DENVER — Supplementation with high-dose cholecalciferol (vitamin D3) did not improve overall survival in patients receiving dialysis for end-stage kidney disease, according to findings from the SIMPLIFIED trial.
Overall survival over a median follow-up of 7.5 years did not significantly differ between patients who received 60,000 IU of cholecalciferol every 2 weeks and those who received standard care without supplementation (conditional HR 0.95, 95% CI 0.86-1.04, P=0.26), reported Rona Smith, MD, of the University of Cambridge in England.
In addition, there were no significant differences in secondary endpoints, including fatal and nonfatal cardiovascular events, infections, fractures, and malignancy.
“The findings don’t support routine supplementation of high-dose cholecalciferol,” Smith said at the American Society of Nephrology Kidney Week annual meeting.
Dialysis patients face poor long-term outcomes, she noted. “By 5 years, half of people who have commenced dialysis will not be alive, and the majority of deaths are caused by cardiovascular disease.”
“We also know that in this population, vitamin D deficiency is very common, and there’s observational data suggesting that low vitamin D is associated with increased mortality and other major adverse outcomes,” she added.
While several previous studies in the general population have evaluated vitamin D supplementation, there is little evidence of benefit for reducing mortality or clinical events. Nevertheless, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest measuring 25-hydroxyvitamin D levels in patients with stage 3-5 chronic kidney disease, including those on dialysis, and initiating replacement therapy if levels are deficient.
The guidelines “recognize that the grade of evidence for this is low,” said Smith, “so the SIMPLIFIED study aimed to address this evidence gap.”
The pragmatic trial randomized 3,866 adults with end-stage kidney disease receiving dialysis at 55 U.K. renal units to 60,000 IU of cholecalciferol or standard care. Key exclusion criteria included a life expectancy under 6 months, receipt of more than 1,000 IU daily of cholecalciferol within the past 30 days, and persistent hypercalcemia. SIMPLIFIED is one of the largest dialysis trials conducted to date, Smith noted.
Apart from the baseline in-person evaluation, follow-up visits occurred remotely, and outcome data were retrieved from routinely collected electronic health records.
At baseline, median participant age was 65 years, 68% were men, 80% were white, and 40% had diabetes. Nearly all (94%) were receiving in-center hemodialysis, with a median dialysis duration of 2.25 years.
After 4 months of treatment, plasma 25-hydroxyvitamin D concentrations rose substantially among supplemented participants compared with controls, as evaluated in the first 206 participants (median 141 nmol/L vs 36.5 nmol/L). During the trial, 1,817 total deaths occurred.
Sensitivity analyses accounting for renal transplantation, COVID-19 infection, and treatment discontinuation showed no impact on the primary endpoint.
Prespecified subgroup analyses suggested a potential signal toward benefit in male patients and individuals of non-white ethnicity.
“However, it is important to note — in the context of the overall null result — that the study was not powered for these subgroups. These should just be viewed as hypothesis-generating findings rather than definitive,” Smith explained. “There’s strong biological plausibility in these subgroup findings, particularly those of non-white ethnicity. They tend to have lower baseline vitamin D levels, so it would certainly be interesting to explore that subgroup [in future studies].”
There was also a nominal reduction in overall major adverse cardiovascular events (HR 0.88, 95% CI 0.78-0.99, P=0.03), primarily driven by the lower risk of peripheral arterial disease events (HR 0.80, 95% CI 0.65-0.99, P=0.04). However, Smith cautioned that the study was not powered to confirm associations for these individual endpoints.
High-dose cholecalciferol was safe and well tolerated. Rates of at least one hospital admission were comparable between arms (69% in the intervention group vs 70% with standard care).
