The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: a randomised controlled trial.
BACKGROUND
Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation.


METHODS
This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study.


CONCLUSIONS
To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis.


BACKGROUND
Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.
Petchey
William G
WG
Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia. william_petchey@health.qld.gov.au
Hickman
Ingrid J
IJ
Duncan
Emma
E
Prins
Johannes B
JB
Hawley
Carmel M
CM
Johnson
David W
DW
Barraclough
Katherine
K
Isbel
Nicole M
NM
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D002762:Cholecalciferol / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000517:prevention & control*; D007333:Insulin Resistance; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D015990:Placebo Effect; D016896:Treatment Outcome; D014808:Vitamin D Deficiency / Q000150:complications* / Q000188:drug therapy*; D055815:Young Adult
D050071:Bone Density Conservation Agents; D002762:Cholecalciferol