Pam Harrison

June 17, 2015

LONDON, United Kingdom — During the first year after kidney transplantation, vitamin D₃ supplementation does not reduce the risk for acute rejection episodes or infection, and might promote the development of hypercalcemia, results from a randomized controlled trial suggest.

"VITA-D was a hypothesis-driven study based on recent evidence showing that effects mediated by the vitamin D system go far beyond mineral and bone metabolism, and include immunomodulatory activities, and that these effects could be achieved by administering the active form of vitamin D," said Ursula Thiem, MD, from the Medical University of Vienna.

"We found that treatment of vitamin D deficiency in kidney transplant recipients did not improve short-term post-transplant outcomes. Our data suggest that vitamin D should not be supplemented in the first year after kidney transplantation," she told Medscape Medical News in an email.

Dr Thiem presented results from the study here at the European Renal Association–European Dialysis and Transplant Association 52nd Congress.

The VITA-D study involved patients with vitamin D deficiency — defined as a calcidol level below 50 nmol/L — who had undergone kidney transplantation. Ninety-seven were randomized to vitamin D₃ 6800 IU/day for 12 months and 92 were randomized to placebo.

After 6 months, 75% of patients in the supplementation group had achieved adequate levels of vitamin D. This was maintained at 12-month follow-up.

The number of infections was similar in the supplementation and placebo groups (237 vs 235), as was the number of acute allograft rejections (19 vs 22). There was "no difference in the severity of these events between the two groups," Dr Thiem reported.

At 12 months, serum creatinine levels — a marker of renal graft function — were slightly higher in the supplementation group than in placebo group in the modified intention-to-treat analysis (1.55 vs 1.48 mg/dL) and in the per protocol analysis (1.54 mg/dL vs 1.42 mg/dL). This suggests that supplementation is associated with potential harm.

Patients in the supplementation group were at a disadvantage because they received older organs than patients in the placebo group. Outcomes are know to be worse when organs come from older donors than when they come from younger donors, Dr Thiem pointed out.

When donor age and other confounding factors were accounted for, "the treatment effect of vitamin D₃ on serum creatinine at 12 months disappeared," she reported.

However, she added, "in our per protocol analysis at 6 months, the difference in serum creatinine levels between the two groups was more pronounced and could not be fully explained by confounding factors such as donor age."

Importantly, 30% of patients in the supplementation group required a reduction in the dose of vitamin D₃ or treatment discontinuation because of hypercalcemia. In addition, 17% in the placebo group developed hypercalcemia, which is not uncommon in the post-transplantation setting.

"Given the lack of an overall benefit of vitamin D supplementation and the fact that a significant number of patients developed hypercalcemia with vitamin D₃ therapy, it does not appear reasonable to supplement vitamin D in these patients in the early post-transplant period, Dr Thiem concluded.

However, the majority of acute rejections episodes, as well as infections, occur during the first year after transplantation, when the burden of immunosuppressive drugs is particularly high, she said.

Later in the post-transplantation period, once the burden of immunosuppression is reduced, studies suggest that vitamin D supplementation might help preserve renal function. In fact, "vitamin D supplementation could possibly mediate similar renoprotective effects."

However, "it was out of the scope of our study to answer these questions," she added.

Vitamin D Deficiency

Almost 70% of patients with chronic kidney disease are deficient in vitamin D prior to receiving supplementation, which they now usually do, said Denis Fouque, MD, from the University of Lyon in France.

"In the early post-transplant situation, however, no evidence for treatment was available until the VITA-D trial," Dr Fouque said in an email to Medscape Medical News.

Although there was no difference between the supplementation and placebo groups in terms of immunologic events, serum creatinine was slightly higher in the group receiving the vitamin D supplement, he pointed out.

"These results were unexpected because of a number of alleged beneficial vitamin D properties," Dr Fouque observed.

"There are many other beneficial targets for vitamin D that were not measured in the study, including muscle strength, cardiac function, bone quality, and parathyroid hormone status," he added, all of which might improve with vitamin D supplementation.

More important, he explained, using serum creatinine to assess renal function might not be appropriate because creatinine can be modified by food intake, muscle mass, gender, and medication, and none of this information was available.

"Only gold-standard measurement of renal function can be used to adequately monitor renal function in this setting," said Dr Fouque.

"Hypercalcemia, which occurred more frequently in the vitamin D supplemented group, may also be the consequence of too much calcium salt supplementation, which is frequently given during the immediate post-transplant period to fight against the deleterious effects of steroids on bone," he added.

"This study does not indicate a beneficial effect of vitamin D supplementation on infectious episodes, but much remains to be analyzed," he said.

Dr Thiem and Dr Fouque have disclosed no relevant financial relationships.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress: Abstract LBA-3564. Presented May 29, 2015.

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