Meta-analysis: Vitamin D Compounds in Chronic Kidney Disease

Context Clinicians often treat patients with kidney disease with vitamin D compounds to prevent secondary hyperparathyroidism. Contribution This meta-analysis of 76 randomized trials found no good evidence that vitamin D compounds reduced risk for de... show more

Context Clinicians often treat patients with kidney disease with vitamin D compounds to prevent secondary hyperparathyroidism. Contribution This meta-analysis of 76 randomized trials found no good evidence that vitamin D compounds reduced risk for death, bone pain, vascular calcification, or need for parathyroidectomy in patients with chronic kidney disease. Compared with placebo, established vitamin D sterols increased risk for hypercalcemia and hyperphosphatemia, whereas newer vitamin D analogues increased hypercalcemia but not hyperphosphatemia. Direct comparisons found no clear benefits of newer analogues over established agents. Implication Though commonly used, vitamin D compounds for chronic kidney disease have unclear benefits and potential harms. The Editors All stages of chronic kidney disease (CKD) are associated with significantly increased rates of all-cause and cardiovascular mortality (1). Several risk factors for death have been identified and targeted by interventions, but registry data have not shown substantial improvements in survival of people with end-stage kidney disease over the past 2 decades (2). Abnormalities of bone metabolism and mineralization, which are risk factors for death in CKD, occur early and become universal as kidney function declines (3). A frequent pattern of biochemical abnormalities includes increased serum phosphorus and parathyroid hormone (PTH) levels, whereas levels of serum calcium may be low, normal, or elevated. These changes are associated with alterations in bone mineral homeostasis, increased bone fragility (4, 5), vascular and soft tissue calcification (6, 7), muscle dysfunction (8), adverse cardiovascular outcomes, and increased mortality (9). Compared with PTH levels of 16.5 to 33.0 pmol/L (150 to 300 pg/mL), levels greater than 66 pmol/L (600 pg/mL) are reported to be associated with a 10% increased risk for death (10). Similar mortality data have been observed for increased serum phosphorus and calcium levels (10). Interventions that are widely used to improve biochemical markers of bone and mineral metabolism include active vitamin D compounds, calcium supplements and noncalcium-containing phosphate binders, and calcimimetics. Vitamin D therapy has historically been based on alfacalcidol (1 -hydroxyvitamin D3) or calcitriol, both of which attenuate secondary hyperparathyroidism (1114). Although these compounds may reduce PTH levels, they increase calcium and phosphorus levels (9, 10, 15, 16). Support for use of the newer vitamin D analogues (22-oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol) is based on reports of similar or superior dose-equivalent suppression of PTH, less calcemic and phosphatemic activity, and the possibility of improved survival when compared with established vitamin D sterols (calcitriol or alfacalcidol) (17, 18). Guidelines have suggested that doxercalciferol and paricalcitol may be preferable to calcitriol and alfacalcidol (19). We evaluated available randomized trials to determine the effects of established vitamin D sterols and newer analogues on biochemical, bone, and cardiovascular end points in CKD together with their optimal dose and route of administration. Methods Data Sources and Searches Literature searches for randomized, controlled trials (RCTs) of vitamin D sterols in CKD were performed in MEDLINE (January 1966 to July 2007) and EMBASE (January 1980 to July 2007) using optimally sensitive search strategies (20). The Cochrane Renal Group Renal Health Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were also searched. The complete search strategy is outlined in Appendix Table 1. Authors followed a standardized published protocol for identification of eligible trials (21). Appendix Table 1. Summary of Search Strategy Study Selection We included randomized and quasi-randomized, controlled trials conducted in patients with CKD and that compared vitamin D compounds with placebo, different vitamin D compounds directly, and different vitamin D dose and administration regimens. Studies enrolling patients with any stage of CKD and measuring the effect of these agents on surrogate biochemical end points at the end of treatment (for example, levels of PTH, calcium, phosphorus, and calciumphosphorus product) and hard patient-level end points (for example, all-cause and cardiovascular mortality, fracture, toxicity) were included. We excluded trials enrolling only participants who had parathyroidectomy or kidney transplantation. We also excluded RCTs of vitamin D compounds in osteoporosis because results of these studies were presented without reference to kidney function or CKD was an exclusion criterion. Data Extraction and Quality Assessment Two independent authors assessed each trial. They extracted data on the characteristics of participants, interventions, comparisons, and clinical outcomes, when reported. Hypercalcemia was defined as a serum calcium level of 2.63 mmol/L or greater (10.5 mg/dL), and hyperphosphatemia was defined as a serum phosphorus level greater than 1.62 mmol/L (>5.0 mg/dL). Because trial investigators generally did not report change in values from beginning to end of treatment for continuous variables, we only considered the end-of-treatment values. Where published outcome data were not provided in sufficient detail, an author contacted the trial investigators by electronic or standard mail requesting additional information. Review authors resolved discrepancies in data extraction and quality assessment through discussion. Data Synthesis and Analysis We summarized treatment effects as relative risks (RRs) for categorical variables and weighted mean differences for continuous variables, with 95% CIs. We pooled estimates from individual trials by using the DerSimonian and Laird random-effects model (22). We repeated all analyses by adding 1/n to treatment groups with zero events and using the odds ratio as the measure of effect. Neither met show less