Again, this adds impetuous to the need for clinical intervention trials with supplement of the circulating

25-OHD pool, which may be less harmful than supplementation with active vitamin D. Currently there is growing interest in the phosphaturic bone-hormone fibroblast growth factor 23 (FGF-23), which acts by binding to a membrane Daporinad nmr bound α-Klotho-FGF receptor 1c complex in the distal tubules of the kidney, and by an unknown signalling mechanism reduces phosphate reabsorption in the proximal tubules.133 FGF-23 also acts as a negative regulator of PTH secretion by the parathyroid glands, and also directly inhibits 1,25-OHD production in the kidneys by reducing CYP27B1 activity.133 FGF-23 levels are elevated in early kidney disease, selleck products and in various observational studies have shown association with vascular calcification, increased left ventricular mass in all stages of CKD, and importantly is an independent predictor of mortality in incident dialysis patients.134 It has been suggested that the

early changes in FGF-23 concentrations to maintain a normal serum phosphate in CKD may explain the alteration in vitamin D metabolism observed and could be the underlying causative factor for increased cardiovascular risk, not abnormal vitamin D metabolism per se. However, to date no Klotho protein complex has been isolated in any tissue pertinent to the cardiovascular system outside the kidneys, and in response to the supposition that supraphysiological levels of FGF-23 encountered

could act in a non-receptor driven fashion, it should be noted that in LY294002 non-renal conditions associated with excessive FGF-23 (e.g. X-linked hypophosphataemia or tumour-induced osteomalacia) notable increases in cardiovascular risk are not encountered. This is a growing area of research attention and more data should be available in the near future. Patients with CKD are at significant risk of cardiovascular disease, beyond that of the normal population, and this is not fully explained by the traditional Framingham risk factors. Vitamin D deficiency is increasingly common as CKD progresses, for a variety of reasons. Experimental and clinical studies suggest that vitamin D may improve cardiovascular risk through such diverse mechanisms as improved glycaemic control, anti-inflammatory actions, enhanced endothelial function, decreased atherosclerosis and atherogenesis, suppression of the RAS, reduction of proteinuria, and improved cardiovascular physiology (summarized in Fig. 2).