Vitamin D compounds for people with chronic kidney disease requiring dialysis

People with reduced kidney function (chronic kidney disease; CKD) develop changes in circulating blood levels of calcium and phosphorus. The kidney gradually loses the ability to remove phosphorus from the blood and cannot activate adequate amounts of vitamin D, to maintain normal levels of calcium. The parathyroid gland senses these changes and compensates to increase calcium by elevating production and release of parathyroid hormone. These metabolic changes alter bone metabolism to release calcium and accordingly lead to bone abnormalities including altered bone production. Consequently bone deformation, bone pain, and altered risks of fracture may occur.

Treatment for these mineral changes in CKD include replacing activated vitamin D to suppress parathyroid hormone release. Earlier activated vitamin D preparations (calcitriol and alfacalcidol) were associated with increased circulating calcium and phosphorus levels through their direct action on the vitamin D receptor. Newer agents have since been developed that similarly suppress parathyroid hormone but may limit increases in calcium and phosphorus. Avoidance of increased calcium and phosphorus is considered important as these minerals may activate calcification in arteries and tissues, potentially leading to heart disease and tissue damage.

We identified 60 studies of vitamin D preparations in people with CKD and requiring dialysis involving 2773 people. No studies were designed to understand the effect of vitamin D therapy on risks of death. Vitamin D agents suppress PTH significantly compared with no treatment, however also increase both circulating calcium and phosphorus levels. Intravenous vitamin D may lower PTH more than oral vitamin D. Few studies directly compare newer vitamin D therapies with earlier (and presently more common treatment options; calcitriol and alfacalcidol); newer treatment options therefore cannot be recommended as superior to established treatments.

In the future, new studies will required to know if vitamin D effects on parathyroid function improve survival, bone pain, and need for parathyroid removal by surgery. It is possible that vitamin D compounds are beneficial to patients regardless of their effects on parathyroid hormone. This can only be adequately evaluated by conducting specific studies that are large enough to be sure of any treatment differences.

Authors' conclusions: 

We confirm that vitamin D compounds suppress PTH in people with CKD and requiring dialysis although treatment is associated with clinical elevations in serum phosphorus and calcium. All studies were inadequately powered to assess the effect of vitamin D on clinical outcomes and until such studies are conducted the relative importance of changes in serum PTH, phosphorus and calcium resulting from vitamin D therapy remain unknown. Observational data showing vitamin D compounds may be associated with improved survival in CKD need to be confirmed or refuted in specifically designed RCTs.

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Background: 

Clinical guidelines recommend vitamin D compounds to suppress serum parathyroid hormone (PTH) in chronic kidney disease (CKD), however treatment may be associated with increased serum phosphorus and calcium, which are associated with increased mortality in observational studies. Observational data also indicate vitamin D therapy may be independently associated with reduced mortality in CKD.

Objectives: 

We assessed the effects of vitamin D compounds on clinical, biochemical, and bone outcomes in people with CKD and receiving dialysis.

Search strategy: 

We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles.

Selection criteria: 

Randomised controlled trials (RCTs) in subjects with CKD and requiring dialysis that assessed treatment with vitamin D compounds.

Data collection and analysis: 

Data was extracted by two authors. Results are summarised as risk ratios (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).

Main results: 

Sixty studies (2773 patients) were included. No formulation, route, or schedule of administration was associated with altered risks of death, bone pain, or parathyroidectomy. Marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis. Compared with placebo, vitamin D compounds lowered serum PTH at the expense of increasing serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance but may be clinically relevant. Newer vitamin D compounds (paricalcitol, maxacalcitol, doxercalciferol) lowered PTH compared with placebo, with increased risks of hypercalcaemia, although inadequate data were available for serum phosphorus. Intravenous vitamin D may lower PTH compared with oral treatment, and be associated with lower serum phosphorus and calcium levels, although limitations in the available studies precludes a conclusive statement of treatment efficacy. Few studies were available for intermittent versus daily and intraperitoneal versus oral administration or directly comparative studies of newer versus established vitamin D compounds.

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