Diets and enteral supplements for improving outcomes in chronic kidney disease

Protein-energy wasting (PEW), which is manifested by low serum levels of albumin or prealbumin, sarcopenia and weight loss, is one of the strongest predictors of mortality in patients with chronic kidney disease (CKD). Although PEW might be engendered by non-nutritional conditions, such as inflammation or other comorbidities, the question of causality does not refute the effectiveness of dietary interventions and nutritional support in improving outcomes in patients with CKD. The literature indicates that PEW can be mitigated or corrected with an appropriate diet and enteral nutritional support that targets dietary protein intake. In-center meals or oral supplements provided during dialysis therapy are feasible and inexpensive interventions that might improve survival and quality of life in patients with CKD. Dietary requirements and enteral nutritional support must also be considered in patients with CKD and diabetes mellitus, in patients undergoing peritoneal dialysis, renal transplant recipients, and in children with CKD. Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions. Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or are ineffective. Controlled trials are needed to better assess the effectiveness of in-center meals and oral supplements.


Introduction
Overnutrition is a major problem in the general population and a serious risk factor for developing metabolic syndrome, cardiovascular disease and chronic kidney disease (CKD), with a subsequent increase in risk of mortality.By contrast, in patients with CKD, and especially in those undergoing maintenance dialysis, the so-called uremic malnutrition 1 (also referred to as protein-energy wasting [PEW]) 2 is by far the strongest risk factor for adverse outcomes and death; 3 surrogates of overnutrition such as obesity or hyperlipidemia seem, counterintuitively, to be associated with increased survival. 4Similar associations have been described in individuals with other chronic disease states, such as respiratory failure and heart failure, 5,6 or in the elderly population. 7In CKD and other chronic diseases that are associated with wasting syndrome, it is believed that pathophysiological pathways associated with malnutrition are killers in the short-term and render risk factors such as obesity or hypertension practically irrelevant with regard to their contribution to mortality.In other words, patients undergoing dialysis die of the short-term consequences of PEW and do not live long enough to die of risk factors associated with overnutrition.This 'timediscrepancy hypothesis' 8 suggests that, in a patient with CKD whose risk of short-term mortality is high, interventions that improve nutritional status and prevent or correct wasting and sarcopenia have the potential to save lives, as compared with conventional interventions such as treating hypercholesterolemia, hypertension or obesity.Indeed, two randomized, controlled trials have shown that lowering cholesterol in patients on dialysis with hyperlipidemia has no effect on survival. 9,10A 10-year cohort study in 206 patients undergoing hemodialysis indicated that serum albumin concentration was far superior as a predictor of mortality than inflammatory markers or intima-media thickness of the common carotid artery. 11PEW seems, therefore, to be a strong predictor of mortality in patients with CKD, and improving nutritional status by dietary and non dietary interventions could be an important step towards improving outcomes in CKD.In this Review, we will focus on the dietary and enteral management of CKD as an important component of patient care.Parenteral and non dietary interventions, including adjunctive therapies, are also mentioned briefly.

PEW, mortality and albumin levels
Evidence indicates that surrogates of PEW, such as low serum levels of albumin or inadequate protein intake, correlate with mortality.Indeed, a low serum albumin concentration is by far the strongest predictor of poor outcomes and mortality, at least in patients on dialysis, when compared with any other risk factor, 12,13 including traditional risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and obesity) or nonconventional risk factors (measures of anemia, mineral and bone surrogates, and dialysis modality). 3The sensitivity of measuring serum levels of albumin to predict outcomes in patients with CKD is high, with a granularity of as little as 2 g/l or less (Figure 1). 14,15In other words, a patient on dialysis with a baseline serum albumin concentration of 2 g/l above or below that of another patient with similar demographic features and comorbidities has a substantially decreased or increased risk of death, respectively.
The association between serum albumin levels and mortality is highly incremental and linear, and the mortality predictability of a serum albumin concentration of <40 g/l has virtually no cut-off level below which the association with death would cease or reverse. 14,15This association is in sharp contrast to most other predictors of outcome in CKD, which have U-shaped or J-shaped survival associations.More importantly, changes in serum levels of albumin over time are associated with proportional and reciprocal alterations in the risk of mortality, in that an increase or decrease in serum albumin concentration of as little as 1 g/l over a period of a few months is associated with increased or decreased survival, respectively (Figure 2). 14Similar predictors of mortality have been reported with Although the debate continues as to whether low serum levels of albumin in patients with CKD are a surrogate of inadequate protein intake or other conditions related to PEW, such as inflammation or comorbidity, 21 there seems to be less disagreement regarding the consistent association of hypoalbuminemia with poor outcomes in dialysis patients and those with nondialysis-dependent CKD. 20Reports indicate that patients attending dialysis clinics that provide superior care and have a good performance exhibit higher serum albumin levels and better survival rates than patients who attend clinics with an inferior performance. 12,24espite ongoing studies to determine whether serum albumin concentration is a nutritional marker or not, the actionability and responsiveness of serum albumin levels to nutritional interventions are far more relevant.Longevity has consistently been observed in those patients with CKD who have a better nutritional status, including larger muscle mass, 25,26 fat mass, 27 better appetite, 28,29 and higher protein intake. 30One study has suggested that imposing dietary protein restrictions to control serum phosphorus levels might cause harm and increased mortality, especially if associated with decreased normalized protein catabolic rate and serum albumin levels; 31 this finding could explain paradoxical observations such as the observed increased survival of patients who do not adhere to the strict rules imposed by clinics that prohibit in-center food ingestion during dialysis therapy. 4her nutritional markers of PEW-A serum prealbumin level of <300 mg/l is another indicator of PEW, and a strong predictor of outcome in patients with CKD. 16Two studies have shown that a change in serum levels of prealbumin over time is associated with corresponding changes in survival of patients on dialysis. 16,17One of these studies found that although baseline serum prealbumin concentration might not be superior to albumin in predicting mortality in hemodialysis patients, prealbumin concentrations of <200 mg/l are associated with an increased risk of mortality even in patients with normal albumin levels, and a decrease in serum prealbumin levels over 6 months is independently associated with an increased risk of death. 16Other nutritional indicators that predict survival in patients on dialysis include serum transferrin levels 32,33 and nutritional scoring systems, such as subjective global assessment 34 and the malnutrition-inflammation score, which also correlate with quality of life (Box 1). 18Some biomarkers exhibit low levels in the setting of inflammation even without undernutrition. 35However, among these biomarkers, serum albumin concentration is measured most frequently (at least monthly to quarterly in most countries in patients on dialysis), making it the most readily available biomarker of PEW.
Ameliorating the PEW-death association-Is the association between PEW and death causal or an epiphenomenon?Whereas the debate on causality has continued, 21,36,37 in our opinion a more clinically relevant and timely question is whether a nutritional intervention can increase serum albumin levels or correct PEW in patients with CKD, and by doing so, does survival and quality of life improve?We believe that the answer to both parts of the question is a cautious "yes" based on the experimental data, [38][39][40][41][42][43][44] despite the fact that no single well-designed randomized, controlled trial with adequate sample size has yet examined this simple question.Importantly, however, the field of nutritional support (such as nutrition for patients with terminal cancer, for patients who have undergone surgery, or geriatric or disabled populations) is based on the premise that provision of nutritional support improves the patient's immediate or short-term outcomes, independent of the cause of wasting and cachexia, whereas the long-term effects are less clear. 35Although we do not deny the paucity of randomized, controlled trials and the difficulties surrounding the feasibility of nutritional interventions or testing their effects on hard outcomes, 45 we believe that inadequate nutritional support during hemodialysis treatments, which might have catabolic effects, is not consistent with good practice.

Dialysis meals and oral supplements
7][48][49] Most patients on dialysis, however, have a lower DEI and DPI than the recommended intake.In 1,901 adult patients on the HEMO Study, the mean DEI and DPI were 23.2 ± 9.5 kcal/kg per day and 0.96 ± 0.43 g/kg per day, respectively, on nondialysis days, and 22.2 ± 9.6 kcal/kg per day and 0.90 ± 0.41 g/kg per day, respectively, on dialysis days. 50Nutritional support for patients on dialysis should make it possible to ensure nutritional intake is in accordance with the current guidelines.Oral supplementation can provide an additional 7-10 kcal/kg per day of energy and 0.3-0.4g/kg per day of protein, which makes it possible to meet the recommended targets of both DEI and DPI.To reach such energy and protein levels, oral supplements should be given two to three times a day, preferably 1 h after main meals.We have identified clinical trials with at least 10 participants in which the effects of enteral nutritional interventions were examined in malnourished patients on dialysis (Tables 1-4). 17,40,43,44, In mst of these studies, enteral therapy was associated with improved nutritional status or other clinical outcomes.
Enteral nutrition for hemodialysis patients-Among hemodialysis patients, who comprise over 90% of all dialysis patients in the USA, PEW is common and associated with poor outcomes. 2A prospective study by Caglar et al. 71 included 55 malnourished patients on hemodialysis who received conventional nutrition counseling for 3 months, followed by 6 months of thrice-weekly intake of a 237 ml oral nutritional supplement specifically designed for patients on dialysis (Nepro®, Abbott Nutrition, Columbus, OH, USA), which was provided during dialysis in the clinic to ensure adherence.Substantial increases in serum albumin and prealbumin concentrations were observed: from 33.3 ± 3.2 g/l and 261 ± 86 mg/l at baseline, to 36.5 ± 2.6 g/l and 307 ± 74 mg/l, respectively at 6 months. 71In another in-center prospective controlled trial of 40 hemodialysis patients with hypo albuminemia (albumin concentration ≤38 g/l), 20 patients received Nepro® accompanied by an additional liquid anti-inflammatory and anti-oxidative oral supplement that included borage oil and fish oil (Oxepa®, Abbott Nutrition). 40After 4 weeks of thrice-weekly nutritional intervention during the hemodialysis treatment, the pre-trial serum albumin level of 34.5 ± 3.1 g/l increased to 36.8 ± 3.4 g/l (P = 0.02). 4053][54][55]57 Serum albumin concentration did not considerably increase in the study by Fouque et al., 56 but high serum levels of albumin and prealbumin were observed in those who achieved increased dietary protein intake.In the trial by Cano et al., 17 186 malnourished patients undergoing hemodialysis were randomly assigned to intradialytic parenteral nutrition versus no intradialytic parenteral nutrition, while both arms received oral supplements.Despite apparently negative results for intradialytic parenteral nutrition, serum levels of albumin and prealbumin increased in both groups treated with oral supple ment therapy, and greater survival was observed in those whose serum prealbumin concentration increased by >30 mg/l at 3 months. 17These data underline the importance of measuring serum prealbumin levels in the follow-up of patients receiving nutritional support.Leon et al. 55 randomly assigned 180 patients on hemodialysis to usual care with targeting of specific nutritional barriers, including poor nutritional knowledge, poor appetite, help needed with shopping or cooking, low fluid intake, inadequate dialysis dose, depression, difficulty chewing or swallowing, gastrointestinal symptoms and acidosis.As part of the intervention, patients with a poor appetite or low fluid intake were given limited amounts of oral nutritional supplements, such as commercially available enteral nutrition drinks and cookies.After 12 months, patients in the intervention group had greater increases in serum albumin levels, energy intake and protein intake than the patients in the control group. 55tradialytic nutrition for hemodialysis patients-Intradialytic and in-center nutrition deserve special comment.Inadequate food intake, especially on hemodialysis treatment days, is common among patients in the USA, 50 whereas meals are routinely served during hemodialysis treatment sessions in many other countries.Until the late 1980s, meals during dialysis were routine practice in the USA and some Veterans Administration hospitals still provide meal trays during dialysis shifts.However, some dialysis clinics in the USA have strict rules against food and drink intake during hemodialysis treatment.When nephrologists and dialysis care providers in the USA were asked as to why meal trays for patients do not exist during dialysis treatments, the most common answers were the following: postprandial hypotension; risk of choking or aspiration; infection control and hygiene issues, including fear of fecal-oral transmission of diseases (such as hepatitis A); increased staff burden and distraction; and diabetes mellitus and phosphorus control (Table 5).81 Meals and nutritional supplements are routinely offered, for free in most part, to the majority of out patients on hemodialysis in many European and South-East Asian countries.Dialysis patients in Germany invariably eat during their hemodialysis treatments and have higher serum levels of albumin and greater survival than their US counterparts.82 Advantages of in-center meals and supplements-Despite the concerns of nephrologists and dialysis care providers regarding meals during dialysis, over the past few years a number of dialysis clinics have provided and even encouraged oral nutritional supplement.[83][84][85] In addition to improving nutritional status, providing in-center meals and/or oral nutritional supplements also improves patient adherence and satisfaction.Patients might be more motivated to attend treatments sessions if they know that a meal will be provided.As many patients already ignore the regulations that prohibit eating in some dialysis clinics and still bring their own foods (including those with a high phosphorus content), dialysis clinics could provide a more appropriate food or supplement with a high protein content and low salt content, low phosphorus to protein ratio, 86 and low potassium content, 87 together with administration of a phosphate-binder regimen and multivitamins at the time of meal or ingested supplement.The educational value of the meal provided in the clinic could be an important influence on patient adherence to dietary recommendations.
Benefits of intradialytic nutrition-Strong evidence indicates that patients on dialysis are subject to multiple metabolic and nutritional derangements that lead to a chronic and persistent negative nutrient balance. 88In addition, labor-intensive studies of protein turnover have indicated that the protein catabolic effects of hemodialysis treatment are profound, affecting the homeostasis of both whole-body and skeletal muscle protein. 89Patients undergoing dialysis experience recurrent infections, acute cardiovascular events, and frequent hospitalizations, in addition to underlying comorbidities.These factors lead to inadequate nutrient supply, altered metabolism, and increased nutrient requirements, mimicking a state of near-starvation. 90A commonly ignored reason for the observed nutrient deficiency is the inevitable loss of amino acids into the dialyzate during hemodialysis, which is equivalent to 6-8 g per dialysis session, or 6.5 kg per year. 91,92If the aim of muscle protein catabolism during hemodialysis is to maintain plasma levels of amino acids 93 and to provide amino acid substrate for acute-phase protein synthesis, 94,95 oral supplementation of amino acids could be a simple and appropriate method to deliver amino acids to the splanchnic bed. 96e catabolic consequence of dialysis therapy can be mitigated, or even converted to, an anabolic state by provision of intradialytic nutritional supplementation, especially in the form of meals or oral supplements.Studies have been carried out that assess the acute physiological response to dialysis and administration of intradialytic oral supplementation, including stable isotope kinetic studies and those measuring readily available nutritional markers such as serum levels of albumin and prealbumin. 97,98Veeneman et al. 98 examined whole-body protein metabolism by primed, constant infusion of L-[1- 13 C]valine to ascertain whether consumption of a protein and energy-enriched meal improved protein balance during hemodialysis.Feeding changed the negative whole-body protein balance observed during fasting to a positive protein balance, and strongly improved whole-body protein balance, probably owing to the increased concentrations of amino acids in the blood. 98In another study of protein turnover, Pupim et al. 83 showed that in eight malnourished patients undergoing hemodialysis, highly positive whole-body net protein balance during hemodialysis and improvement of skeletal muscle protein homeostasis was achieved with both intradialytic parenteral nutrition and an intradialytic oral nutritional supplement compared with during the control period.Oral therapy during hemodialysis resulted in persistent anabolic benefits for muscle protein metabolism in the posthemodialysis phase, whereas the anabolic benefits of intradialytic parenteral nutrition dissipated during the same period (Figure 3). 83These data support both the anabolic and anticatabolic roles of intradialytic enteral nutritional support.Well-designed controlled trials are now needed to examine hard clinical end points such as survival.
Enteral nutrition during peritoneal dialysis-When devising a plan for enteral support for patients undergoing peritoneal dialysis, a few important factors need to be considered.First, peritoneal dialysis is associated with obligatory glucose absorption from the dialyzate, which provides 300-600 kcal per day over that obtained through the diet.These calories obtained through glucose depend on the peritoneal transport rate and dialysis prescription, and partly compensate for the low oral energy intake of patients on peritoneal dialysis. 99Second, patients on peritoneal dialysis lose 5-7 g of protein per day in the dialyzate effluent; these losses are substantially increased during episodes of peritonitis. 100,101The peritoneal protein losses contribute, in part, to the lower serum levels of albumin and higher daily protein requirements observed in patients on peritoneal dialysis than in those treated with hemodialysis. 102However, the protein losses are not large enough to make a substantial contribution to PEW. 99 Third, intraperitoneal administration of dialyzate has been shown to worsen gastric emptying, including in nondiabetic patients with end-stage renal disease, and could contribute to the inadequate oral intake as well as intolerance of oral supplements frequently seen in these patients. 1037][78][79][80] Although these studies show mixed results, some generalizations can be made.First, in a single-meal study, administration of oral supplements did not lead to a substantial decrease in dietary intake. 79his result indicates that oral supplements can increase the total daily energy and protein intake of patients on peritoneal dialysis.Second, a large proportion of patients are either intolerant to, or non adherent with, the supplement prescription; 44,53,76,78,80 in some studies this intolerance or nonadherence affected over 50% of the participants. 44,78This high dropout rate has led many studies to be underpowered to detect statistically significant improvements in PEW and also highlights the limitations in using oral supplements.Third, in adherent patients who were able to tolerate supplements, considerable improvements were seen. 53,54,76,80For example, use of oral nutritional supplements in the randomized controlled trial by Teixidó-Planas et al. 80 resulted in substantial increases in triceps skinfold thickness, circumference of the mid-arm muscle, and lean body mass in the as-treated analysis.Fourth, studies that have examined high-biological-value supplements, such as calcium caseinate or egg albumin-based supplements, showed greater benefits than studies using standard oral supplements. 53,54,78,80This difference could be explained, in part, by increased tolerance and therefore improved adherence to supplements.Taken together, these data indicate that an increase in enteral intake is feasible and could improve PEW in adherent patients on peritoneal dialysis.

Nutrition in CKD patients with diabetes
Although diabetes mellitus is independently associated with poor outcomes and increased mortality, the presence of CKD greatly increases the mortality rate, 104 indicating that CKD itself is a strong independent determinant of poor outcomes.Despite concerns regarding the glycemic burden of nutritional interventions in patients with diabetes mellitus, such considerations might have less relevance in malnourished patients on dialysis.Indeed, in approximately one-third of patients on dialysis with diabetes mellitus, a state of 'burnt-out diabetes' is observed in which frequent episodes of hypoglycemia necessitate a decrease or even total discontinuation of most or all diabetic medications, including insulin injections and oral hypoglycemic agents. 105,106Many of these patients exhibit normal to low levels of hemoglobin A 1c , even without medication for diabetes mellitus and when they originally suffered from diabetic nephropathy as the etiology of their CKD. 107,108Some studies have found no association between glycemic control and outcomes in patients on dialysis. 109,110emodialysis sessions themselves can lead to moderate to severe intradialytic hypoglycemia. 111,112Hypoalbuminemia and intradialytic hypotension were found to be the main predictors of intradialytic hypoglycemia in patients with diabetes mellitus undergoing hemodialysis in one study. 111Therefore, in the USA and many other countries, the dialyzate bath includes high concentrations of glucose (11.1 mmol/l) to avoid hypoglycemia during hemodialysis. 112In our opinion, a history of diabetes mellitus is not a contraindication for oral nutritional therapy or meals during hemodialysis, and should not be a reason to withhold nutritional interventions, especially among dialysis patients with hypo albuminemia and normal to low levels of hemoglobin A 1c .

Nutritional therapy and ketoanalogues
PEW is also common in patients with nondialysis-dependent CKD, 3 in whom a decline in protein and calorie intake usually develops when glomerular filtration rate (GFR) falls to <25-35 ml/min/1.73m 2 , 113 although such changes may start when the GFR is as high as 55 ml/min/1.73m 2 . 1146][117] Enteral protein intake has, however, not been well-examined as a therapeutic strategy in this patient population, largely because of the belief that a low intake of protein is necessary to slow the progression of CKD and improve outcomes. 118,119A high intake of protein could affect GFR through various mechanisms, including alterations of glomerular hemodynamics. 120Restricted protein intake (for instance <0.8 g/kg per day or even <0.6 g/kg per day [121][122][123][124] as compared with the 1.2 g/kg per day that is recommended for patients on dialysis), in particular in combination with keto analogues of amino acids, has been used successfully to delay the progression of CKD in some, 125,126 but not all, 127,128 studies.[131] Whereas a low protein diet can be implemented by adhering to dietary restriction, manufactured disease-specific and hypercaloric oral supplements can improve management of CKD without causing malnutrition.However, very few studies have examined the use of oral nutritional supplements in patients with nondialysis-dependent CKD.In a Spanish study of 22 patients with non dialysis-dependent CKD on a low protein diet (0.6 g/kg per day), half the patients also received a portion of their prescribed dietary proteins and calories via a low protein and hypercaloric supplement for 6 months. 132In the group receiving the oral supplement, the nutritional measures were better and their protein intake seemed to be closer to the target low protein diet objective than that of the control group.Patients receiving the supplement also had better adherence and a smaller decrease in renal function than the control group. 132e Modification of Diet in Renal Disease study examined the effect of a low protein diet versus a very low protein diet supplemented with keto acids and amino acids on GFR and on the incidence of end-stage renal disease and death. 133Intention to treat analyses did not indicate any benefit with the very low protein diet. 133In a series of post hoc analyses of the Modification of Diet in Renal Disease study, a lower achieved protein intake (0.5-1 g/kg per day) was associated with slowing of the progression of CKD, 134 but the very low protein diet supplemented with a mixture of essential keto acids and amino acids (0.28 g/kg per day) compared with a low protein diet (0.58 g/kg per day) was associated with increased mortality and accelerated progression of renal failure. 135As it is unclear why some patients achieved low protein intake but others did not, 134,135 these results might not be construed as conclusive evidence towards the benefit or harm of a low protein diet with or without ketoanalogues.Nevertheless, enthusiasm about the use of ketoanalogues seems to be increasing, [136][137][138][139][140] as reflected in a consensus statement that mentions bene ficial effects that include: a decrease in uremic toxins; reduced protein uria; salutary effects on mineral and bone disorders and on lipid profile; as well as a potential delay in the progression of kidney disease and dialysis initiation with reduced likelihood of engendering malnutrition. 141We believe that ketoanalogues could have a role in the treatment of patients with nondialysis-dependent CKD, especially if combined with a tailored low protein diet with highbiological-value supplements or oral nutritional supplements specifically designed for this patient population. 132Emerging data indicate that in patients on peritoneal dialysis, ketoanalogues could contribute to preserving residual renal function, 136 although their role in the treatment of patients on maintenance hemodialysis with minimal residual renal function is questionable.Caution with regard to the use of ketoanalogues should be exercised even in patients on peritoneal dialysis as long-term safety of these dietary regimens in the clinical setting has not yet been established.

Nutritional therapy in transplant recipients
After a successful renal transplantation with a functioning allograft, patients normally experience a dramatic increase in appetite and weight gain. 142,143However, in many transplant recipients, especially in those with chronic allograft nephropathy, a worsening nutritional status is observed similar to that seen in patients with nondialysis-dependent CKD.Several specific factors relating to transplantation can potentially induce PEW in kidney transplant recipients in addition to conditions related to uremia.The immune response to the graft, the frequency and severity of rejection events, the degree of impaired renal function, and the use of immunosuppressive regimens might all contribute to the pathways that cause PEW. 144The deleterious effects of PEW on clinical outcomes might be mediated by the inflammatory response, leading to worsening anemia, 145 erythropoietin hyporesponsiveness 146 and de novo diabetes mellitus. 147Examining the nutritional status of transplant recipients and the influence of a transplant on clinical outcomes has been hampered by a lack of clinically applicable and standardized methods to assess the presence of PEW in these patients.
Investigators of a cohort study of 993 prevalent renal transplant recipients examined the relationship between nutritional status by means of assessing the malnutrition-inflammation score and relevant clinical indicators. 144The malnutrition-inflammation score negatively correlated with abdominal circumference and positively correlated with markers of inflammation, including serum levels of C-reactive protein, interleukin 6, and tumor necrosis factor; the malnutrition-inflammation score reflected both PEW and inflammation in kidney transplant recipients. 1449][150][151] We recommend, therefore, that the same enteral nutritional support should be given to transplant recipients as for patients with nondialysisdependent CKD.

Enteral nutrition in children with CKD
PEW often presents as growth retardation in children with CKD.One of the major goals in the treatment of infants and children with CKD is to achieve normal growth and development.Even fairly mild CKD can cause substantial anorexia in children. 152Poor growth owing to inadequate food intake has been observed in infants with a GFR as high as 70 ml/min/1.73m 2 . 153Meeting normal nutritional requirements in infants with CKD can be difficult: the nutrition care plan requires frequent monitoring and adjustments in response to changes in the child's nutritional status, age, development, anthropometrics, food preferences, residual renal function, renal replacement therapy, medications, and psychosocial status. 154In the majority of cases, infants with severe CKD will require tube feeding. 155Certain formulas, such as Good Start® (Nestlé, Vevey, Switzerland) and Similac® PM 60/40 (Abbott Nutrition), contain low amounts of phosphorus and potassium and are preferred for some infants with CKD.To meet requirements, commercial carbohydrate and/or fat products can be added to feedings to increase their standard energy density from 20 kcal/oz or 0.67 kcal/ml to as high as 60 kcal/oz or 2 kcal/ml without substantially increasing electrolyte and mineral content.A gradual increase in energy density often improves tolerance.
Infants and children with CKD who experience anuria and polyuria have very different food and fluid requirements from those who do not have these conditions.Both these subsets of children require adequate nutrition to maximize growth.Children with polyuria may be given and maintained on a diluted formula and undergo pre-emptive kidney transplantation, thus never requiring dialysis.However, it is important to monitor the amount of nutrients being delivered to infants with polyuria.Those who are oliguric or anuric often require frequent (sometimes daily) dialysis to offset the large-volume feeds that occur with standard formulas.In the absence of pediatric renal feeding supplements, adult renal products that are available with normal and reduced protein content, and designed to be calorie dense and low in minerals and electrolytes, can be recommended for children who are aged >4 years; these adult supplements have also been successfully used at diluted strength in children aged <1 year. 156A study showed that children with CKD and hyperkalemia demonstrated improved growth rates while receiving adult renal formulas, which were well-tolerated and effective in lowering potassium exposure. 157e early anticipation and correction of PEW, especially in infants, is important to avoid loss of growth potential.Initial studies demonstrated that growth of infants with CKD is compromised when energy intake falls below 80% of the recommended daily allowance. 158ncreasing energy intake to the recommended daily allowance can increase weight gain and stabilize growth rates in children of all ages and achieve catch-up growth in infants who are treated before they reach 2 years of age. 159According to some studies, however, the energy requirements of children with CKD have not been shown to differ from healthy children, 160 nor is there evidence that children with CKD will show improved growth if their intake exceeds recommended amounts for healthy children. 154Growth hormone therapy is indicated and widely accepted for treatment of growth retardation in children with CKD, but its use is only justified after ensuring adequate nutritional management. 161,162Given the importance of growth and development in children, we encourage monitored in-center enteral nutrition therapy for all infants and children who require maintenance dialysis treatment.

Beyond protein and calorie control
Enteral nutritional support can provide a variety of macronutrients and micronutrients in addition to calories and protein.9,70 Supplemental fish oil and other sources of omega 3 fatty acid have been tested.In a randomized trial by Tietze et al., 62 fish protein (8 g daily) and fish-based ingredients were tested for up to 6 months with some success.Kalantar-Zadeh et al. 40 supplemented a thriceweekly CKD-specific supplement with an additional 237 ml can of fish oil, borage oil, and other antioxidative and anti-inflammatory ingredients (originally designed for patients with acute pulmonary failure 163 ).Fanti et al. 73 showed that an oral soy isoflavone supplement taken for 8 weeks lowered serum levels of C-reactive protein in patients undergoing hemodialysis.In a randomized trial, Ewers et al. 164 examined the effects of oral unsaturated fat for 6 weeks in 14 patients undergoing hemodialysis and found that levels of C-reactive protein were decreased.Native (nutritional or inactive) vitamin D compounds, such as cholecalciferol, and other antioxidative vitamins can also be used in the form of multivitamins or as added ingredients to oral nutritional supplements. 40Other under-utilized and as yet undiscovered dietary and pharmacological ingredients are likely to be used as adjunct to conventional calorie and protein in the future.

Nonenteral nutritional interventions
In addition to meals and nutritional supplements during hemodialysis, there are other potential interventions to improve the nutritional status of patients, including appetite stimulants with or without antidepressant properties (megesterol, 165 ghrelin, 166 and mirtazapine 167 ), anabolic hormones (testosterone) and growth factors, 168 and anti-oxidative and anti-inflammatory agents (pentoxifylline and cytokine modulatory agents) (Box 2). 169,170In patients undergoing hemodialysis with severe hypoalbuminemia (albumin concentration <30 g/l) who do not improve with oral interventions, even with adjunctive pharmacological therapy, or those in whom enteral interventions are not possible, parenteral interventions such as intradialytic parenteral nutrition should be considered. 97,171ntradialytic parenteral nutrition is especially effective in patients with such low serum albumin values. 39Finally, non-nutritional interventions, such as dialysis treatment modalities and techniques that lead to decreased inflammation or protein loss, should also be considered. 172,173

Conclusions
In patients with CKD, PEW is a condition that is distinct from undernutrition and is associated with inflammation, increased resting energy expenditure, low levels of albumin and prealbumin, sarcopenia, weight loss and poor clinical outcomes.Although the debate on the relative contribution of inflammation versus malnutrition to the development of PEW continues, dietary interventions and nutritional support seem effective in mitigating or correcting PEW and improving outcomes in patients with CKD.Another ongoing debate is that regarding the recommendation of low protein intake with or without amino acid supplementation or ketoanalogues for patients with nondialysis-dependent CKD. 174Based on the data discussed in this Review, we suggest provision of maintenance meals and dietary supplements during each hemodialysis session and visit to the dialysis clinic.A maintenance regimen can ensure adequate protein intake and reinforce similar dietary habits at home.If serum levels of albumin remain <40 g/l despite maintenance meals or oral supplements, then the intensity of the dietary protein intake should be increased and other potential causes of hypoalbuminemia, such as persistent inflammation and urinary albumin losses, should be examined.Alternatively, tube feeding can be considered in those not capable of swallowing or at high risk of aspiration.Several ongoing randomized, controlled trials are examining the role of CKD-specific oral nutritional support 175 or in-center meals during hemodialysis, with a focus on phosphorus control. 176We recommend that all patients with CKD are assessed periodically (monthly or quarterly) for the presence of PEW and be offered oral nutritional support following the algorithm shown in Figure 5.We also recommend the frequent intake of small amounts of protein-rich liquid oral supplement with prescribed pills to replace water, which has been shown to improve outcomes in elderly individuals and those in nursing homes. 177 we move towards longer hemodialysis sessions, 178 and in anticipation of drastic changes in practice patterns as a result of implementation of the expanded bundle payment system in the USA, we need to rethink meals and oral supplements provided during dialysis therapy.Although meals during dialysis are routine practice in Europe and most other countries, the majority of patients on dialysis in the USA are deprived of nutritional intervention during dialysis.The consistent strong association of nutritional status, and in particular serum albumin levels, with survival in patients with CKD has been clearly shown.Given the fact that the provision of meals and oral supplements would require only a small fraction of the funds currently used for the expensive medications given to patients on dialysis with no proven outcome modification, 179 providing meals or oral nutritional supplements and other nutritional interventions to patients with CKD is the most promising way to increase serum albumin concentration and improve longevity and quality of life in this patient population.

Key points
■ Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is manifested by low serum levels of albumin or prealbumin, sarcopenia, and weight loss ■ PEW is one of the strongest predictors of mortality in patients with CKD ■ Although PEW might be the result of non-nutritional conditions, dietary interventions such as enteral feeding with high-protein meals or supplements might improve nutritional status and outcomes ■ Subjective global assessment and its modifications (Dialysis Malnutrition Score 181 and Canada-USA Study 182 ) in the malnourished range ■ Other scoring tools in the malnourished range [183][184][185] *Serum albumin levels are based on bromocresol green.Use of bromocresol purple can result in low values.‡ These values may be considered within the normal range in patients with nondialysis-dependent CKD or in other patient populations.§ Racial and ethnic variations should be considered; e.g.low BMI ranges might be considered within the acceptable range in Asian patients with CKD.Weight must be edema-free body mass (e.g.postdialysis dry weight).∥ Distinction between subcutaneous and visceral fat should be considered.¶ In relation to the 50 th percentile of a reference population.# In patients undergoing thrice-weekly hemodialysis who have minimal residual renal function a low predialysis serum creatinine concentration of <442 μmol/l could be a sign of sarcopenia.Creatinine appearance is influenced by both muscle mass and meat intake.**Assessed by dietary diaries and interviews; protein intake in patients on dialysis can be estimated by calculation of normalized protein equivalent of total nitrogen appearance as determined by urea kinetic measurements.Abbreviations: CKD, chronic kidney disease; PEW, protein-energy wasting.

Review criteria
We reviewed the literature to identify all clinical trials with at least 10 participants in which the effects of enteral (oral or tube-feeding) nutritional interventions were examined in malnourished patients with chronic kidney disease.Both the PubMed and Google Scholar databases were searched for all studies published or reported in English or with an English abstract since 1970.One paper in Spanish was considered relevant and translated into English.Full-text articles deemed pertinent were selected and the reference lists of the identified reports and articles were searched for further material.Effect of nutritional therapy modality on forearm muscle homeostasis.Metabolism of forearm muscle protein before, during and after hemodialysis, comparing controls, IDPN, and ONS in eight patients with deranged nutritional status.Skeletal muscle protein homeostasis during hemodialysis improved with both IDPN and ONS versus control (P = 0.005 and P = 0.009, respectively).ONS resulted in persistent anabolic benefits in the posthemodialysis phase when anabolic benefits of IDPN had dissipated.*P <0.05 versus control.Abbreviations: IDPN, intradialytic parenteral nutrition; ONS, oral nutritional support.Data obtained from Pupim, L. B., Majchrzak, K. M., Flakoll, P. J. & Ikizler, T. A. J. Am.Soc.Nephrol.17, 3149-3157 (2006).Serum albumin concentration and survival in patients with nondialysis-dependent CKD.Unadjusted and multivariable-adjusted all-cause mortality associated with various categories of serum albumin level in 1,220 US veterans with nondialysis-dependent CKD.Most patients had CKD stage 3 (56%) and stage 4 (30%), with fewer patients having CKD stage 1 (1%), stage 2 (7%), and stage 5 (5%).Adjustments were made for age, race, Charlson comorbidity index, etiology of CKD, diabetes mellitus, cardiovascular disease, smoking, systolic and diastolic blood pressure, BMI, estimated glomerular filtration rate, serum levels of calcium, phosphorus, hemoglobin, bicarbonate, cholesterol, and 24 h urine protein.Abbreviations: CKD, chronic kidney disease; HR, hazard ratio.Permission obtained from Kovesdy, C. P., George, S. M., Anderson, J. E. & Kalantar-Zadeh, K. Am.J. Clin.Nutr.90, 407-414 (2009).Proposed algorithm for enteral nutritional support in patients with CKD.The target of total protein intake should be a DPI of ≥1.2 g/kg per day for patients on dialysis, and 0.6 g/kg per day for patients with nondialysis-dependent CKD, including renal transplant recipients.Abbreviations: CKD, chronic kidney disease; DEI, dietary energy intake; DPI, dietary protein intake; IDPN, intradialytic parenteral nutrition; K, potassium; MIS, malnutritioninflammation score; Na, sodium; P, phosphorus; PEG, percutaneous endoscopic gastrostomy; RTR, renal transplant recipient; SGA, subjective global assessment.

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In-center meals and oral supplements during dialysis therapy and at home are inexpensive interventions that might improve survival and quality of life in patients with CKD ■ Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions ■ Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or ineffective Box 1 Diagnostic criteria for PEW and enteral nutrition in patients with CKD Biochemical markers Serum albumin concentration <40 g/l for hemodialysis patients, or <38 g/l for peritoneal dialysis patients and patients with nondialysis-dependent CKD* ■ Serum prealbumin concentration <300 mg/l (for maintenance dialysis patients) ‡ ■ Serum transferrin concentration <1.85 μmol/l (or total iron-binding capacity <2.46 μmol/l) ■ Serum levels of total cholesterol <2.59 mmol/l Body mass ■ BMI <23 kg/m 2 § ■ Unintentional loss of dry weight over time: 5% over 3 months or 10% over 6 months ■ Total body fat percentage <10% ∥ Muscle mass ■ Sarcopenia: reduced lean body mass >5% over 3 months or >10% over 6 months ■ Reduced mid-arm muscle circumference (<10 th percentile) ¶ ■ Low serum creatinine concentration (adjusted for renal status), or low calculated creatinine appearance # Dietary intake (unintentionally low)** ■ Dietary protein intake <1.0 g/kg per day for dialysis patients, or <0.5 g/kg per day for patients with nondialysis-dependent CKD ■ Dietary energy intake <25 kcal/kg per day for at least 2 months ■ Relative anorexia: Subjectively reported poor appetite Nutritional scoring systems ■ Malnutrition-inflammation score ≥5 180

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Meals during dialysis treatment ■ Oral nutritional supplements ■ Tube feeding (via temporary nasogastric tubing or percutaneous endoscopic gastrostomy) Parenteral or peritoneal nutrition ■ Intradialytic parenteral nutrition ■ Intraperitoneal nutrition ■ Total parenteral nutrition Pharmacological ■ Appetite stimulants ■ Promotility agents in patients with gastroparesis ■ Antidepressants ■ Anti-inflammatory and/or antioxidative agents ■ Anabolic and/or muscle-enhancing agents Other interventions ■ Dialysis technique ■ Dialysis treatment factors ■ Improving dental health, including use of dentures

Figure 1 .
Figure 1.Baseline serum albumin concentration and survival in patients on hemodialysis.Mortality predictability of 3-month averaged serum albumin levels in 58,058 patients on hemodialysis from 524 DaVita dialysis facilities in the USA.Case-mix-adjusted covariates included age, sex, diabetes mellitus, African-American race, Hispanic ethnicity, and dialysis vintage.The arrows and numbers indicate the incremental increase in mortality risk compared with the previous group.Abbreviation: HR, hazard ratio.Data obtained from Kalantar-Zadeh, K. et al.Nephrol.Dial.Transplant.20, 1880-1888 (2005).

Figure 2 .
Figure 2. Change in serum albumin levels and survival in hemodialysis patients.Association of the change in serum albumin concentration over two consecutive calendar quarters with subsequent mortality over 2 years in 30,827 patients on maintenance hemodialysis.Abbreviations: HR, hazard ratio; MICS, malnutrition-inflammation complex syndrome.Kalantar-Zadeh, K. et al.Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction.Nephrol.Dial.Transplant.(2005) 20 (9), 1880-1888 © by permission of Oxford University Press.

Table 1
Randomized trials of nutritional support in patients undergoing hemodialysis or peritoneal dialysis

Table 4
Nonrandomized trials in patients undergoing peritoneal dialysisIncreased serum levels of total protein, albumin, prealbumin, transferrin, total amino acids, EAA/non-EAA ratio, Kt/V urea, PCR Albumin levels rose from 32.5 g/l to 33.1 g/l in patients given the dessert, whereas patients in the control group had an albumin level of 38.8 g/l and 37.7 g/l before and after the study period, respectively Drinking the supplement 2h before lunch resulted in a significant increase in total caloric intake as compared with during the placebo visit (843 kcal vs 430 kcal, respectively; P<0.001) and protein intake (41.3 g vs 27.6 g, respectively; P= 0.006) Increased total lymphocyte count in the 'intention to treat' analysis In the 'as treated' analysis (9 cases, 20 controls): increased body weight (P<0.03),triceps skinfold thickness (P<0.01),mid-arm-muscle circumference (P<0.03),lean body mass (P<0.002),creatinine generation rate (P<0.002) in the group taking the supplement High noncompliance rate: 15 patients stopped ONS Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; CKD, chronic kidney disease; DEI, dietary energy intake; DPI, dietary protein intake; EAA, essential amino acid; nPCR, normalized protein catabolic rate; ONS, oral nutritional supplement; PD, peritoneal dialysis.

Table 5
Meals and oral supplements for hemodialysis patients with CKD and low serum albumin concentration Nat Rev Nephrol.Author manuscript; available in PMC 2013 December 31.