Muscle Wasting in Dialysis Patients

Muscle Wasting in Dialysis Patients
T. Alp Ikizler, MD
January 12 2010

Muscle wasting, also termed protein-energy wasting (PEW), is a state of metabolic and nutritional derangements that is closely associated with high morbidity and mortality in CKD patients. Present in 20%-50% of maintenance dialysis patients, muscle wasting can have multiple etiologies, including insufficient intake of dietary nutrients, excessive catabolism due to dialysis, metabolic acidosis, chronic inflammation, and hormonal derangements (Kidney Int. 1996;50:343-357 and Kidney Int. 2008;73:391-398) (see figure 1). Because the presence and severity of muscle wasting has a high association with mortality risk in maintenance dialysis patients, prevention and treatment of this unfavorable condition is of upmost importance. The multifactorial origin of muscle wasting renders this task especially challenging.

Total body-protein content is considered to be the most physiologically relevant nutritional parameter and an important determinant of PEW. Accordingly, a cluster of approaches referred to as anabolic interventions are focused on improving PEW through enhancing protein synthesis, decreasing protein catabolism, or a combination thereof, to maximize total body-protein stores. In this review, we will discuss the rationale and efficacy of using selected agents, nutritional supplementation, and exercise as anabolic interventions to enhance total body-protein content for the maintenance dialysis patient who has PEW or is at risk of having it, with a specific emphasis on recent advancements in this area.

Epidemiology

Muscle wasting is considered to be at its peak at the time of initiation of maintenance dialysis and has been correlated with the degree of uremia. Although evidence of improvement in nutritional parameters is usually observed within three to six months of initiating maintenance dialysis (Am J Kidney Dis. 2002;40:143-151), muscle wasting can remain in a significant portion of the dialysis patient population, regardless of the renal replacement modality (Am J Kidney Dis. 2002;40:143-151). Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed the prevalence of muscle wasting to be 7.6% and 11% for moderately and severely malnourished chronic hemodialysis patients in the U.S., respectively, based on subjective global assessment (SGA) (Am J Kidney Dis. 2004;44[5 Suppl 2]:39-46). Another study showed that of 224 patients undergoing continuous ambulatory peritoneal dialysis at six centers in Europe and North America, 32.6% had mild to moderate malnutrition and 8% had severe malnutrition, again using SGA (Am J Kidney Dis. 1991;17:462-471).

Possible causes

The mechanisms leading to muscle wasting in dialysis patients are still being elucidated; they cannot be attributed to any single factor. Nevertheless, a common pathway for all the metabolic derangements leading to muscle wasting appears related to exaggerated protein degradation and, to a degree, to decreased protein synthesis.

Dietary nutrient intake. The observation that CKD patients decrease their protein and energy intake as they progressively lose kidney function has led some to conclude that uremia per se causes protein catabolism stimulated by decreased nutrient intake. This conclusion has been challenged to a certain extent because even in patients with advanced CKD, nitrogen balance studies show a concomitant decrease in both protein synthesis and degradation. However, accelerated protein degradation stimulated by acute illnesses or stress conditions could lead to excessive and uncompensated loss of protein stores.

An additional stimulus for protein loss is the dialytic treatment per se. Recent measurements of protein synthesis and degradation unequivocally demonstrate the catabolic effects of hemodialysis. Both whole-body and skeletal-muscle protein homeostasis are disrupted, and there are consistent findings of decreased protein synthesis and increased protein breakdown at the whole-body level. Evidence also exists for a significant increase in net skeletal-muscle protein breakdown. These undesirable catabolic effects, which persist for at least two hours following the completion of hemodialysis, can be compensated for by intradialytic nutritional supplementation (J Am Soc Nephrol. 2006;17:3149-3157).

Chronic inflammation and insulin resistance. Recent epidemiologic studies have found increased levels of inflammatory markers to be highly prevalent in maintenance dialysis patients. The metabolic and nutritional responses to chronic inflammation are many and closely mimic the PEW that appears to be common in advanced CKD patients, including exaggerated protein catabolism. This raises the possibility of a “cause-and-effect” relationship between inflammation and loss of protein stores. Although not proven, pro-inflammatory cytokines are thought to play an integral role in the muscle catabolism of maintenance dialysis patients.

Patients with CKD who also have diabetes mellitus have a higher incidence of PEW than those without diabetes. The degree of insulin resistance and/or insulin deprivation seems to play the most critical role in this process. As with inflammation, decreased sensitivity to insulin can cause muscle-protein losses. Insulin resistance is detectable in maintenance hemodialysis patients—both obese and nonobese—and is strongly associated with increased muscle-protein breakdown, even after controlling for inflammation. In addition to the protein catabolism that occurs with insulin resistance, diabetic maintenance hemodialysis (MHD) patients are more likely to suffer protein depletion because of associated gastrointestinal symptoms (e.g., gastroparesis, nausea and vomiting, bacterial overgrowth in the gut, and pancreatic insufficiency).

Metabolic and hormonal derangements. Metabolic acidosis, a common abnormality in patients with progressive CKD, promotes muscle wasting by increasing muscle protein catabolism. Even a small adjustment to a low serum bicarbonate concentration will improve nutritional status by correcting essential amino acid catabolism. In addition, maintenance dialysis patients often have abnormalities in thyroid hormone-stimulated metabolism, specifically, low circulating thyroxine and triiodothyronine concentrations. Finally, abnormalities in the growth hormone and insulinlike growth factor-1 axis could be important factors in the development of muscle wasting in maintenance dialysis patients. For example, growth hormone administration improves the growth of children with CKD. Resistance to growth hormone would impede such beneficial effects as enhanced protein synthesis, reduced protein degradation, increased fat mobilization, and increased gluconeogenesis.

Prevention and treatment

Managing the nutritional concerns of maintenance dialysis patients includes a comprehensive combination of preventive maneuvers to diminish protein and energy depletion. Standard therapies for maintenance dialysis patients with muscle wasting include provision of adequate dialysis, treatment of metabolic acidosis, adjustments of dietary factors, and treatment of infections.

Nutritional supplementation. The susceptibility of maintenance dialysis patients to PEW resulting from decreased protein and energy intake can be ameliorated by increasing nutrient intake through dietary supplements, especially during hemodialysis. Nutritional supplementation should be delivered by the oral route if at all possible; otherwise, parenteral nutritional supplements can be administered. In a meta-analysis that included 18 studies (five randomized controlled trials [RCTs], 13 non-RCTs), Stratton et al concluded that enteral nutritional support can increase total energy and protein intake and raise serum albumin concentrations by an average of 0.23 g/dL with no adverse effects on electrolyte status (serum phosphate and potassium) (Am J Kidney Dis. 2005;46:387-405). Results from the French Intradialytic Nutrition Evaluation study (FINEs) have provided further insights into effects from long-term use of nutritional supplementations in chronic hemodialysis patients with muscle wasting (J Am Soc Nephrol. 2007;18:2583-2591).This RCT involving 186 subjects showed that oral and combined oral–parenteral methods of supplement delivery have similar effects with regard to mortality and improvement of nutritional markers in chronic hemodialysis patients with muscle wasting, as long as equal and adequate amounts of protein and calories are provided.

Exercise. Numerous exercise regimens, including aerobic exercise, resistance exercise, or a combination of both, have been suggested as nutritional interventions in maintenance dialysis patients (J Am Soc Nephrol. 2007;18:1845-1854). The rationale for such intervention is that exercise can induce significant physiological, functional, and psychological benefits without serious adverse events, as has been shown in healthy adults, elderly patients, and those who are frail and/or have chronic disease (J Gerontol A Biol Sci Med Sci. 2002;57:M262-M282, Am J Kidney Dis. 2005;45:912-916, and Am J Nephrol. 2005;25:352-364). Overall, the available studies indicate that the presumed beneficial effects of resistance exercise, such as improvements in muscle quality and quantity, strength, and physical functioning, are not consistently observed in maintenance dialysis patients. Further research is necessary to understand both the observed lack of obvious benefits and the strategies that could lead to improved exercise regimens.

Anabolic agents. Besides the well-documented benefits of growth hormone in children with CKD, short-term administration to dialysis patients results in anabolic responses. Most if not all long-term studies indicate a significant increase in lean body mass in maintenance hemodialysis patients treated with growth hormone. Significant improvements in body composition and physical function have been reported in hemodialysis patients who are given nandrolone decanoate (J Am Soc Nephrol. 2006;17:2307-2314). In addition, increases in cross-sectional area of the quadriceps muscle (by MRI measurements) and in lean body mass (by dual-energy x-ray absorptiometry) were also noted. Curiously, combining resistance exercise with nandrolone decanoate did not improve the beneficial effects of the drug.

Appetite stimulants. Examples of pharmacologic agents that may stimulate appetite include megestrol acetate, dronabinol, cyproheptadine, melatonin, thalidomide, and ghrelin. While most of these agents have not been studied systematically in maintenance dialysis patients with muscle wasting, they have been used in other catabolic illnesses. Megestrol acetate has been associated with such side effects as hypogonadism, impotence, and increased risk of thromboembolism. In maintenance hemodialysis patients, megestrol acetate can stimulate appetite and induce small increases in serum albumin, but large-scale prospective studies are needed to assess whether any of the previously mentioned agents provides adjunctive nutritional therapy for maintenance dialysis patients.

Conclusion

The available evidence suggests that the imbalance between protein synthesis and degradation in patients undergoing dialysis can be compensated for by various anabolic strategies. Nutritional supplementation, administered orally or parenterally, is effective in the treatment of PEW. Resistance or endurance exercise, while effective in the short term, seems to lack consistent evidence in improving lean body mass over the long term. Various anabolic agents are shown to increase visceral protein concentrations as well as muscle mass and strength simultaneously. Additional larger-scale RCTs of anabolic interventions, used individually or in combination, should be performed to assess their efficacy on quality of life, morbidity, and mortality of maintenance dialysis patients.

Additional information on this topic will be presented at the National Kidney Foundation (NKF) 2010 Spring Clinical Meetings in Orlando, Fla. For additional information, go to www.nkfclinicalmeetings.org or contact the NKF at 800.622.9010 or via e-mail at clinicalmeetings@kidney.org.

Dr. Ikizler is Catherine McLaughlin Hakim Professor of Medicine and Medical Director of the Outpatient Dialysis Unit at Vanderbilt University in Nashville.

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