Pathogenesis and treatment of malnutrition in patients on maintenance hemodialysis

INTRODUCTION — Measures of protein and energy stores such as body size [1-7], muscle mass [8,9], fat mass [8,9], serum albumin [10-12], and cholesterol [13] levels are strong predictors of survival in patients on dialysis.

In 2009, the International Society of Renal Nutrition and Metabolism (ISRNM) recommended the term protein-energy wasting (PEW) syndrome to describe the loss of body protein mass and fuel reserves in patients on dialysis [14]. The ISRNM developed objective criteria for the definition of PEW syndrome in patients on dialysis and those with chronic kidney disease (CKD) [14].

This topic reviews the pathogenesis and treatment of PEW syndrome in patients on hemodialysis.

The assessment of nutritional status and the effect of malnutrition on outcomes among patients on hemodialysis are discussed elsewhere. (See "Assessment of nutritional status in patients on hemodialysis" and "Patient survival and maintenance dialysis".)

The assessment, prevention, and treatment of malnutrition among patients on maintenance continuous peritoneal dialysis are discussed elsewhere. (See "Nutritional status and protein intake in patients on peritoneal dialysis".)

PATHOGENESIS — Protein-energy wasting (PEW) syndrome has two components, including protein (somatic, visceral, and serum) wasting and energy wasting (mainly decrease in fat stores). Although strong experimental data link inflammation, insulin resistance, and metabolic acidosis to protein wasting, it is unclear whether these mechanisms also lead to energy wasting. On the contrary, energy excess as manifested by adiposity is a major driver of inflammation and insulin resistance in patients on dialysis. Overall, the pathogenesis of PEW syndrome is incompletely understood and likely multifactorial. There have been many proposed mechanisms, but we believe these provide an incomplete explanation for the causation of PEW syndrome. Proposed mechanisms include the following:

●Decreased intake and anorexia – Thirty-five to 50 percent of patients with end-stage kidney disease (ESKD) are reported to have anorexia [15].

With progression of kidney failure, there is a spontaneous decline in protein intake [16,17]. This decline likely results from the accumulation of nitrogenous waste products and increases in enteric hormones, adipokines (leptin and visfatin), and elevated inflammatory cytokines, all of which regulate appetite [18-22]. Anorexia may be worsened by depression, which is very common in patients with chronic kidney disease (CKD) and, particularly, those on dialysis.

Among patients on hemodialysis, under-dialysis commonly causes anorexia and decreased taste acuity. In one study, an increase in dialysis dose from a Kt/V of 0.82 to 1.32 increased the protein catabolic rate (reflecting increased protein intake and better nutrition) from 0.81 to 1.02 g/kg per day over a three-month period [23]. The rise in protein catabolic rate (PCR) was likely due to improved appetite. A second group in which the dialysis regimen was unchanged had no increase in either Kt/V or PCR.

However, an increase in dialysis beyond accepted recommended target doses does not appear to have an effect on protein intake. As an example, in the Frequent Hemodialysis Network (FHN) study, compared with conventional three times a week dialysis, more frequent dialysis did not result in an increase in protein intake as measured by equilibrated PCR [24]. Recommendations regarding dialysis dose are discussed elsewhere. (See "Prescribing and assessing adequate hemodialysis", section on 'Target Kt/V'.)

●Hypercatabolic state – Some patients with CKD, particularly those on dialysis, are hypercatabolic. In one study, measured resting energy expenditure (REE) among patients with CKD (including 15 with advanced CKD, 15 on chronic hemodialysis, and 10 on peritoneal dialysis) was 10 to 20 percent higher than predicted values derived in populations without kidney disease [25]. REE was higher among both patients on peritoneal and hemodialysis compared with patients with CKD who were not on dialysis.

However, not all patients with CKD and on dialysis are hypercatabolic. The net energy expenditure is the sum of REE plus physical activity expenditure. Many patients are sedentary, resulting in decreased physical activity expenditure [26,27]. As a result, the body mass index (BMI) of patients on incident hemodialysis has been increasing [28].

●Inflammation and comorbidities – The presence of an acute, chronic, or occult systemic illness may adversely affect nutritional status. Chronic lung disease, congestive heart failure, and malignancy are associated with PEW syndrome [29]. Acute illness also contributes to poor nutritional status; nutritional indices such as serum albumin are known to worsen after recent hospitalization [29]. Gastroparesis (by slowing gastric emptying) may contribute to anorexia. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Clinical features'.)

Although the mechanism by which inflammation contributes to PEW is not clear, inflammation causes increased energy expenditure. Proinflammatory cytokine levels and oxidative stress likely contribute. (See "Inflammation in patients with kidney function impairment".)

In experimental models, activation of the ubiquitination pathway by inflammatory cytokines such as tumor necrosis factor (TNF)-alpha leads to proteolysis and muscle wasting [30]. A marker of nutrition, serum albumin is inversely related to the inflammatory marker, C-reactive protein (CRP) [31]. Thus, systemic inflammation could lead to protein wasting.

It is unclear whether inflammation leads to energy wasting in dialysis patients. Indeed, despite the higher prevalence of comorbidities, higher concentrations of CRP, lower concentrations of plasma albumin, and lower muscle mass, patients on dialysis have higher BMI and higher waist circumference compared with the national norms [32].

Furthermore, adipose tissue is a major source of inflammatory cytokines, and obesity is associated with elevated CRP levels in patients with nondialysis CKD [33] and in patients on dialysis [34].

●Insulin resistance – Studies suggest that insulin resistance may contribute to muscle protein breakdown among hemodialysis patients with and without type 2 diabetes, although this has not been conclusively proven [35,36].

The oral hypoglycemic agents that improve insulin action, such as rosiglitazone, ameliorate proteolysis in animal models of diabetes [37].

However, while insulin resistance could lead to protein wasting, insulin resistance is primarily caused by adiposity [38].

●Metabolic acidosis – Animal models and clinical studies of patients with CKD and those on dialysis suggest that metabolic acidosis may contribute to proteolysis and correction may provide benefit [39-43].

As an example, in a randomized, controlled trial, peritoneal dialysis using high-lactate (40 mmol/liter) or low-lactate (35 mmol/liter) alkali dialysate was compared among 200 patients on incident continuous ambulatory peritoneal dialysis (CAPD) [42]. At one year, patients undergoing high-lactate dialysis had a greater increase in body weight (6.1±0.7 kg versus 3.7±0.6 in patients receiving low-lactate dialysis). The midarm circumference was also higher in the high-lactate group (1.26±0.16 cm versus 0.61±0.16 cm) [42]. Another randomized trial compared oral bicarbonate supplementation to standard care (ie, no supplementation) among 134 adult patients with CKD with reduced creatinine clearance (15 to 30 mL/min/1.73 m²) and metabolic acidosis (serum bicarbonate 16 to 20 mmol/L) [43]. At two years, nutritional parameters improved with bicarbonate supplementation compared with standard care [43].

However, among patients on hemodialysis, serum bicarbonate and serum creatinine (an indicator of muscle mass) are inversely correlated (ie, serum bicarbonate is high in those with decreased muscle mass) [44]. As the serum bicarbonate is already normal or high in those with low muscle mass, the role of bicarbonate supplementation on improving muscle mass in those with established PEW remains to be determined.

●The dialysis procedure – The dialysis procedure itself may be catabolic due to reduced protein synthesis and the loss of amino acids in dialysate [45,46]. Amino acid losses into dialysate can average 4 to 8 g/day with peritoneal dialysis or hemodialysis [47,48]. Among patients on hemodialysis, amino acid losses may be more prominent when a bioincompatible membrane is used. (See "Clinical consequences of hemodialysis membrane biocompatibility", section on 'Protein catabolism'.)

In addition, with hemodialysis, certain reuse procedures result in increased losses of protein into dialysate. Protein loss as high as 20 grams in one hemodialysis session has been reported with polysulfone dialyzers reused with bleach [48]. (See "Reuse of dialyzers".)

Nonetheless, more frequent dialysis does not appear to worsen nutritional indices [24].

●Dietary restrictions – Dietary restrictions can make food less palatable. Furthermore, fluid restriction to minimize interdialytic weight gain may lead to a decrease in caloric intake [49]. Solid food has a high fluid content, and many beverages contain a substantial amount of calories.

●Medications – Medications, such as phosphate binders, can impair nutrient absorption.

DIETARY RECOMMENDATIONS TO PREVENT PROTEIN-ENERGY WASTING — We agree with the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) and the European Best Practice guidelines that recommend the following diet [50,51]:

●1.2 g/kg protein per day; at least 50 percent should be of high biologic value

●30 to 35 kcal/kg of calories per day

The recommended protein allowance is higher than the recommended daily allowance for healthy adults (which is 0.8 g/kg/day). These recommendations are largely based upon observational data that suggest that low protein intake is associated with increased mortality among patients on hemodialysis [1-13]. (See "Patient survival and maintenance dialysis", section on 'Nutrition'.)

However, there are no adequate randomized, controlled trials that have established that high protein or calorie intake prevents the development of protein-energy wasting (PEW) syndrome in patients on dialysis.

Among patients who do not spontaneously achieve the recommended protein intake, we do not use oral protein supplements, unless patients have specific indications, which are defined below.

In the absence of defined clinical indications, the role of nutritional supplements is unclear.

Furthermore, as body weight helps to determine the recommended protein intake (since it is defined in g/kg per day), many patients with overweight or obesity have low dietary protein intake despite adequate nutrition.

It is important to closely follow metabolic parameters (including urea) if a high protein diet is prescribed to patients on dialysis. It is conceivable that very high protein intake could be deleterious in patients on dialysis by worsening uremic toxin production [52,53], metabolic acidosis [44], and hyperphosphatemia [54].

Patients on routine hemodialysis usually have these parameters checked monthly. (See "Prescribing and assessing adequate hemodialysis", section on 'Patient-specific parameters'.)

DIAGNOSIS OF PEW — The diagnosis for protein-energy wasting (PEW) syndrome is discussed elsewhere. (See "Assessment of nutritional status in patients on hemodialysis", section on 'Diagnosis of protein-energy wasting'.)

MANAGEMENT OF PEW — Patients who have a progressive decrease in protein intake as evidenced by dietary history, protein nitrogen appearance (PNA, which is a marker for protein intake among patients on dialysis), or decline in serum albumin or who have an unintentional decrease in dry weight should have interventions to improve nutritional status. All patients should be carefully evaluated for causes of anorexia and for other possible contributors to protein-energy wasting (PEW). (See 'Evaluate and treat comorbid conditions' below.)

Evaluate and treat comorbid conditions — All patients with a history of decreased protein intake and a progressive decrease in body mass index (BMI), albumin, and PNA should be carefully evaluated. History and physical examination are essential elements of the evaluation and may reveal signs and symptoms of depression or infection that could lead to decrease in appetite [55]. Psychosocial issues such as access and affordability of food and ability to prepare meals may need intervention from the multidisciplinary team.

Patients with diabetes should be questioned regarding symptoms of gastroparesis and diarrhea, both which are common manifestations of autonomic neuropathy and could contribute to PEW syndrome. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis' and "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Diabetic diarrhea'.)

Insulin requirements and glycemic control should be reviewed. It is not clear whether tight control of blood sugars in patients with diabetes on hemodialysis prevents development or progression of PEW syndrome. Short-term studies suggest increased proteolysis in patients with diabetes and insulin resistance [36,37]. HbA1C goals among dialysis patients are discussed elsewhere.

It is not clear how to treat patients with overweight or obesity who have early signs of PEW syndrome. Inflammation is a major cause of muscle wasting in patients on dialysis, and adipose tissue is a site of inflammatory cytokines production. Furthermore, increased visceral fat area as measured by magnetic resonance imaging (MRI) is associated with decreased physical function [56].

It is possible that interventions targeted towards decreasing fat mass while preserving or increasing muscle mass might prevent the development of PEW syndrome in patients on dialysis [57,58]. Such interventions particularly include resistance training [59] or the use of human growth hormone [60,61].

Large randomized trials are needed to determine whether increasing physical activity in patients on dialysis with overweight or obesity decreases the development of PEW syndrome in this population.

Review and optimize dialysis prescription — The dialysis prescription and achieved Kt/V should be reviewed. Among patients who are not achieving the minimum target Kt/V, we alter the dialysis prescription to provide more dialysis. Uremia resulting from insufficient dialysis decreases appetite [15]. (See "Prescribing and assessing adequate hemodialysis".)

Among patients who are already achieving the minimum target Kt/V, we do not increase the dialysis dose further. The maintenance of Kt/V that is higher than the accepted standard has not been shown to improve nutritional indices. This was shown in the Hemodialysis (HEMO) trial in which a high versus standard hemodialysis dose (equilibrated Kt/V 1.53±0.09 versus 1.16±0.08) did not result in improved nutritional indices [62,63]. More frequent dialysis (six times a week versus three times a week) in the Frequent Hemodialysis Network (FHN) trial also did not improve nutritional indices [64]. (See "Short daily hemodialysis", section on 'Frequent Hemodialysis Network (FHN) daily trial'.)

Nutritional supplements

Indications for treatment — The following are indications for treatment with dietary supplements:

●An unintentional loss of 5 percent of nonedematous weight within three months or 10 percent of nonedematous weight over six months

or

●An albumin <3.8 g/dL

These thresholds for treatment with supplements are based on clinical judgement and experience. The effect of nutritional supplementation on clinically important outcomes is unclear. There has been only one randomized trial that examined the effects of protein supplementation on mortality in patients on dialysis [65]. However, that study compared intradialytic parenteral nutrition with oral protein supplement and did not include a usual care arm [65]. In both groups, PNA increased along with an increase in body weight and serum albumin, but there were no differences between the two groups regarding the primary endpoint of mortality [65]. A 2020 Cochrane review including 22 randomized trials that examined oral protein-based nutritional supplements in patients on maintenance dialysis concluded that supplementation likely increased serum albumin, especially in patients on hemodialysis and those with malnutrition, and may have increased serum prealbumin and mid-arm muscle circumference [66].

Two large, observational studies of oral nutritional supplement suggested better survival associated with nutritional supplement [67,68]. Protein supplementation was associated with a 29 percent decreased mortality over a mean follow-up of 14 months (hazard ratio [HR] 0.71, 95% CI 0.58-0.86). However, in both studies, residual confounding related to patient-, or facility-related factors cannot be excluded. In addition, the mechanism underlying benefit is not clear; an obvious effect of supplementation on the serum albumin concentration, muscle mass, or protein anabolism has not been conclusively demonstrated [26,65,69-78].

Our approach — For most patients selected for treatment with dietary supplements, we suggest oral supplements rather than intravenous supplements. For most patients on hemodialysis, intradialytic parenteral nutrition (IDPN) and oral supplements are equally effective. In one comparative study, 186 patients on hemodialysis patients with malnutrition were randomly assigned to oral nutritional supplements, with or without one year of IDPN [65]. At two years, there was no difference in mortality, hospitalization rate, and nutritional status between the two groups. Specific oral agents are discussed below. (See 'Oral supplements' below.)

However, for patients who continue to lose weight or have very low serum albumin (<3.2 g/dL) despite oral supplementation for three months, we use IDPN, providing the patient can consume at least 50 percent of the prescribed caloric intake [51]. (See 'Intradialytic parenteral nutrition' below.)

If this degree of oral intake cannot be reached, we may try a nasoenteral feeding tube with nighttime enteral nutrition or, if oral intake is not tolerated, institute total parenteral nutrition (TPN) [79]. However, most of the patients with malnutrition resistant to both oral supplements and IDPN have an underlying terminal illness such as metastatic malignancy or advanced heart failure. In such patients, options including TPN, withdrawal of dialysis, or comfort care measures should be discussed. (See "Nutrition support in intubated critically ill adult patients: Parenteral nutrition" and "Kidney palliative care: Withdrawal of dialysis", section on 'Indications for withdrawal of dialysis'.)

We do not treat patients with dietary supplements who do not have the specific indications listed above. (See 'Indications for treatment' above.)

In the absence of specific indications, we believe that many patients on dialysis (who often have higher than optimal BMI and waist circumference) do not have PEW syndrome. We believe the reason that many studies did not show a benefit of protein supplementation on nutritional markers may have because patients included in the study did not have PEW syndrome. By contrast, in studies where the BMI was low [65,71] or serum albumin was low [65,70,71], protein supplementation was effective in increasing serum albumin and body weight.

Oral supplements — For most patients selected for treatment with dietary supplements, we use oral supplements.

Several supplements are formulated specifically for patients with end-stage kidney disease (ESKD) and are low in potassium and dense in nutrients, which provides adequate calories and protein and minimizes the risk of hyperkalemia and fluid overload. However, these supplements are more costly than less specific preparations, which often decreases compliance. Our selection of a specific agent depends on patient characteristics:

●Among patients who have no history of interdialytic hyperkalemia or volume overload (and are able to tolerate the increase in potassium and fluid intake), we use general supplements such as Ensure or Boost Nutritional Drink because of their low cost.

●Among patients who have a history of hyperkalemia or volume overload on dialysis (due, for example, to heart failure), we use a specific "kidney failure" supplement, such as Novasource Renal or Nepro, which have double the calorie and protein and 30 to 35 percent less potassium and phosphorus content per mL of supplement.

A different regimen is required in patients with severe anorexia who are unable to increase their oral intake. Overnight supplementation by nasoenteral feeding tube may be effective in this setting [80,81]. A short course of overnight tube feeding can lead to a sufficient improvement in nutritional status and overall wellbeing so that adequate dietary oral can be resumed.

We do not prescribe oral essential amino acids, although some evidence suggests that the administration of essential amino acids may be modestly beneficial to patients with significant hypoalbuminemia [70,82]. Further study is needed prior to any recommendation concerning their use.

Intradialytic parenteral nutrition — For patients who continue to lose weight or have very low serum albumin (<3.2 g/dL) despite oral supplementation and for patients such as those with severe gastroparesis who may be unable to tolerate oral supplementation, we use IDPN.

IDPN is convenient because it is delivered during dialysis and is likely to be beneficial in some patients [83]. However, although a number of case reports and studies suggest that IDPN provides substantial benefit, the studies were mostly retrospective or poorly designed [79,84,85].

IDPN is the most costly and least efficient nutritional supplement. IDPN often costs twice as much as dialysis itself, and only 70 percent of the nutrients are actually delivered to the patient because of loss into the dialysate [86].

In addition, IDPN may provide insufficient protein and calories to treat PEW syndrome since IDPN is administered only three days per week for approximately four hours [80]. As noted above, we do not use IDPN for hemodialysis patient who cannot consume at least 50 percent of the prescribed caloric intake [51]. (See 'Our approach' above.)

IDPN solutions are similar to those used for TPN. (See "Nutrition support in intubated critically ill adult patients: Parenteral nutrition", section on 'Composition'.)

A typical solution contains 10 percent amino acids and 40 to 50 percent glucose, 10 to 20 percent lipids, or a mixture of carbohydrate or lipids, depending upon the needs of the patient.

IDPN may be associated with a lower than expected delivered dose of dialysis due, possibly, to increased urea generation [87].

Experimental methods — Recombinant human growth hormone, androgenic anabolic steroids, antiinflammatory drugs, and zinc have been studied in patients on dialysis with PEW. We do not use any of these agents for routine clinical use:

●Human growth hormone – Some studies suggest that administration of recombinant human growth hormone can reduce wasting and catabolism, improve nutritional status, and lower the blood urea nitrogen (BUN) in patients on hemodialysis [60,61,88-93]. The benefit from recombinant human growth hormone may be mediated by an increase in free insulin-like growth factor-1 (IGF-1) levels [94,95].

However, significant long-term nutritional benefits with human growth hormone are not consistently observed [96], and effects of this costly agent on malnutrition-associated morbidity and mortality are unclear [82].

The OPPORTUNITY randomized trial was designed to assess the effect of human growth hormone on survival but was prematurely terminated because of slow recruitment [97].

●Androgenic anabolic steroids – Limited data are available on the effects of androgenic anabolic steroids among patients on dialysis [98-100]. Although increases in body weight, muscle mass, and serum albumin have been reported, the long-term efficacy and risk for adverse effects is unclear.

●Antiinflammatory agents – The use of antiinflammatory agents in patients with malnutrition-inflammation syndrome complex is reviewed separately. (See "Inflammation in patients with kidney function impairment".)

●Zinc – Patients on dialysis often have decreased taste acuity, which is controversially associated with zinc deficiency [101]. The role of zinc deficiency has never been established.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Dialysis and diet (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Protein-energy wasting syndrome – Patients on hemodialysis are commonly depleted of protein and energy stores as a result of either deficient nutrition or protein and energy wasting. The term protein-energy wasting (PEW) syndrome describes the loss of body protein mass and fuel reserves in patients with end-stage kidney disease (ESKD). PEW syndrome is associated with a poor prognosis. (See 'Introduction' above and 'Pathogenesis' above.)

●Pathogenesis of PEW – The pathogenesis of PEW is incompletely understood and likely multifactorial. There have been many proposed mechanisms, but all provide an incomplete explanation for the causation of PEW syndrome. (See 'Pathogenesis' above.)

●Dietary recommendations to prevent PEW – Dietary recommendations for patients on hemodialysis include the following:

•1.2 g/kg protein per day; at least 50 percent should be of high biologic value

•30 to 35 kcal/kg of calories per day (see 'Dietary recommendations to prevent protein-energy wasting' above)

●Management of PEW – Patients with a history of decreased protein intake and any evidence of progressive decrease in body mass index (BMI), albumin, and protein nitrogen appearance (PNA) should be carefully evaluated for cause. Comorbidities and under-dialysis, both which could contribute to anorexia should be addressed. (See 'Evaluate and treat comorbid conditions' above and 'Review and optimize dialysis prescription' above.)

•Indications for nutritional supplementation – Indications for treatment with dietary supplements include an unintentional loss of 5 percent of nonedematous weight within three months or 10 percent of nonedematous weight over six months or an albumin <3.8 g/dL. (See 'Indications for treatment' above.)

•Types of nutritional supplementation – For most patients selected for treatment with dietary supplements, we suggest oral supplements rather than intravenous supplements (Grade 2C). Oral supplementation is safe, equally effective as, and less costly than intravenous supplementation. An exception is patients who continue to lose weight or have very low serum albumin (<3.2 g/dL) despite oral supplementation for three months; for such patients, we use intradialytic parenteral nutrition (IDPN), providing the patient can consume at least 50 percent of the prescribed caloric intake. (See 'Our approach' above and 'Oral supplements' above and 'Intradialytic parenteral nutrition' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marsha Wolfson, MD, FACP, who contributed to earlier versions of this topic review.