The role of 25-hydroxyvitamin D in insulin resistance and inflammation in patients with Chronic Kidney Disease: A randomised controlled trial.

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Chronic Kidney Disease (CKD) is associated with increased cardiovascular morbidity and mortality. Addressing traditional cardiac risk factors in this population does not ameliorate the disease burden to the same extent as the background population. As such, novel risks are being explored. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis. The vitamin D receptor is found in almost all human tissues, and whilst it was once thought that only the kidneys metabolised vitamin D to its active form (calcitriol), other tissues (such as peripheral blood mononuclear cells, PBMCs) are recognised as possessing the metabolising enzyme, raising the question of whether vitamin D effects are in part an auto/paracrine response, highlighting the importance of precursor availability. Approximately 50% of patients with CKD stage 3 are vitamin D insufficient (measured as the serum precursor calcidiol). They have increased circulating inflammatory cytokines and are often sub-clinically insulin-resistant. These factors are known to be associated with cardiovascular risk, and are integrally linked. Indeed, Interleukin-1beta (IL-1b), Interleurkin-6 (IL-6)and Tumour Necrosis Factor alpha (TNFa)have been associated with pancreatic Beta-cell apoptosis, and diminished cellular insulin processing. In experimental models vitamin D can reduce the activation of the pro-inflammatory transcription factor Nuclear Factor-kappaB in various cell lines, and in isolated PBMCs vitamin D decreases production of IL-6 and TNFa. In vitro studies also suggest vitamin D may improve insulin receptor substrate phosphorylation and GLUT 4 translocation in skeletal muscle, together with direct effects on the pancreatic Beta-cells. Lastly, recent animal studies have implicated the vitamin D responsive bone protein osteocalcin in glucose metabolism, possibly through promotion of adiponectin production, an adipokine with known beneficial glycaemic properties. This double-blinded trial will assess the benefit of vitamin D supplementation in early CKD to raise circulating calcidiol and improve insulin resistance, possibly through reduced inflammatory burden. Patients will be randomised to either vitamin D3 2000IU/day or placebo for 6 months. At baseline and end-of-study a hyperinsulinaemic euglycaemic clamp study will be performed to assess peripheral insulin response and correlation with PBMC NF-kappaB activity and circulating inflammatory burden (as quantified by IL-1b, IL-6, TNFa, known gene products of NF-KappaB). Osteocalcin, adiponectin and markers of bone turnover will also be assessed.