High-Dose Vitamin D of No Benefit in Dialysis

DENVER — Patients undergoing dialysis treated with high dose cholecalciferol (vitamin D3), as is recommended in guidelines, showed no significant improvements in all-cause mortality compared with no supplementation, according to results from the randomized SIMPLIFIED trial. “SIMPLIFIED is one of the largest dialysis trials ever conducted, and the pragmatic design showcases use of routinely collected healthcare data sources,” said first author Rona M.

Smith, MD, of Addenbrooke’s Hospital and the University of Cambridge, UK. However, “we found no evidence that high-dose cholecalciferol improved survival or other major clinical outcomes in an unselected dialysis population,” said Smith, who presented the results here at Kidney Week 2026: American Society of Nephrology Annual Meeting .

Vitamin D Deficiency Common, Contributes to Mortality Risk Among patients requiring kidney dialysis, mortality rates are increased, with cardiovascular disease, infection, and malignancies among the leading causes of death. Vitamin D deficiency is known to be very common among patients on dialysis and is further associated with an increased risk of death, fracture and other poor outcomes.

KDIGO guidelines call for baseline and repeated testing of 25(OH)D and recommend correction of vitamin D deficiency and insufficiency with the use of “treatment strategies recommended for the general population.” To address the evidence gap, and in consideration of the more profound vitamin D deficiency in the dialysis population, Smith and colleagues conducted the multicenter SIMPLIFIED open-label trial, enrolling 3866 participants at 55 renal centers in the UK.

The participants were randomized 1:1 to receive oral cholecalciferol 60,000 IU every 2 weeks (n = 1940) or standard care (n = 1926). The patients had a median age of 65 years; 68% were male, and 80% were White, about 10% Black, and 8% Asian. Their median dialysis exposure was 2.25 years.

Patients were excluded if they had persistent hypercalcemia , had received more than 1000 IU of daily cholecalciferol in the prior 30 days, were pregnant, or had a life expectancy of less than 6 months. Median plasma 25(OH)D levels in a subgroup of the first 204 patients after 4 months of treatment were 36.5 nmol/L in the standard care group (n = 100) compared with 141 nmol/L in the cholecalciferol group (n = 104).

For the primary endpoint of all-cause mortality, with follow-up extending for up to 7.5 years, 883 (45.5%) of those the cholecalciferol group died compared with 934 (48.5%) in the standard care group; this result did not reach statistical significance (hazard ratio [HR] 0.95; P = .27).

There were also no significant benefits with cholecalciferol in reducing a first hospitalization for a composite of cardiovascular factors, including cardiovascular death, myocardial infarction , coronary revascularization, stroke or peripheral arterial disease (HR, 0.96; P = .44), infection (HR, 0.96; P = .43), or fracture (HR, 0.89; P = .32).

The receipt of cholecalciferol was associated with reduced mortality in non-White participants (HR, 0.72), and, to a lesser degree, among males (HR, 0.89). But, Smith cautioned, it is “important to consider those results in the context of the overall null result of the study,” as the subgroups were not powered to adequately detect a difference.

The prespecified major adverse cardiovascular events (MACE) composite was significantly less frequent with cholecalciferol (HR 0.88; P = .03). However, Smith noted that the impact was largely driven by coronary vascularization and again cautioned that “the study was not powered for this specific outcome.” In terms of serious adverse events, the rates of having at least one hospital admission were nearly the same between the groups (69% with cholecalciferol and 70% with standard care).

Overall, “these findings do not support routine dialysis population-wide supplementation with high-dose cholecalciferol,” Smith said. She noted that “ the observed subgroup findings by ethnicity and sex should be considered hypothesis-generating and require independent confirmation before influencing clinical practice.” Activated Vitamin D vs Cholecalciferol?

In the discussion following Smith’s talk, audience members questioned whether results might have been different with the use of activated vitamin D vs cholecalciferol. Smith noted that some participants did receive activated vitamin D and didn’t rule out the possibility of different outcomes had more patients received that supplementation.

“Cholecalciferol (nutritional) vitamin D was used to correct the vitamin D deficiency/insufficiency in the participants,” she told Medscape Medical News . “Activated vitamin D does not do this,” she explained. “It is primarily used for management of secondary hyperparathyroidism and parathyroid control in dialysis patients, and so [it] could not be used instead of cholecalciferol.” As a pragmatic study design was used, the authors did not collect data on the use of active vitamin D drugs throughout the trial, she added.

“It is possible that the absence of a significant mortality benefit with cholecalciferol may partly reflect concomitant use of active vitamin D compounds in the dialysis population,” she noted, “but ultimately, outcomes were very poor in both groups.” Based on the results, Smith said “KDIGO should consider this data when updating guidelines.” However, she added, “although the results of this trial do not support population-wide supplementation of cholecalciferol in this patient population, there are nuances to the data which need to be considered by this expert panel.” Smith reported no relevant financial relationships.