The role of vitamin D in the association between tuberculosis and end-stage renal disease

To the Editor:

We read with great interest the study by Hu et al. [1] in which the authors report a significantly increased risk of tuberculosis (TB) within 2 years of onset of end-stage renal disease (ESRD) in their population-based cohort study. The authors suggested that this association is likely to be a consequence of an immunocompromised state and frequent hospital attendance of patients with ESRD. Indeed, whereas these factors plausibly contribute substantially to increased TB risk, vitamin D deficiency may also be an important factor contributing to the observed association between TB and ESRD.

The primary source of vitamin D in the body is endogenous synthesis following UVB exposure to the skin (with a small proportion of vitamin D intake obtained through diet) [2]. Upon UVB exposure, 7-dehydrocholesterol in the epidermal skin layer is converted to previtamin D₃ which rapidly undergoes a thermal reaction to produce cholecalciferol (an inactive form of vitamin D₃) [2]. Subsequently, cholecalciferol is hydroxylated in the liver by 25-hydroxylase to form 25-hydroxyvitamin D₃. This molecule is finally hydroxylated in the kidney by the enzyme 1-alpha-hydroxylase to form calcitriol (1,25-dihydroxyvitamin D₃), the active form of vitamin D [2]. Patients with chronic kidney disease including ESRD are thought to have a high incidence of vitamin D insufficiency and deficiency in part as a result of impaired renal function and reduced ability to generate the active form of vitamin D [3]. An American study of 825 consecutive patients on haemodialysis found that 78% of patients were vitamin D-deficient and 18% classified as severely deficient [4]. Low vitamin D levels in haemodialysis patients has also been associated with increased mortality [4, 5]. Further, a substantial evidence base of both basic science and clinical research has shown that vitamin D deficiency is significantly associated with active TB (odds ratio 2·9, 95% confidence interval 1·3–6·5) [6]. This is also supported, for example, by the historical use of phototherapy in the treatment of TB.

Vitamin D receptors are found on a variety of human cells including monocytes, macrophages and dendritic cells and both in vivo and in vitro studies have shown that vitamin D has an immune-modulatory role against Mycobacterium tuberculosis [7, 8]. Therefore, information on the use of vitamin D supplementation in the reported patients with ESRD would have been highly interesting, but we appreciate that this may not have been available to the authors. Nevertheless, a strong association between chronic kidney disease and vitamin D deficiency suggests that vitamin D supplementation, particularly in individuals with ESRD, may be important in reducing vitamin D-associated comorbidities, including TB. Given that Taiwan has the highest incidence and prevalence of ESRD in the world, this may potentially be an important public health issue for its population.