Clinical outcomes

The functions of vitamin D are far more diverse than being purely a regulator of bone and mineral metabolism. Most cell types in the human body express vitamin D nuclear receptors, and their stimulation results among others in down-regulation of hyperproliferative cell growth, immune modulation, and down-regulation of the renin-angiotensin system.32-34

Given such overarching effects there is the possibility that the consequences of vitamin D deficiency could also be far more heterogeneous. Ecological studies have indicated that individuals living at higher latitudes have higher rates of various chronic diseases such as cancers, hypertension, or multiple sclerosis, and also experience higher mortality rates from certain types of malignancies.

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This has led to speculations that lower exposure to UVB radiation with resultant lower 25OHD levels might account for the observed geographical differences in outcomes. Subsequent epidemiologic studies have thus been conducted to explore if there is a direct association between 25OHD levels and these various clinic­al outcomes.

All-cause mortality

The first studies examining associations between serum 25OHD levels and mortality were small single center studies, secondary analyses of clinical trials, or studies conducted in special populations at high risk for adverse outcomes. These studies have found associations between lower 25OHD levels and mortality in patients with coronary artery disease35 and with colorectal36 and non-small cell cancer.37

There has only been one large study examining the effects of low 25OHD levels on all-cause mortality in the general population. The study involved 13,331 adult NHANES III participants.38 This study found that those in the lowest versus the highest quartile of serum 25OHD level (below 17.8 vs. greater than 32.1 ng/mL) had a 26% higher all-cause mortality. 

Hypovitaminosis D in CKD and ESRD patients

A number of studies have examined outcomes associated with 25OHD levels in patients with CKD or ESRD, who experience a high prevalence of hypovitaminosis D and who also have extremely high rates of morbidity and mortality. Two of these studies examined patients with pre-dialysis CKD. Ravani et al studied 168 patients at a single medical center and found that lower 25OHD levels were significantly associated with higher all-cause mortality.39

This study also found 
that hypovitaminosis D was associated with a higher incidence of ESRD, implicating vitamin D deficiency in processes related to progressive loss of kidney function. A larger study by Mehrotra et al examined 3,011 patients with CKD from NHANES III, and indicated that patients with 25OHD levels below 15 ng/mL had higher mortality compared with those with levels above 30 ng/mL (hazard ratio 1.56 (95% CI: 1.12-2.18).40 Patients on chronic dialysis were studied by Wolf et al, who examined 825 HD patients.

The researchers reported higher all-cause mortality in patients with lower 25OHD and 1,25(OH)2D levels.27 An interesting finding of this study was that the mortality risk was not higher in patients with low 25OHD levels who received treatment with active vitamin D. While this latter finding may indicate a benefit from active vitamin D therapy, the retrospective nature of the study renders it hypothesis-generating, even though the finding is in concordance with earlier pharmacoepidemiologic studies that have also indicated a lower risk of mortality in patients with CKD and ESRD treated with various forms of active vitamin D.41-45

Notable Recent Studies

  • Sankar Navaneethan and colleagues at Cleveland Clinic in Ohio reported at the 2011 World Congress of Nephrology (Poster SU331) that deficiency in 25OHD is independently associated with an increased risk of death from any cause among CKD patients and that the likelihood of 25OHD deficiency increases with body mass index (BMI). Data showed that 25OHD deficiency—defined as a level below 15 ng/mL—was associated with a 33% increased risk of death after adjusting for multiple variables. Furthermore, compared with patients with a BMI of 18.5-24.9 kg/m2, those with a BMI of 30-34.9 had an approximately 1.5 times increased risk of 25(OH)D deficiency. Those with a BMI of 35-39.9 and 40 or higher had a nearly twofold and threefold increased risk, respectively.
  • An Austrian study by Pilz et al. (Nephrol Dial Transplant. 2011; published online ahead of print) showed that vitamin D deficiency is associated with an increased risk of all-cause and cardiovascular (CV) mortality in CKD patients. Compared with patients with vitamin D sufficiency, those with severe vitamin D deficiency had a 3.8 times and 5.6 times increased risk of all-cause and cardiovascular mortality, respectively.
  • Data presented at the 2011 National Kidney Foundation Spring Clinical Meetings in Las Vegas (abstract 87) showed that treating 25OHD deficiency with ergocalciferol in patients with moderate CKD is associated with a significant reduction in the risk of CV events. The finding is based on a study of 126 men with 25OHD deficiency. Investigators defined successful 25OHD replacement as a prescription of ergocalciferol sufficient to raise serum 25OHD by 25% from baseline within six months. Ninety patients met this definition and were considered the treatment group. The other 36 patients were considered untreated controls. After adjusting for multiple variables, patients with successful 25OHD replacement had a 63% decreased risk of CV events.

Part 2, appearing in the July issue, will discuss cause-specific outcomes of hypovitaminosis D.


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