What is the background to this?
Metabolic disturbances of calcium, phosphate and parathyroid hormone (PTH) are common in patients with chronic kidney disease (CKD). They not only cause significant bone disease but also contribute to cardiovascular disease (CVD) . However, treatment that may benefit the skeleton may contribute further to CVD, making the choice of treatment complex . Interventions widely used in this arena include vitamin D compounds, calcium supplements and phosphate binders. This meta-analysis aimed to determine whether vitamin D therapy, which is widely used to prevent and treat secondary hyperparathyroidism, improves not only biochemical markers of mineral metabolism but also cardiovascular (CV) and mortality outcomes in CKD.
What does this study claim? – The authors claim that the efficacy of vitamin D in improving biochemical and clinical outcomes is unproven in CKD and, therefore, the value of such treatment is uncertain. PTH levels were not consistently reduced with vitamin D, and the few trials assessing patient-orientated outcomes, such as death, fracture, bone pain or parathyroidectomy, found no significant effects (see below for details).
How does this relate to other studies?
A NICE guideline on the early identification and management of adults with chronic kidney disease in primary and secondary care is expected in September 2008. The scope of this guideline includes the management of renal bone disease. Much of the guidance currently available in this area is from the Renal Association. In their concise UK guidelines from 2005, the Renal Association recommends the following with respect to Vitamin D treatment in stage 3 CKD:
Check parathyroid PTH concentration when stage 3 first diagnosed.
If raised check serum 25-hydroxyvitamin D;
If this is low treat with ergocalciferol or cholecalciferol with calcium supplement (not calcium phosphate).
Repeat PTH after 3 months and refer if still raised.
This meta-analysis included studies in which the vitamin D compounds used were different from those currently recommended in the UK It is unclear whether the choice of vitamin D compound is a significant factor in reducing important patient-related outcomes. This study highlights the issue that practice guidelines surrounding the treatment of metabolic bone disease in CKD are largely based on opinion and interpretation from observational studies . The evidence supporting Vitamin D treatment seems to be much weaker than many of us had assumed and it highlights the need for good quality, adequately powered RCTs in this area. Until data from such studies are available, the clinical value of vitamin D supplementation in patients with CKD remains unproven.
Action This meta-analysis alone should not change practice. However, it does highlight the uncertainty surrounding the widespread use of Vitamin D in CKD, and guidance from NICE regarding the management renal bone disease is eagerly awaited.
This meta-analysis included 76 randomised controlled trials of varying quality where vitamin D compounds were compared with either placebo or different vitamin D compounds/doses/administration regimens in CKD (n=3,667 patients with any stage of CKD). Most studies measured biochemical outcomes (e.g. levels of PTH, calcium, phosphorus and calcium X phosphorus product). Only eight trials measured patient-orientated outcomes, such as all-cause and CV mortality, fracture and toxicity.
Results: Compared with placebo, established vitamin D compounds (calcitriol, alfacalcidol) increased the risk of hypercalcaemia (Relative Risk [RR] 2.37; 95%CI 1.16 to 4.85) and hyperphosphataemia (RR 1.77; 95%CI 1.15 to 2.74) but did not show consistent reductions in PTH levels. Compared with placebo, more recently developed vitamin D compounds (paricalcitol▼, doxercalciferol or 22-oxacalcitriol) increased the risk of hypercalcaemia (RR 5.15; 95%CI 1.06 to 24.97) but not hyperphosphataemia, and levels of PTH were reduced (weighted mean difference –10.77pmol/l; 95%CI, –20.51 to –1.03pmol/l). Intravenous administration was superior to oral vitamin D for suppression of PTH, but higher intravenous doses were used. Vitamin D compounds did not reduce the risk for death, bone pain, fracture, vascular calcification or parathyroidectomy. However, the latter results were based on just 8 trials which reported patient-orientated outcomes, none of which were powered to assess these outcomes. There was no evidence that newer vitamin D compounds were superior to established vitamin D compounds on any outcome, although the analysis identified only five direct head-to-head trials.
Partial funding for this project was provided by the Cochrane Renal Group.
Chronic Kidney Disease in Adults: UK Guidelines for Identification, Management and Referral. Renal Association June 2005. Accessed from http://www.renal.org/CKDguide/full/UKCKDfull.pdf on January 17 2008
Tonelli M. Vitamin D in patients with chronic kidney disease: nothing new under the sun. Ann Intern Med 2007;147:880-1