Mushroom Clouds for Vitamin D?

Values of serum 25-hydroxyvitamin D (25OHD) defined as insufficient or deficient are common in the general community, particularly among the elderly and people with chronic illnesses and reduced skin exposure to sunlight. Ultraviolet B exposure is essential for skin synthesis of vitamin D3 (cholecalciferol), the precursor to 25OHD3 and 1,25-dihydroxyvitaminD (calcitriol). Dietary sources of vitamin D include animal sources of cholecalciferol such as oily fish, and plant sterols that provide dietary vitamin D2 (ergocalciferol). Patients with CKD often fall within the populations at risk of vitamin D deficiency.1 After the establishment of a causal relationship of vitamin D deficiency to rickets, fortification of foods with vitamin D was initiated in some countries, with dramatic improvements on bone deformity in children. Subsequent observational studies have linked lower serum 25OHD values to increased risks of cardiovascular, malignant, endocrine, pulmonary, and autoimmune diseases, resulting inwidespread testing of serum 25OHD levels and the prescription or self-initiation of vitamin D at doses that often exceed dietary reference values. This medicalization of vitamin D has also resulted in divergent health care messages on the risks of sun exposure, the usual major source of vitamin D, as well as food fortification and supplementation.2 Even the terminology is loaded, with vitamin D deficiency and insufficiency reflecting cut points for disease associations rather than values at which interventions are proven to influence patient-level outcomes. Many tissues express both vitamin D receptors (VDRs) and cytochrome p450 27B1 (CYP27B1), the 1-a-hydroxylase enzyme that converts 25OHD to calcitriol, but in patients with CKD, renal calcitriol production may be reduced or absent. It has been proposed that vitamin D supplementation may, nevertheless,maintain sufficient 25OHD substrate for extrarenal calcitriol production, to allow the paracrine and autocrine actions of vitamin D and the modulation of vitamin D–responsive genes.3 In addition, serum 25OHDmay act directly through the VDR if calcitriol levels are low. Bone is an obvious target tissue for extrarenal conversion of 25OHD to calcitriol, and in a cross-sectional study of patients on hemodialysis, 25OHD values ,20 ng/ml (50 nmol/L) were associated with reduced bone turnover on histomorphometry, and values .40 ng/ml (100 nmol/L) were associated with increased bone turnover, independent of serum calcitriol and parathyroid hormone (PTH) values.4 Experimental support for extrarenal conversion comes from tissue culture of human osteoclasts.5 When incubated with physiologic 25OHD concentrations, these cells produce calcitriol and upregulate key osteoclast transcription factors and expression of the osteoblast coupling factor ephrin-b2. Low values of 25OHD have also been associated with muscle weakness and falls risk in patients on dialysis, independent of calcitriol values,6 but whether these abnormalities are a consequence of hypovitaminosis D or secondary to associated mineral disturbances is unclear, particularly because the identification of VDR in muscle has been questioned.7 Other associations of lower 25OHD levels include sudden cardiac death, cerebrovascular and all-cause mortality in patients on dialysis with diabetes,8 and a plethora of associations with morbidity and mortality in the general population. Therefore, given the plausible physiology and despite the potential for bias in these observational studies, the temptation to treat is difficult to resist. However, acolytes of vitamin D must, nevertheless, respect the science, and in a number of areas, evidence for and against a role for vitamin D in CKD has been accumulating. The paper by Miskulin et al.9 published in this issue of the Journal of the American Society of Nephrology adds to this evolving evidence base and contrasts with an earlier cross– sectional study10 that reported a 2.8-fold increase in anemia prevalence for patients with CKD who were in the lowest versus the highest tertile of serum 25OHD values. This study by Miskulin et al.9 randomized 276 patients on hemodialysis with baseline 25OHD levels #12 ng/ml (30 nmol/L) to ergocalciferol or placebo for 6 months. Treatment was effective, with 25OHD values rising from 16.065.9 to 39.2614.9 ng/ml (40615 to 98637 nmol/L) in the ergocalciferol arm, and there was no significant change for patients receiving placebo. Active vitamin D was used in 82% of patients, but doses were unchanged during the study. The study reports no significant differences between groups in the primary end point of epoetin requirements or in BP, change in serum PTH, phosphorus, calcium, inflammatory markers, or use of cinacalcet, calcitriol, or phosphate binders.9 These data9 and those of a similar but smaller randomized, controlled trial using cholecalciferol11 erode support for the use of nutritional vitamin D in the short-term management of anemia for patients on dialysis or patient-level outcomes assessed by functional or muscle Published online ahead of print. Publication date available at www.jasn.org.