Vitamin D Deficiency Increases Death Risk

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1,25-hydroxyvitamin D
1,25-hydroxyvitamin D

Low levels of vitamin D may be associated with an increased risk of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD), according to a recently published study.

Their findings, published online ahead of print in Nephrology Dialysis Transplantation, support the 2009 Kidney Disease: Improving Global Outcomes clinical guidelines with respect to the recommendation to correct reduced 25-hydroxyvitamin D [25(OH)D] levels in CKD patients, researchers concluded.

An Austrian research team led by Stefan Pilz, MD, of the Medical University of Graz, studied 444 patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 from the Ludwigshafen Risk and Cardiovascular Health Study.

During a median follow-up time of 9.4 years, 227 patients died, 159 from cardiovascular causes. Compared with vitamin D sufficient patients, those with severe vitamin D deficiency had a 3.8 and 5.6 times increased risk of all-cause and cardiovascular mortality, respectively, after adjusting for numerous confounders. Each 10 ng/mL increment in 25(OH)D levels was associated with a 37% and 41% decreased risk of all-cause and cardiovascular mortality.

The researchers defined vitamin D sufficiency, insufficiency, moderate deficiency, and severe deficiency as a 25(OH)D level (in ng/mL) of 30 or higher, 20-30, 10-20, and below 10, respectively.

Additionally, compared with patients in the fourth quartile of 25(OH)D level (above 20.3), those in the first, second, and third quartiles (less than 8.3, 8.3-13.7, and 13.8-20.3, respectively) were at 4.4, 2.2, and 2.0 times increased risk for all-cause mortality and 4.3, 2.5, and 2.2 times increased risk for cardiovascular mortality.

Parathyroid hormone (PTH) levels did not influence these associations, suggesting that 25(OH)D measurements might be useful for risk stratification in virtually all patients with an eGFR below 60, Dr. Pilz and his colleagues stated.

Study findings, they noted, add significantly to the current knowledge of the association of 25(OH)D levels and mortality in CKD. “We are, to the best of our knowledge, the first to show that low 25(OH)D concentrations are significantly associated with total mortality in CKD patients stages 3-5 not on dialysis,” they wrote.

Csaba P. Kovesdy, MD, a nephrologist who has conducted research on the association between vitamin D levels and outcomes in renal disease patients but did not participate in the new study, praised the study by Dr. Pilz's group as an important addition to the literature on the subject.

“The study shows a very robust association of lower vitamin D levels with both higher all-cause and cardiovascular mortality,” said Dr. Kovesdy, Associate Professor of Clinical Medicine at the University of Virginia in Charlottesville and Chief of Nephrology at the Salem VA Medical Center in Salem, Va. “Notably, these associations appeared to be independent of other markers of bone and mineral disorders, such as PTH levels, suggesting that pathways other than bone-mineral metabolism may be responsible for the observed effects.”

Dr. Pilz's team described associations between lower serum 1,25-hydroxyvitamin D levels and higher mortality, Dr. Kovesdy pointed out, but these associations appeared less robust compared with those for 25(OH)D.

This study complements a number of other observational studies in patients with CKD and end-stage renal disease, which mostly show similar results, Dr. Kovesdy added. The unique advantages of the study by Dr. Pilz's group are the prospective nature of the study cohort—which allowed for precise ascertainment of both vitamin D levels and outcome—and the very long follow-up, he said.

“These results underscore yet again the potential importance of vitamin D in the morbidity and mortality of patients with CKD,” Dr. Kovesdy said. “As there are now increasing numbers of observational studies showing similar results it is imperative that the potential benefit of vitamin D is tested in clinical trials.”

While there is some evidence from small clinical trials to suggest biochemical benefits of vitamin D supplementation, such as PTH suppression, the more important question of whether supplementation improves clinical endpoints, such as mortality, remains unanswered, he said. It is also unclear to what extent vitamin D supplementation can be used in lieu of therapy with active vitamin D, as head-to-head comparisons of the effects of these two medication classes are still not available.

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