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.