Accumulating evidence supports the notion that vitamin D exerts a wide variety of pleiotropic effects, beyond its important role in bone and mineral metabolism [4
]. Since there are few dietary sources rich in vitamin D, humans obtain most of the vitamin D through the conversion of 7-dehydrotachysterol in the skin via ultraviolet light. Vitamin D formed in the skin is 25-hydroxylated in the liver and circulating 25-hydroxyvitamin D levels is a sensitive measure of body stores of vitamin D [4
]. Large proportions of populations living in temperate climates have vitamin D levels that are insufficient to prevent secondary hyperparathyroidism. Recent studies have also demonstrated that vitamin D deficiency is an independent risk factor for fatal and non-fatal cardiovascular events (reviewed in [5
]). Hypovitaminosis D is much more prevalent in dark-skinned individuals, and thus, is more prevalent in the two largest disadvantaged populations in the United States (Blacks and Mexican-Americans) [6
]. Similarly, despite abundant sunlight and low use of sunscreens, hypovitaminosis D is highly prevalent in India [7
The odds of vitamin D deficiency (serum 25-hydroxyvitamin D < 15 ng/ml) are 32% higher in individuals with CKD, compared to the general population [8
]. Most Blacks have serum 25-hydroxyvitamin D levels < 30 ng/ml; the prevalence of vitamin D deficiency and insufficiency is also more common in Mexican-Americans, when compared to Whites () [8
]. As in the general population, there is a graded, inverse relationship between vitamin D levels and all-cause mortality in chronic kidney disease [9
]. This raises the possibility that the higher risk for death in racial and ethnic minorities with CKD in the United States may be, at least in part, secondary to vitamin D deficiency.
Figure 1 Prevalence of vitamin D deficiency (< 15 ng/ml), insufficiency (15 – 30 ng/ml), and sufficiency (> 30 ng/ml) in Whites, Blacks, and Mexican-Americans with chronic kidney disease. Data taken from the Third National Health and Nutrition (more ...)
Emerging evidence also links hypovitaminosis D to progression of CKD. The biologic data linking hypovitaminosis D to progression of CKD is elegantly summarized in a review by Tian et al. [10
]. Thus, vitamin D deficiency has been associated with 1) increased inflammation, 2) mesangial and epithelial proliferation, 3) activation of the renin-angiotensin-aldosterone system, 4) glomerular hyperfiltration and hypertrophy, 5) proteinuria, 6) increased renal expression of pro-fibrotic transforming growth factor-β, and 7) decreased expression of E-cadherin, a key first step in epithelial-mesenchymal transformation [10
]. All of these processes are expected to lead to increased glomerulosclerosis, and tubulointerstitial fibrosis.
There are at least three interventional studies suggesting that treatment with active vitamin D compounds may have an antiproteinuric effect. Pooling data from three placebo-controlled, randomized controlled trials (28% non-White, 59% diabetic), Agarwal et al. [11
] showed that twice as many Stage 3 or 4 CKD subjects treated with paricalcitol had regression of proteinuria, when compared to those treated with placebo (51% vs. 24%, p = 0.004). In a follow-up randomized controlled trial of 24 CKD subjects, either 1 µg, or 2 µg of parcialcitol was associated with an almost 50% reduction in urine albumin excretion over 1 month; subjects treated with placebo had a 35% increase in albuminuria over the same time-period [12
]. The reduction in albuminuria was also associated with reduction in serum high-sensitivity C-reactive protein levels that achieved statistical significance in subjects treated with 2 µg parcialcitol [12
]. Finally, in an open-label, uncontrolled study, 0.5 µg calcitriol twice weekly was associated with a significant reduction in proteinuria in 10 subjects with biopsy-proven IgA nephropathy [13
Each of these three studies has significant limitations – small sample size, the decision to treat with active vitamin D compounds was not based on measurement of serum 25-hydroxyvitamin D levels, and none of the studies measured change in glomerular filtration, or racial differences in response to therapy. Despite their limitations, they raise the possibility that hypovitaminosis D may underlie at least some of the increased risk for progression of CKD in racial/ethnic minorities in the United States. Given the potential for significant benefits, randomized, controlled trials are needed to determine if correction of hypovitaminosis D will reduce the racial disparities in CKD – to reduce the risk for both the progression to ESRD, and cardiovascular risk. It is also important to determine if hypovitaminosis D is an operative mechanism for progression of CKD in disadvantaged populations in other parts of the world.