Complexities of Vitamin D in CKD Require Individualization

When it comes to issues of vitamin D in chronic kidney disease (CKD), core certainties include that most patients with CKD have dysregulated 25-hydroxy vitamin D (25[OH]D) and nutritional supplementation can increase those levels.

Beyond that, complexities abound, with evidence fraught with confounders regarding who may or may not benefit from supplementation. While evidence is weak regarding meaningful benefits such as mortality, in other scenarios, such as prevention of type 2 diabetes in adults with prediabetes, there is solid evidence of benefit.

Ultimately, “just because you can measure vitamin D and raise the level doesn’t mean your patients will feel any better,” Anastassios G. Pittas, MD, chief of the Division of Endocrinology at Tufts Medical Center, Boston, noted, speaking at the National Kidney Foundation 2src25 Spring Clinical Meetings.

“Routine testing is not needed for patients with CKD who are otherwise healthy,” he told Medscape Medical News. “A thoughtful, individualized approach is better than a one-size-fits-all practice, especially since 25(OH)D thresholds vary by populations.”

Key research detailing the benefits, or lack thereof, includes a meta-analysis of 128 studies involving 11,27src patients comparing vitamin D with a wide range of variables including placebo, other vitamin D formulations, different doses or routes of administration, calcium, or cinacalcet, in people with advanced CKD (stage III, IV, or V), explained co-presenter Daniel Weiner, MD, medical director of clinical research for Dialysis Clinic, Inc.

Overall, the analysis showed that compared with placebo, vitamin D therapy likely had no effect on the outcomes examined including all-cause death (relative risk [RR], 1.src4), “uncertain” effects on fracture (RR, src.68), and cardiovascular death (RR, src.73) in this population with advanced CKD.

“We can see from these findings that, whether it is nutritional vitamin D or activated [vitamin D], in the CKD population, there simply is not a mortality benefit associated with supplementation,” Weiner said.

Compared with placebo, vitamin D therapy did show a lowering of serum parathyroid hormone (PTH) and alkaline phosphatase in the analysis but increased serum calcium.

Based on the collective evidence, current guidelines from Kidney Disease Improving Global Outcomes on whether to screen for vitamin D in CDK only go as far as making suggestions (as opposed to official recommendations).

“In patients with CKD G3a-G5D, we suggest that 25(OH)D (calcidiol) levels might be measured, and repeated testing determined by baseline values and therapeutic interventions (level of recommendation, 2C),” the guidelines stated.

In terms of treatment, the guidelines further “suggest that vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population.”

Weiner emphasized that “these are only suggestions, not based on strong data.”

The lack of more conclusive recommendations “tells us more about what we don’t know than what we do know,” he added.

Recommendations further discourage the routine use of calcitriol and vitamin D analogs in adult patients with CKD stages G3a-G5 not on dialysis, while “it is reasonable to reserve the use of calcitriol and vitamin D analogs for patients with CKD G4-G5 and severe and progressive hyperparathyroidism,” the guidelines stated.

While the guidelines noted evidence suggesting that activated vitamin D therapy effectively lowers PTH and raises serum calcium, “what we do not know is if lowering PTH if not severe and progressive, with vitamin D or any other agent, is associated with positive outcomes, particularly in the kidney failure population,” Weiner noted.

Prediabetes and Vitamin D

Perhaps some of the strongest evidence of a significant benefit of vitamin D supplementation is seen in reducing the risk for prediabetes advancing to diabetes, as detailed in a systemic review and meta-analysis, involving individual participant data from three randomized controlled trials by Pittas and colleagues.

That study showed that vitamin D supplementation at doses higher than the recommended daily allowance reduced progression to diabetes in adults with prediabetes by 15% in the intention-to-treat analyses.

Endocrine Society Clinical Practice Guideline

The results were reflected in the 2src24 Endocrine Society Clinical Practice Guideline on vitamin D for the prevention of disease. The guideline recommendation stated that “for adults with high-risk prediabetes, in addition to lifestyle modification, we suggest empiric vitamin D supplementation to reduce the risk of progression to diabetes.”

Of note, the trials informing the recommendation primarily included adults with high-risk prediabetes and dosages ranging from 85src to 75srcsrc IU, with the estimated weighted average daily dose of vitamin D supplementation of 35srcsrc IU.

Ultimately, “the evidence for [vitamin D] in the prevention of diabetes or to lower the risk of diabetes in people with prediabetes is pretty strong, and the evidence is consistent. There are now four meta-analyses by four different research teams, all showing the same result,” said Pittas who served as the co-chair of the Guideline Development Panel.

“Not only does the research show a lower risk of people progressing to diabetes, but vitamin D also increases the likelihood of regressing to normal glucose regulation.”

In terms of routine 25(OH)D levels screening, the guideline recommends against testing in otherwise healthy individuals, including among adults with dark complexions and in adults with obesity.

One reason is “we don’t know what thresholds are appropriate for specific populations and outcomes,” Pittas said.

In fact, the guideline does not include the terms “normal,” “deficiency,” or “sufficiency,” due to widely varying interpretation and context of such references.

“Confounding is a major pitfall of observational studies with vitamin D, and there are no agreed-upon definitions for these terms,” Pittas added.

Noting that “routine 25(OH)D testing is often performed unnecessarily,” Pittas urged instead that “in early CKD (stages I-III), decisions about supplementation with vitamin D should follow the 2src24 Endocrine Society Guideline on Vitamin D for Prevention of Disease, which focuses on specific populations.”

“For example, a patient with CKD stage II and prediabetes should take vitamin D higher than the recommended daily allowance for his age to lower the risk of developing diabetes.”

Pill Burden

In terms of adding any extra pill in the kidney disease population, however, Weiner noted that patients’ pill burden is an important consideration.

“There is the pill burden to think about with CKD patients,” he said. “If I’m needing to add one extra pill, I’d rather it be for blood pressure or an SGLT2 [sodium-glucose cotransporter 2] inhibitor or something like that that we know is going to make a more meaningful difference,” Weiner said.

Samira Farouk, MD, a transplant nephrologist and associate professor of Medicine and Medical Education at Icahn School of Medicine, New York City, agreed that the polypharmacy issue and the potential of a pill that may or may not provide benefit is a concern, particularly for patients who have had a transplant.

“If I’m seeing patients who are taking vitamin D and we’re trying to reduce their pill burden, that’s definitely one of the first targets I try to remove to prevent polypharmacy, which kidney transplant recipients in particular are [prone to],” she told Medscape Medical News.

“I think that the general consensus [on vitamin D in patients who have had a transplant] is that the data are weak and mixed enough that I don’t think there is even any standardized practice around it.”

“I think there’s a very heterogeneous clinical approach to it,” Farouk added.

“Patients will sometimes read something about it, and if they don’t mind taking another pill, we generally don’t stop them unless we see evidence of some kind of toxicity or high calcium levels.”

Pittas has consulted for Abiogen Pharma S.p.A. Weiner has been an investigator on trials for Cara, Vertex, and CSL Behrin