplementation Among the many risk factors that affect outcomes of chronickidney disease (CKD) patients, especially ones with end-stagerenal disease (ESRD) and on maintenance dialysis, a stateof metabolic and nutritional derangements, more aptly called  protein-energy wasting (PEW) of chronic kidney disease ,plays a major role. 1–3 Multiple studies now indicate that PEWis closely associated with major adverse clinical outcomes andresults in increased rates of hospitalization and death in thesepatients. 4,5 A significant number of factors affect nutritional andmetabolic status in CKD, leading to multiple adverseconsequences (Figure 1). 6 Accordingly, prevention andtreatment of PEW of CKD should involve an integratedapproach to limit protein and energy depletion, in additionto therapies that will avoid further losses and replenishalready wasted stores. 7 This article aims to provide a broadapproach for the management of PEW, with a specificemphasis on interventions targeted on etiological factors of PEW in CKD patients. The overarching aim is to describemethods to counteract the catabolic processes leading toPEW in CKD and provide means to treat the problem inpatients already with PEW. In doing so, the rationale and review  http://www.kidney-international.org &  2013 International Society of Nephrology Correspondence:  T. Alp Ikizler, Vanderbilt University Medical Center,Division of Nephrology, 1161 21st Avenue South, S-3223 Medical Center North Nashville, Tennessee 37232-2372, USA.E-mail: alp.ikizler@vanderbilt.edu Received 14 February 2013; revised 28 February 2013; accepted 7 March2013; published online 22 May 20131096  Kidney International   (2013)  84 , 1096–1107  efficacy of nutritional interventions in CKD will also bediscussed. This review is focused on stage 3–5 CKD andESRD patients on maintenance dialysis, with literatureselection and interpretation mostly based on the opinion of the authors and is not a systematic review of the literature. PREVENTION OF PEW IN CKDDietary nutrient intake in CKD patients A frequent and important cause of PEW in CKD patients,especially those on maintenance dialysis, is inadequatedietary protein and energy intake. 8–12 A major contributingfactor to inadequate dietary intake in these patients isanorexia. Anorexia may develop as a result of retention of uremic toxins, 13 dialysis procedure, intercurrent illness,inflammation, 4,14 acidemia, and/or cardiovascular disease.Inadequate nutrient intake may also occur secondary to comor-bid illness that affects gastrointestinal function, depression,poor socioeconomic situation, or early satiety feeling withperitoneal fluid infusion, and peritoneal glucose absorptionin peritoneal dialysis (PD). 15,16 Furthermore, additional nutrientloss during dialysis such as amino acids, some peptides, blood,vitamins, trace elements, and glucose may further predisposethese patients to an increased risk of PEW. 17,18 Several strategies can be employed to prevent inadequatenutrient intake in CKD patients (Table 1). In clinically stablepatients with stage 3–5 CKD who are not on dialysis, dietary protein and energy intakes of 0.6–0.8g/kg of ideal body weight per day and 30–35kcal/ kg of ideal body weight perday, respectively, are able to preserve their protein storesthroughout the progression of kidney disease. 19–21 However,these levels should be adjusted when hypermetabolicconditions such as acute illness and hospitalizations occur.In ESRD patients on maintenance dialysis, there areadditional protein catabolic stimuli such as the unavoidableloss of amino acids and albumin into the dialysate andthe inflammatory stimulus associated with the dialysisprocedure. Accordingly, the minimum protein and energy requirements for patients on maintenance hemo- andperitoneal dialysis are 1.2g/kg of ideal body weight per day and 30–35kcal/kg of ideal body weight per day basedon physical activity level, respectively. Furthermore, it isimportant that at least 50% of the protein intake should be of high biological value. In elderly CKD patients who tend tolead a sedentary lifestyle, an energy intake of 30kcal/kg body weight per day is acceptable. In addition to conventionalstrategies to improve dietary nutrient intake, monitored, ProteinenergywastingInfectionCardiovasculardiseaseFrailty, depressionCauses of PEW Consequences of PEWLoss of kidney functionUremic toxinsComorbid conditions(IR, diabetes, CVDdepression)Dialysis-associatedcatabolismMetabolic derangements(HPT, metabolic acidosis,hypogonadism, GH resistance)DietarynutrientintakeInflammation(–)(–)(–)(–)(–)(–)(–)(–)(+)(+)(+) Figure 1|The conceptual model for etiology and consequences of protein energy wasting (PEW) in chronic kidney disease.  CVD,cardiovascular disease; GH, growth hormone; HPT, hyperparathyroidism; IR, insulin resistance. Table 1|Recommended minimum protein, energy, and mineral intakes for chronic kidney disease (CKD) and maintenancedialysis patients Nondialysis CKD Hemodialysis Peritoneal dialysis Protein 0.6–0.8g/kg/dayIllness 1.0g/kg 4 1.2g/kg/day  4 1.2g/kg/dayPeritonitis  4 1.5g/kgEnergy 30–35 a kcal/kg/day 30–35 a kcal/kg/day 30–35 a kcal/kg/day including kcal from dialysateSodium 80–100mmol/day 80–100mmol/day 80–100mmol/dayPotassium  o 1mmol/kg if elevated  o 1mmol/kg if elevated Not usually an issuePhosphorus 800–1000mg and binders if elevated 800–1000mg and binders if elevated 800–1000mg and binders if elevated Greater than 50% of high biological value protein (that is, complete protein sources, containing the full spectrum of essential amino acids) is recommended. a Based on physical activity level. In sedentary elderly adults, recommended energy intake is 30kcal/kg/day. All recommendations are based on ideal body weight. Regularfollow-up supports compliance. TA Ikizler   et al.: Prevention and treatment of PEW in CKD patients  review Kidney International   (2013)  84 , 1096–1107  1097  in-center provision of high-protein meals or supplementsduring hemodialysis is a feasible strategy and should beadvocated in patients at risk. 22 An important consideration regarding strategies toimprove dietary protein intake in ESRD patients is thepotential increase in the intake of several potentially harmfulelements, especially phosphorus. 23 Although strictly limitingdietary phosphorus intake may indirectly lead to increasedrisk for PEW, allowing an unrestricted protein intake willundoubtedly increase phosphorus load. Epidemiologic dataindicate that in maintenance hemodialysis (MHD) patients,a combination of decreased serum phosphorus and increasedprotein intake had the best outcomes, whereas a combinationof low serum phosphorus and protein intake had the worstoutcomes. 24 Therefore, dietary recommendations to improveprotein intake should take into account the phosphoruscontent of the specific protein sources and other phosphorus-containing nutrients. An increase in serum phosphorus,especially following an increase in protein intake, is usually modest and may be primarily due to phosphorus containedin additives/preservatives from processed food. 25,26 In thatcontext, a small randomized clinical trial (RCT) indicatedthat the source of protein (that is, vegetarian diet leadinglower serum phosphorus levels) has a significant effect onphosphorus homeostasis in patients with CKD. 27 Renal replacement therapy Dialysis adequacy has long been viewed as a cornerstoneamong measures to prevent and treat PEW in maintenancedialysis patients, and a minimum dose of dialysis has beenrecommended to maintain optimal dietary nutrient intake.On the other hand, studies directly evaluating the effect of increased dialysis dose on nutritional parameters are scarce.The results of the National Cooperative Dialysis Study showed an association between lower protein intake andhigher time-averaged urea concentrations, suggesting arelationship between underdialysis and anorexia. 28 Thesesubjects also had poor clinical outcomes. Several subsequentstudies suggested that protein nitrogen appearance isdependent on the type and the dose of dialysis. 29,30 In anuric PD patients, increasing the dialysis dose has alsobeen shown to improve dietary intake and nutritionalstatus. 31 However, these retrospective and/or cross-sectionalstudies did not definitively show a cause and effectrelationship between dose of dialysis and nutrition. In theHEMO study, the higher delivered dose of dialysis (eKt/V1.53 ± 0.09) neither prevented nor reversed the decline of several indices of nutritional status in prevalent MHDpatients as compared with conventional dose of dialysis(eKt/V 1.16 ± 0.08). In PD patients, the ADEMEX trial didnot show a significant difference in nutritional markersbetween subjects randomized to control versus high clearance(peritoneal creatinine clearance value of 60l/week per1.73m 2 ). 32 Thus, it can be concluded that what is currently considered adequate dialysis in various guidelines is sufficientto preserve the nutritional status. Increasing dialysis dosebeyond these targets has not been shown to improve thenutritional status any further.Dialysis membrane characteristics might have importantimplications in nutritional management of MHD patients.Middle molecules, such as  b 2-microglobulin, are moreefficiently removed by high-flux dialyzers than low-flux dialyzers, although in the HEMO trial most nutritionalparameters studied did not differ between the two groups. 33 In the European MPO trial, the effects of high-flux versuslow-flux dialysis were studied in incident MHD patients.Although there was no difference for the patient group as awhole, there was a nominally significant survival benefit inpatients with baseline serum albumin levels  o 40g/l(prespecified analysis) and with diabetes mellitus (  post hoc  analysis) randomized to high-flux dialysis. 34 The effects of an increase in dialysis frequency on variousoutcome measures are reported in nonrandomized studiesand suggest that daily dialysis increases appetite, protein andenergy intake, body weight after hemodialysis, interdialyticweight gain, serum albumin, normalized protein nitrogenappearance, and serum cholesterol. 35 However, the resultsof the FHN trial indicate no appreciable difference in nutri-tional markers between subjects randomized to 6  /week in-center hemodialysis versus standard 3  /week in-centerhemodialysis. 36 Hemodiafiltration has also been promoted asan efficient method for the removal of uremic toxins; however,no randomized prospective studies are available on the effectsof hemodiafiltration on nutritional parameters. 37 Metabolic acidosis Metabolic acidosis, a common abnormality in patients withprogressive CKD, promotes PEW by increasing muscleprotein catabolism via suppression of insulin/insulin growthfactor-1 signaling and activation of the ubiquitin–proteasomesystem. 38 In addition, acidosis stimulates the oxidationof essential amino acids and therefore raises proteinrequirements for MHD patients. 39 There are a number of studies indicating improvement in nutritional status withoral bicarbonate supplementation. 40 Metabolic studies in PDpatients showed that correction of a low serum bicarbonateconcentration will downregulate muscle proteolysis, althoughno appreciable effect is observed in net protein synthesis. 41 In an RCT in 134 patients with stage 4 CKD where serumbicarbonate was increased to 24mmol/l dietary protein andenergy intake, mid-arm muscle circumference and serumalbumin improved and progression of CKD was slowed over2 years compared with maintaining a serum bicarbonate levelof 20mmol/l. 40 An RCT in continuous ambulatory peritonealdialysis patients showed similar nutritional benefits exceptfor serum albumin. 42 Accordingly, a steady-state serumbicarbonate level should be  4 22mmol/l in PD patients.Predialysis bicarbonate reflects protein intake in adequately dialyzed MHD patients. To avoid alkalosis after hemodialysis,which associates with adverse outcomes in epidemiologicalstudies, 43 we recommend a predialysis goal of 22–24mmol/lin MHD patients with PEW. 1098  Kidney International   (2013)  84 , 1096–1107 review  TA Ikizler   et al.: Prevention and treatment of PEW in CKD patients  Systemic inflammation Emerging evidence suggests that inflammation is a majordriving force for the uremic phenotype, which commonly includes both premature cardiovascular disease and PEW.Although much information has been gained regardingthe etiology and effects of persistent uremic inflammationin CKD, little knowledge is available with regard to itstreatment. The initial step for treatment of persistentinflammation should be elimination of etiological factorssuch as the use of central hemodialysis catheters in MHDpatients. 44 Short daily dialysis, as compared with conven-tional HD, was associated with improved inflammatory status, 45 and lower levels of interleukin 6 (IL-6) wereobserved following on-line hemodiafiltration as comparedwith conventional HD. 46 As the dialysis procedure  per se might stimulate the immune system, proinflammatory effectsof dialysis membranes and fluids should also be taken intoaccount in maintenance dialysis patients. Overall, dialysisprescription may have a significant impact on systemicinflammation. Appropriate management of fluid status mightimprove systemic inflammation in ESRD patients. Volumeoverload leads to immunoactivation and increased cytokineproduction via bacterial or endotoxin translocation. 47 It hasbeen reported that PD patients that are high transportersare more often inflamed than low transporters. 48,49 Failedkidney transplants are an unrecognized cause of systemicinflammation in maintenance dialysis patients. 50 Finally,there are also data to suggest that bowel bacteria overgrowthand pathologically altered bacterial flora may contribute toinflammation in ESRD patients. 51,52 Comorbidities in CKD CKD patients often have other comorbid diseases that canadversely affect their nutritional status. Patients with CKD *Periodic nutritional screeningSAlb, weight, BMI, MIS, DPI, DEINutritional assessment (as indicated)SPrealb; SGA; anthropometricsã Continuous nutritional counselingã Optimize RRT-Rx and dietary nutrient intakeã Manage comorbidities (acidosis, DM, inflammation, CHF, depression)Indications for nutritional interventions despite preventive measuresã Poor appetite and/or poor oral intakeã DPI<1.2 (CKD 5D) or <0.7 (CKD 3–4); DEI < 30 kcal/kg/dayã SAIb < 3.8 g/dl or Sprealb^< 28 mg/dlã Unintentional weight loss – > 5% of IBW or EDW over 3 monthsã Worsening nutritional markers over timeã SGA in PEW rangeMaintenance nutritional therapy goalsã SAlb > 4.0 g/dlã SPrealb > 30 mg/dlã DPI > 1.2 (CKD-5D) and > 0.7 g/kg/day (CKD 3–4)ã DEI 30–35 kcal/kg/dayStart CKD-specific oral nutritional supplementationã CKD 3–4: DPI target of > 0.8 g/kg/day (± AA/KA or ONS)ã CKD 5D: DPI target > 1.2 g/kg/day (ONS at home or duringdialysis treatment; in-center meals)Intensified therapyã Dialysis prescription alterationsã Increase quantity of oral therapyã Tube feeding or PEG if indicatedã Parenteral interventions:ã IDPN (esp. if SAlb <3.0 g/dl)ã TPNSAlb > 3.8; SPrealb > 28weight or LBM gainNo improvementor deteriorationAdjunct therapiesã Anabolic hormonesã Androgens, GHã Appetite stimulantsã Anti-inflammatory inventionsã Omega 3; IL-1raã Exercise (as tolerated)Continuous preventive measures Figure 2|Proposed algorithm for nutritional management and support in patients with chronic kidney disease.  *Minimum every 3months, monthly screening recommended. ^Only for ESRD patients without residual renal function. AA/KA, amino acid/keto acid; BMI, bodymass index; CHF, congestive heart failure; CKD, chronic kidney disease; DEI, dietary energy intake; DM, diabetes mellitus; DPI, dietary proteinintake; EDW, estimated dry weight; GH, growth hormone; IBW, ideal body weight; IDPN, intradialytic parenteral nutrition; IL-1ra, interleukin-1receptor antagonist; LBM, lean body mass; MIS, malnutrition–inflammation score; ONS, oral nutritional supplement; PEG, percutaneousendoscopic gastrostomy; PEW, protein energy wasting; RRT-Rx, renal replacement therapy prescription; SAlb, serum albumin (measured bybromocresol green); SGA, subjective global assessment; SPrealb, serum prealbumin; TPN, total parenteral nutrition. Kidney International   (2013)  84 , 1096–1107  1099 TA Ikizler   et al.: Prevention and treatment of PEW in CKD patients  review
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