What's new in vitamin D for the nephrologist?

synthesis that accompanies renal insufficiency results Introduction in increased parathyroid stimulation from each of the principal modulators, namely decreased calcium, In this review we discuss some of the clinical implicaincreased phosphate, and decreased calcitriol. This tions of progress in our understanding of the action of scenario is further complicated by the blunted target vitamin D and its derivatives on calcium, phosphate organ responsiveness to both PTH and calcitriol in homeostasis and skeletal function in uraemia. uraemia. The parathyroid glands synthesize and secrete parathyroid hormone (PTH ) in response to low calcium, low 1,25-dihydroxyvitamin D3 (calcitriol ), and high phosphate concentrations. The interplay between these The vitamin D receptor elements is complex, operating through several feedback mechanisms. Both PTH and calcitriol regulate Calcitriol mediates its genomic effects through the circulating calcium and phosphate concentrations vitamin D receptor (VDR), which is a member of the through their action on target organs, namely the steroid/thyroid superfamily of nuclear receptors. kidney, bone, and intestine. PTH and calcitriol regulate Calcitriol binding to VDR results in changes in tranone another’s production, and additionally are both scription rates for those genes that contain vitamin D regulated separately by extracellular calcium and phosresponsive elements (VDREs). There are many other phate, as schematically illustrated in Figure 1. The facets to this process, the details of which are beyond impairment of phosphate excretion and of calcitriol the scope of this review. Interested readers are directed to other reviews of this topic [1,2]. Uraemia diminishes the tissue response to calcitriol and this is likely to be due, at least in part, to abnormal regulation and function of the VDR [3]. Down-regulation of VDR content has been demonstrated in the parathyroids of uraemic animals [4]. Uraemic toxins have been shown to decrease the ability of the VDR to bind the VDRE as demonstrated for the osteocalcin gene [5] and it is possible that these effects could be ameliorated by early institution of vitamin D therapies. Experiments in the uraemic rat have shown that administration of either calcitriol or the analogue 22-oxacalcitriol (OCT) can prevent the decrease in VDR content of the parathyroids [6 ]. Recently, homozygous VDR knockout mice have been generated [7,8]. These animals demonstrate phenotypic characteristics similar to that of clinical hypocalcaemic vitamin D-resistant rickets (HVDRR). Fig. 1. The interrelationships between homeostatic hormones. When these mice are placed on a ‘rescue diet’, in which Augmentation and reduction of linked processes/concentrations are mineral ion homeostasis is ‘normalized’, they do not depicted as positive (+ve) or negative (−ve) respectively. *These develop hyperparathyroidism or the bone abnormalrelationships are qualitatively preserved in uraemia with the excepities observed in untreated animals [9], suggesting that tion of PTH-driven phosphaturia. The absence of phosphaturia in ESRD results in PTH acting as a phosphataemic hormone, as part the major consequence of VDR ablation is the impairof a positive feedback loop with phosphate. ment of intestinal calcium absorption and mobilization of skeletal calcium. Correspondence and offprint requests to: Dr J. Cunningham, Studies of vitamin D receptor gene polymorphisms Department of Renal Medicine and Transplantation, Royal London Hospital, Whitechapel, London E1 1BB, UK. have suggested an influence on bone mineral density.