Vitamin D and Cardiac Autonomic Tone in Hemodialysis (VITAH)

Vitamin D Supplementation and Cardiac Autonomic Tone in Hemodialysis Patients: A Blinded, Randomized-controlled Trial

Despite advances in treatment of conventional cardiovascular risk factors, patients with kidney disease remain at high risk for fatal cardiac events. To date, kidney disease affects approximately 2 million Canadians; however, this patient population remains grossly understudied due to the complex nature of the disease. The inadequacy of the literature to address the cardiovascular-related mortality rates in those with kidney disease reflects the urgent need for investigation of novel risk factors. One cardiovascular risk factor which has recently been validated is the clinical measurement of cardiac autonomic tone (CAT). CAT refers to the amount of activity contributed by the stimulatory and inhibitory limbs of the cardiac autonomic nervous system, which work in concert with one another to control heart rate. CAT can be quantified computer analysis of heart rate over time, captured by a simple Holter electrocardiogram (ECG) recording. Abnormal CAT, which occurs when the autonomic system does not control heart rate properly in response to physical demands or stress, is associated with risk of adverse cardiovascular events in both healthy and high risk populations. It has recently been shown that patients with severe kidney disease demonstrate significant CAT abnormalities, thus exaggerated susceptibility to cardiac death. Vitamin D (VD) deficiency is also common in this patient population due to the fact that the kidney plays a crucial role in VD metabolism. Given that VD deficiency is an established cardiovascular risk factor on its own, it is possible that kidney disease patients experienced compounded risk due to the combination of VD deficiency and abnormal CAT. However, no study has ever investigated whether VD deficiency influences CAT in healthy or diseased populations. To our knowledge, this will be the first trial to ever examine the effect, if any, of different VD supplementation treatments (standard of care vs. combination) on CAT in a population burdened with overwhelming risk and incidence of cardiovascular and sudden cardiac death risk.

6 weeks - alfacalcidol 0.25mcg + placebo 3x per week, 12 week washout, 6 weeks - alfacalcidol 0.25mcg 3x per week + 50,000IU ergocalciferol 1x per week (placebo the 2 remaining days)

6 weeks - alfacalcidol 0.25mcg 3x per week + 50,000IU ergocalciferol 1x per week (placebo the 2 remaining days), 12 week washout, 6 weeks - alfacalcidol 0.25mcg + placebo 3x per week

percentage of normal waves which differ in frequency > 50 ms compared to the wave directly before (heart rate variability time domain)

Low-frequency (ms squared and normalized units), thought to reflect sympathetic contribution from the cardiac autonomic nervous system

High-frequency (ms squared and normalized units), thought to reflect parasympathetic contribution from the cardiac autonomic nervous system

Inclusion Criteria: age ≥ 18 years 3x weekly hemodialysis outpatient within Calgary for at least 3 months prior to enrolment physician consent to participate in VD supplementation regimen ability and agreement to cease any VD medication for 4 weeks prior to initiation of study able to comprehend study and provide oral and written consent in English Exclusion Criteria: any major cardiovascular event (new onset arrhythmia, hospitalization for a cardiac event) noted in patient chart within the 6 month period prior to initiation of the study currently on VD therapy/refusal to cease VD therapy for 4 weeks prior to initiation of study physician anticipates death or adverse event within the next year- known discharge from hemodialysis (transfer to peritoneal dialysis, kidney transplant)

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Mann MC, Exner DV, Hemmelgarn BR, Hanley DA, Turin TC, MacRae JM, Wheeler DC, Sola DY, Ramesh S, Ahmed SB. The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial. Nutrients. 2016 Sep 28;8(10):608. doi: 10.3390/nu8100608.

Mann MC, Exner DV, Hemmelgarn BR, Hanley DA, Turin TC, MacRae JM, Ahmed SB. The VITAH trial VITamin D supplementation and cardiac Autonomic tone in Hemodialysis: a blinded, randomized controlled trial. BMC Nephrol. 2014 Aug 6;15:129. doi: 10.1186/1471-2369-15-129.