The present study constitutes the first randomized, placebo-controlled trial of oral leucine-enriched BCAA supplement among elderly patients with CKD. Leucine-enriched BCAA supplement promotes a significant increased lean muscle mass among elderly patients with CKD, but the supplement did not demonstrate benefits concerning biomarkers of muscle activity and functional capacity. Risk of serious adverse event was not higher among patients receiving leucine-enriched BCAA supplement. From the result of the study, the clinical trial provided evidence concerning leucine-enriched BCAA supplement among elderly patients with CKD compared with standard treatment on improving lean muscle mass.
Sarcopenia is common among elderly patients with CKD, especially for patients with more advanced stages of the disease [14]. CKD is characterized by a status of abnormal amino acid metabolism [15] and blood BCAA levels and reduced peripheral release of leucine in CKD with uremia suggests an increased degradation of leucine [16, 17]. Data on the benefits and risks of oral EAAs enriched with leucine in this setting remain limited. Two studies found that leucine supplement increased muscle mass and reversed an attenuated response of muscle protein synthesis among healthy elderly patients [6, 12]. Recently, a systemic review showed that leucine supplementation improved muscle mass among elderly adults [18]. Additionally, amino acid supplementation acutely stimulated muscle protein synthesis among elderly individuals [19]. From the mechanism, concentrate of about 35% leucine in oral EAA decreased proteolysis of muscle mass, and stimulated mTOR to increase protein synthesis [7, 8]. Our study also supported that EAAs enriched with leucine (60% leucine in oral EAA) improved muscle mass among elderly patients with CKD. The findings indicated that EAAs enriched with leucine might have therapeutic potential due to their proven protein anabolic effects among elderly patients with CKD.
The mechanisms for muscle wasting among patients with CKD indicated decreased synthesis of muscle mitochondrial proteins [20] and IGF-1 resistance play a role in decreasing muscle protein synthesis [21]. Uremic toxins also accelerated muscle atrophy by inducing myostatin expression as a negative regulator of skeletal muscle [22]. One study reported that chronic EAA supplementation improved postabsorptive muscle protein fractional synthesis rate and IGF-I muscle protein expression augmenting protein synthesis in muscle tissue [6]. Our study also found that serum IGF-1 levels decreased from baseline after EAAs, enriched with leucine supplement, but no significant difference was observed in the changes of serum IGF-1 and myostatin levels between groups. Physiological responses to stimuli frequently cite upregulation of muscle IGF-I messenger RNA; whereas, the circulatory results may have distinct effects on muscle mass regulation [23]. Myostatin, in different disease conditions, produced conflicting results to muscle mass or muscle wasting and serum myostatin as a potential biomarker for muscle wasting. Thus, the relationship between serum and skeletal muscle mass remains unclear [24, 25]. Further studies need to measure tissue IGF-1 and myostain after EAAs, enriched with leucine intervention.
The synergistic effects of protein supplementation and resistance exercise to increase muscle mass and strength gains have been explored among elderly subjects [26]. Similarly, combined exercise and BCAA stimulated cell signaling to promote muscle protein synthesis in CKD model rat [27] and combined exercise with oral nutritional supplementation produced larger effects concerning physical functions among patients undergoing dialysis [28]. Conflicting evidence was noted regarding the benefits of dietary EAA supplementation on increased muscle strength during resistance exercise training [29, 30]. In a systemic review, leucine-rich protein supplementation was found to exert beneficial effects on lean body mass but not muscle strength among older individuals [31]. Our study did not provide evidence for muscle strength benefits of leucine-enriched BCAA supplemention among elderly patients with CKD. The apparent discrepancy may be attributed to inadequate exercise intensity and short duration of EAAs enriched with leucine supplement in settings of advanced age, more comorbidities and CKD. Long term use of leucine-enriched BCAA supplement combined with physical resistance exercise may provide a significant change of physical strength among elderly patients with CKD.
The limitations of the study included a relatively small size for a clinical trial, the fact that most outcome measurements were only obtained at baseline and the end of the study, 12 weeks later. Muscle biopsy and tissue biomarkers such as tissue IGF-1 and myostatin levels, which are standard and accuracy measurements for improving muscle wasting were not used to evaluate study results. The strength of the study stemmed from measuring lean muscle mass among elderly patients with CKD by dual energy X-ray absorptiometry as the reference standard to measure muscle mass[32]. In the study, all participants were monitored by nutritionists regarding dietary intake and exercise. Adherence to the medication assessed by pill count appeared adequate in both groups at 90 to 95%. Long term efficacy and safety effects among elderly patients with CKD could not be assessed in the study.