Vitamin D supplementation in pre-dialysis chronic kidney disease: A systematic review.

Dermato-Endocrinology 4:2, 118–127; April/May/June 2012; G 2012 Landes Bioscience Vitamin D supplementation in pre-dialysis chronic kidney disease A systematic review Jessica A. Alvarez,1,* Haimanot Wasse2 and Vin Tangpricha1 1 . e nc Division of Endocrinology, Diabetes, and Metabolism; Emory University School of Medicine; Atlanta, GA USA; 2Division of Nephrology; Emory University School of Medicine; Atlanta, GA USA Keywords: vitamin D, cholecalciferol, ergocalciferol, renal disease, secondary hyperparathyroidism, chronic kidney disease e i c s o i B . e s t e u d b i n r a t L s i 2 d 1 t 0 o 2 n o © D Abbreviations: 25(OH)D, 25-hydroxyvitamin D or calcidiol; 1,25(OH)2D, 1,25-dihydroxyvitamin D or calctriol; [Ca2+]i, intracellular calcium concentration; BAP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; FGF-23, fibroblast growth factor-23; GFR, glomerular filtration rate; KDOQI, Kidney Disease Outcomes Quality Initiative; PTH, parathyroid hormone; VDBP, vitamin D binding protein Vitamin D deficiency is associated with a variety of skeletal, cardiometabolic, and immunologic co-morbidities that are present in chronic kidney disease (CKD). We performed a systematic review to investigate the effects of vitamin D supplementation, in the form of ergocalciferol or cholecalciferol, on various health outcomes in early CKD. Seventeen clinical trials were identified, only two of which were randomized, placebo controlled trials. The majority of studies supplementing with . 2,000 IU/day of cholecalciferol achieved optimal vitamin D status, whereas studies supplementing with ergocalciferol were less consistent. Studies varied widely in their effects on lowering serum parathyroid hormone concentrations. Few studies investigated effects of vitamin D treatment on other clinical health indicators in early CKD. Rigorous studies are necessary to investigate optimal vitamin D dosing strategies in early CKD for the maintenance of adequate vitamin D status, management of secondary hyperparathyroidism and improvement of nonskeletal related clinical outcomes. Introduction With the increasing prevalence of obesity, hypertension, and type 2 diabetes, there has also been an increase in the prevalence of chronic kidney disease (CKD).1 Complications of CKD include progression to end stage renal disease and need for costly dialysis or renal transplantation, bone disease and premature cardiovascular disease (CVD) morbidity and mortality.2 Strategies to manage CKD are thus a high priority, not only from a clinical, but also a public health perspective.3 Vitamin D may play a key role in the disease management of CKD. Accumulating evidence *Correspondence to: Jessica A. Alvarez; Email: Submitted: 02/01/12; Revised: 03/01/12; Accepted: 03/02/12 http://dx.doi.org/10.4161/derm.20014 118 from epidemiological and experimental research suggests that vitamin D is integral not only for its classical effects on the skeletal system, but also for its extra-skeletal benefits such as those on cardiovascular health and immune function.4,5 In this regard, a recent meta-analysis indicated that higher circulating 25-hydroxyvitamin D (25(OH)D or calcidiol) concentrations were associated with lower all-cause mortality risk in all stages of CKD.6 Altered vitamin D metabolism and resultant changes in bone and mineral metabolism are key features of CKD. The kidneys are the primary site of 25(OH)D conversion to the hormonal form of vitamin D, calcitriol (1,25(OH)2D), by the enzyme 1a-hydroxylase.7 As kidney disease progresses and renal mass decreases, there is a decline in the availability of 1a-hydroxylase enzyme resulting in a decrease in calcitriol, followed by compensatory increases in parathyroid hormone (secondary hyperparathyroidism) to offset impaired intestinal calcium absorption and resultant hypocalcemia.8,9 Other abnormalities of CKD, such as elevated fibroblast growth factor (FGF)-23,10,11 accumulation of parathyroid hormone (PTH) fragments (N-terminally truncated or C-terminal)12 and uremic toxins,13 and reductions in glomerular filtration rate (GFR) and megalin contribute to calcitriol defects in CKD.8 Because of defects in renal calcitriol production, studies in the past have primarily focused on the use of calcitriol replacement (or other active vitamin D analogs) to control hyperparathyroidism in CKD.2,14 However, there is evidence that patients with end stage renal disease (ESRD) retain some capacity to produce calcitriol from 25(OH)D, either through residual renal functioning or extra-skeletal production of calcitriol.15,16 Extra-renal cells, such as parathyroid cells, smooth muscle cells, endothelial cells, pancreatic cells and immunomodulatory cells, contain the machinery to locally produce calcitriol.17 This may explain the associations of adequate vitamin D status with lower chronic disease risk. Thus, the ability to maintain sufficient serum concentrations of 25(OH)D, the substrate for extra-renal 1a-hydroxylase and local production of active vitamin D, is particularly important in CKD. Dermato-Endocrinology Volume 4 Issue 2 REVIEW Recent reports estimate up to 84% prevalence of vitamin D deficiency and insufficiency (defined in this review as 25(OH)D , 20 ng/ml and 25(OH)D , 30 ng/ml, respectively18) in CKD populations.19,20 Reasons for high prevalence of vitamin D deficiency in the CKD population compared with the general population are not clear. Elevated proteinuria and thus loss of urinary vitamin D binding protein (VDBP),20,21 reduced recycling of 25(OH)D by megalin in proximal tubular cells,22,23 and differences in diet, reduced sun exposure, and other lifestyle factors such as limited outdoor activity2,24 may provide explanations. Given the dysregulated vitamin D metabolism and the high prevalence of vitamin D deficiency in patients with CKD, the increasingly recognized pleiotropic benefits of the vitamin D system,17 and the elevated risk of premature morbidity and mortality associated with both CKD25,26 and vitamin D deficiency,27,28 optimizing vitamin D status through supplementation may be of particular relevance in CKD patients, specifically in pre-dialysis CKD wherein renal capabilities of 25(OH)D conversion to calcitriol have not been exhausted. To this end, the purpose of this review is to investigate the effects of vitamin D supplementation (cholecalciferol or ergocalciferol) on health outcomes and biomarkers related to mineral and bone metabolism, CKD progression, diabetes, and cardiovascular disease in predialysis stages of chronic kidney disease (Stages 2 to 4). in the English language. Titles and abstracts were reviewed. Review articles, cross-sectional studies, and non-human studies were excluded. Manuscripts were further excluded for review if (1) they did not use oral cholecalciferol or ergocalciferol; (2) they used analog compounds of vit (...truncated)