Anabolic Interventions in ESRD: Light at the End of the Tunnel?

What Does This Important Study Show? 

Nass et al15 studied the effects of MK-677, a ghrelin mimetic, on age-associated changes in body composition. This was a 2-year, double-blind, placebo-controlled, modified-crossover clinical trial in which 65 healthy men and women 60 to 81 years of age received 25 mg of MK-677 or placebo each morning. The primary outcome measurements at 1 year included 24-hour GH secretory profiles, morning IGF-1 serum concentrations, fat-free mass, and abdominal visceral fat. Secondary outcome measures included various other body composition, endocrine-metabolic profile, strength, physical performance, and quality-of-life measures.

Results of the study were very intriguing in that after 1 year, daily administration of MK-677 significantly increased GH and IGF-1 to levels of healthy young adults without serious adverse effects. This was accompanied by statistically significant increases in fat-free total body and limb mass and intracellular water (consistent with an increase in cell mass) in the group receiving MK-677, whereas all those parameters showed an additional decrease in the group receiving placebo. Body weight increased 0.8 kg (confidence interval, −0.3 to 1.8) in the placebo group and 2.7 kg (confidence interval, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). In contrast, there were no significant differences in total and abdominal fat, although the average increase in limb fat (as well as fat-free mass) was greater in the MK-677 group than the placebo group (1.1 vs. 0.24 kg; P = 0.001), consistent with redistribution of fat deposits from the abdomen to periphery. The statistically significant increase in fat-free mass was accompanied by improvements in muscle strength and function (when corrected for baseline muscle mass).

Secondary analyses further showed that low-density lipoprotein cholesterol levels decreased slightly, whereas cortisol, fasting blood glucose, and hemoglobin A1c levels increased in the group receiving MK-677. In addition, the QUICKI index of insulin sensitivity16 decreased slightly and appetite and body weight increased somewhat in the MK-677 group. Two-year exploratory analyses were performed in a subset of 53 of 65 participants, which confirmed the 1-year results such that the GH, IGF-1, and fat-free mass changes persisted. Interestingly, in participants treated for 2 years with MK-677, fasting blood glucose values were no longer increased. Concentrations of IGF-1 returned to normal after study completion. Limitations of this study include the small sample size, possible confounding effects of sex or hormone replacement therapy, and limited clinically relevant outcome measures.

How Does This Study Compare With Other Studies? 

Patients with CKD have low circulating levels of certain anabolic hormones (eg, testosterone), increased levels of some catabolic hormones (cortisol), and resistance to other anabolic hormones (ie, GH). It therefore is reasonable to speculate that pharmacological doses of anabolic hormones could be of potential value in treating the PEW of maintenance dialysis patients. Johansen et al17 showed that treatment with nandrolone decanoate led to significant improvements in quadriceps muscle cross-sectional area and an increase in whole-body lean body mass and physical functioning. In light of a recent study showing a significant inverse correlation between testosterone levels and mortality in long-term dialysis patients,18 additional studies are needed to assess the implications of long-term nandrolone treatment in this population.

Acquired resistance to the anabolic actions of GH is another potential cause of increased net protein catabolism in dialysis patients.3 A recent randomized, double-blind, placebo-controlled, 26-week, proof-of-concept clinical trial in 139 adult long-term dialysis patients showed that GH led to statistically significant gains in lean body mass compared with placebo.19 Statistically significant beneficial changes in other (cardiovascular) biomarkers of mortality (homocysteine, transferrin, and high-density lipoprotein cholesterol) and HRQoL were observed. There was also a trend (P = 0.06) toward increased levels of serum albumin compared with placebo. This promising phase 2 trial was followed by a large-scale 2-year clinical trial (the OPPORTUNITY Study; ClinicalTrials.gov registration no. NCT00503698) testing whether GH would produce improvements in mortality. OPPORTUNITY was prematurely terminated, but not for reasons of any adverse outcomes.20

Ghrelin or ghrelin mimetics also potentially could be of great value compared with other anabolic agents in long-term dialysis patients. Epidemiological studies indicate that plasma des-acyl and total ghrelin concentrations are markedly increased in long-term dialysis patients, possibly because of impaired clearance or metabolism of ghrelin.21 In these patients, total and active plasma ghrelin levels are increased, particularly in anorexic patients, and correlate with fat mass, plasma insulin, and serum leptin levels.22 Abnormally increased total and active ghrelin levels are decreased after a single course of hemodialysis, and increases in body fat mass observed in peritoneal dialysis patients correlate with decreases in plasma ghrelin levels.13 In an experimental study, administration of ghrelin and 2 synthetic ghrelin-receptor agonists (BIM-28125 and BIM-28131) increased food intake, attenuated muscle protein degradation, and decreased circulating inflammatory cytokine levels in nephrectomized animals.23 There also are preliminary studies of subcutaneous ghrelin administration in long-term dialysis patients. Wynne et al24 administered subcutaneous ghrelin (3.6 nmol/kg) and saline placebo in a randomized double-blind crossover protocol to 9 peritoneal dialysis patients with mild to moderate PEW. Administration of subcutaneous ghrelin significantly increased short-term food intake (690 ± 190 versus 440 ± 250 kcal; P = 0.0062) without significant side effects.24

What Should Clinicians and Researchers Do? 

The clinical importance of PEW in patients with CKD and potential improvements from the use of anabolic interventions should make such trials a priority. Among several potential candidates, ghrelin and ghrelin mimetics appear to be of great potential value to achieve this goal, at least in long-term dialysis patients who have apparent PEW unresponsive to conventional therapies. The GH-like properties of ghrelin combined with its orexigenic and anti-inflammatory effects make it a unique drug to combat this multifaceted PEW syndrome that is so evident in these patients. The study by Nass et al15 provides exciting data to support this hypothesis. Clinical studies exploring the efficacy and feasibility of ghrelin or ghrelin mimetics are greatly needed in this high-risk patient population.