Vitamin D in renal transplantation - from biological mechanisms to clinical benefits

Abstract

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti-microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho-mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically-related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized-controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.

Keywords: cancer; cardiovascular disease; immune system; renal transplantation; transplant rejection; vitamin D.

Figure 1. Effects of vitamin D on mineral biology

(A) schematic showing biogenesis of vitamin D. Vitamin D3 derived from either the diet or UVB irradiation in the skin is metabolized to 25-hydroxyvitaminD (25(OH)D₃) in the liver through an enzymatic reaction catalyzed by CYP27A1. 25(OH)D₃ is subsequently metabolized to the active form 1,25-dihydroxyvitaminD (1,25(OH)₂D₃) in the kidneys by CYP27B1. Both 25(OH)D₃ and 1,25(OH)₂D₃ are converted by CYP24A1 to 24 hydroxylated products and excreted. CYP27B1 is tightly regulated: a drop in serum calcium levels is detected by the parathyroid gland and results in secretion of parathyroid hormone (PTH). Both PTH and reduced serum calcium and phosphate concentration directly stimulate CYP27B1 activity, and thus increased 1,25(OH)₂D₃ production. 1,25(OH)₂D_3, in a negative feedback loop, down-regulates its own production through inhibiting CYP27B1 activity as well as PTH production. 1,25(OH)₂D₃ has multiple systemic effects which ultimately result in restoration of serum calcium levels, as well as re-calcification of bones. FGF-23 is produced by osteocytes and decreases circulating concentrations of 1,25(OH)₂D₃, through induction of CYP24A1 and suppression of CYP27B1. In the schematic, black arrows represent induction, red arrows represent inhibition. (B) factors controlling CYP27B1 activity. * a low calcium diet reduces extra-renal CYP27B1, particularly in the colon, and enhances renal CYP27B1.

Figure 2. Biological functions of Vitamin D in the immune system and their potential relevance to transplantation

The biological impact of vitamin D on different immune parameters are shown on the left and the mechanisms by which these effects may impact on renal transplantation is indicated on the right.