Editorial Cholecalciferol in Chronic Dialysis Patients: Not Strong Enough?

Vitamin D deficiency and insufficiency, defined by circulating concentrations of 25-hydroxyvitamin D [25 (OH)D], have garnered increasing attention in clinical medicine and research. The vitamin D receptor regulates diverse biologic systems, including calcium and bone metabolism, renin-angiotensin activity, inflammation, and muscle functioning (1,2). Lower serum concentrations of 25(OH)D are associated with many chronic diseases across a range of cohort studies (3,4). Serologic testing for 25(OH)D and empirical therapy with vitamin D supplements have increased substantially worldwide, with significant costs. Large clinical trials are now underway to determinewhether vitamin D supplementation can improve cardiovascular, bone, and cancer outcomes in the general population (5). Nephrologists have long recognized disturbances in vitamin D metabolism among patients who have CKD. In contrast to substrate 25(OH)D deficiency found in the general population, the primarymetabolic deficit in CKD is a decline in 1,25-dihydroxyvitamin D [1,25(OH)2D], the biologically potent form of vitamin D. Causes of reduced 1,25(OH)2D) in CKD are multifactorial, including reduced functional renal mass and inhibition of 1-a hydroxylase by fibroblast growth factor-23, phosphate excess, and metabolic acidosis (6,7). Treatment with 1,25(OH)2D or related analogs has been the mainstay of vitamin D therapy in ESRD patients; however, vitamin D substrate (cholecalciferol and ergocalciferol) can also stimulate pathways responsive to the vitaminD receptor in CKD through localized production of 1,25(OH)2D in nonrenal sites, stimulation of 1-a hydroxylase activity in residual kidney tissue, or both (8). Therefore, there is growing interest in whether vitamin D supplementation can improve patient outcomes in CKD. In this issue of CJASN, Hewitt et al. (9) take an important step forward by conducting a clinical trial of cholecalciferol supplementation on skeletal muscle function in chronic dialysis patients. The loss ofmuscle function (sarcopenia) is a frequently overlooked but important consequence of kidney failure, with serious clinical and quality-of-life implications (10). In the current study, 60 chronic dialysis patients who had serum 25(OH)D concentrations#24 ng/ml were randomly assigned to receive 50,000 IU oral cholecalciferol or matching placebo weekly for 8 weeks and then monthly for 4 months. A total of 21 patients in the cholecalciferol group (70%) and 24 patients in the placebo group (80%) returned for scheduled 6-month follow-up evaluations. Over the 6-month follow-up period, cholecalciferol significantly increased serum 25(OH)D and 1,25(OH)2D concentrations compared with placebo. However, there were no differences between the treatment groups in the primary study outcomes of upperand lower-extremity muscle strength. Similarly, there were no differences in secondary study outcomes of 6-month serum levels of parathyroid hormone, bone alkaline phosphatase, and C-reactive protein, and there were no differences in end-of-study pulse wave velocity, BP, or quality of life. Hewitt et al. (9) should be commended on several important aspects of their study that can help inform future clinical trials in nephrology. First, by conducting an interventional trial, Hewitt et al. (9) minimized the potential for confounding, the primary limitation of observational studies of vitamin D. Second, Hewitt et al. (9) selected a primary study outcome, skeletal muscle performance, that is clinically important while minimizing attention on parathyroid hormone, a common but clinically ambiguous outcome of vitamin D studies. Third, the study used broad entry criteria with minimal exclusions and simplified treatment andmonitoring procedures to enhance generalizability and increase participant retention. Of 70 subjects who met study eligibility criteria, 60 subjects participated in the trial. Fourth, the study took advantage of frequent scheduled contacts for in-center hemodialysis patients to directly administer the study medication and increase compliance. The obvious weaknesses of the study are the small sample size and loss of some participants during follow-up. The small sample size enables the study to exclude only large effects of cholecalciferol on skeletal muscle function in dialysis patients; small or moderate effects with potential clinical importance remain possible. Although physical activity interventions can substantially improve muscle strength in general and geriatric study populations, medications alone are unlikely to produce such large changes. The inclusion of baseline physical performance values in the analysis could have increased study power. In addition, it is important to recognize that loss to follow-up in a Division of Nephrology, University of Washington, Kidney Research Institute, Seattle, Washington