More than 40,000 Canadians live with end-stage kidney disease (ESKD)—roughly 1 out of every 1,000 people, a number that has tripled over 20 years – and require life-sustaining dialysis or transplantation [
1]. Patients with ESKD have a 20% annual mortality rate and an age-specific cardiovascular death rate that is 10-100x higher than the general population [
2]. Sudden cardiac death (SCD) accounts for more than a quarter of deaths in the hemodialysis population, making it the leading cause of death [
2]. However, as is repeatedly reflected by negative trials evaluating the effects of treatment of traditional cardiovascular disease risk factors in patients with ESKD [
3‐
6], these deaths are not associated with typical coronary artery disease, suggesting alternative mechanisms for SCD in ESKD. As such, the pathophysiology of SCD in the ESKD population is complex and believed to require the interaction between a transient event (i.e. intermittent hemodialysis) and underlying substrate. This process induces electrical instability and ventricular arrhythmias followed by hemodynamic collapse. Two factors specific to ESKD patients that have emerged as potential contributors to this SCD-susceptible state are altered mineral metabolism, including vitamin D deficiency, and impaired cardiac autonomic tone [
7‐
10].
Cardiac autonomic tone
Cardiac autonomic tone is derived from beat to beat measurements of the time intervals between successive QRS intervals, specifically RR intervals. Measurement of HRV provides direct insight into abnormalities of the autonomic nervous system, which consists of the sympathetic nervous system (SNS) and the parasympathetic (vagal) nervous system (PNS) limbs [
7,
11,
12]. HRV assesses the dynamic interaction and balance between the SNS and PNS at the level of the heart, overall providing a measure of cardiac autonomic competence [
11,
12]. The
a priori main outcomes of interest are measures of the frequency domain as these parameters are direct measures of cardiac autonomic tone [
11] and are most commonly described in the ESKD study population [
10,
13‐
15]. No one parameter of HRV has been established as superior in regards to their predictive ability as surrogate markers for adverse cardiovascular events [
7,
16‐
19].
Decreased HRV is associated with an increased risk of arrhythmias and cardiac death in both the general population [
7] and patients with ESKD on dialysis [
8,
9,
12‐
15]. Further, alterations in HRV occur more frequently in dialysis patients and corresponds with an increased risk of SCD and cardiovascular mortality [
9,
13]. In a study of 30 ESKD patients, 53% had autonomic dysfunction, in which 40% was isolated to the vagal (PNS) limb and 13% had combined sympathetic and vagal dysfunction [
20]. Similarly, HRV findings in a study of 239 hemodialysis patients demonstrated drastic sympathetic over-activity and vagal withdrawal [
15]. Another study of 383 patients with ESKD on hemodialysis found that impaired cardiac autonomic tone was independently associated with an increased risk of all-cause and cardiovascular death after adjustment for traditional cardiovascular risk factors [
8]. Although HRV is a surrogate measurement, it has been established as an important and validated, non-invasive measure of cardiovascular-related mortality risk in the ESKD population [
12,
13,
20,
21]. Consequently, interventions enhancing measures of HRV, and therefore influencing cardiac autonomic control, could potentially have considerable survival benefits in the high-risk ESKD patient population.
Vitamin D
There are multiple pharmacological analogues and formulations of vitamin D available for clinical use [
22,
23]. To be effective in disorders resulting from vitamin D deficiency, nutritional sources of vitamin D (cholecalciferol, vitamin D
3; and ergocalciferol, vitamin D
2) must undergo two enzymatic hydroxylations: 1) in the liver to 25-hydroxyvitamin D (25OHD); 2) in the kidney, 1α-hydroxylase converts 25OHD to the biologically active form of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol) or 1,25- dihydroxyergocalciferol [
22,
23]. The liver hydroxylation is largely substrate driven, but the kidney’s 1α-hydroxylase is very tightly regulated by hormones (e.g. parathyroid hormone) and concentrations of calcium and phosphate ions [
22,
23]. In the VITAH trial, we use the following terminology for the specific vitamin D analogues; nutritional vitamin D therapy is provided in the form of ergocalciferol, and alfacalcidiol, is provided as the active (activated) vitamin D derivative.
In ESKD, progressive loss of functional kidney activity reduces the availability of 1α-hydroxylase within the renal tissue, which in turn reduces 1,25-dihydroxyvitamin D
3 production [
24]. ESKD patients are also commonly deficient in 25OHD due to decreased nutritional intake from intensive dietary restrictions, lack of sun exposure due to decreased mobility, and dysregulated mineral metabolism [
24].
In general, vitamin D deficiency is common and associated with worse cardiovascular outcomes in both the healthy [
25] and ESKD [
26] populations. Furthermore, low vitamin D levels are associated with increased risk of SCD in both non-ESKD [
27] and ESKD patients [
28,
29]. In relation to cardiovascular pathophysiology, vitamin D has been shown to influence cardiac contractility and myocardial calcium homeostasis in humans [
30‐
33]. Furthermore, a small study of hemodialysis patients showed that treatment with activated vitamin D reduced the QT interval on electrocardiography [
34]. Recently, we have not only shown that low vitamin D levels are associated with vascular physiology that increases cardiovascular risk [
35], but also that poor vitamin D status is associated with an impaired ability to maintain cardiac autonomic tone in response to endogenous angiotensin II in healthy humans [
36], a hormone that is chronically upregulated in the ESKD population. Furthermore, we have also demonstrated that vitamin D supplementation is associated with
normalization of autonomic tone in response to an acute angiotensin II stressor in healthy subjects [
37]. As vagal activity is markedly reduced in hemodialysis patients [
15], it is possible that vitamin D supplementation could improve the cardiac autonomic response to stressors such as hemodialysis. Regardless, the impact of vitamin D therapy in the ESKD population, and on other surrogate clinical measures of cardiovascular risk has not been assessed. In an observational study, serum 25OHD predicted total and cardiovascular mortality in incident ESKD patients, but this association was abolished in patients provided therapy with calcitriol or its active analogues [
26]. This novel observation suggests that intensive vitamin D therapy inclusive of 1,25-dihydroxyvitamin D
3 analogues as well as other vitamin D derivatives may provide a more significant therapeutic and survival benefit within the severely deficient ESKD population, and thus provides the basis for assessing the therapeutic role of intensive and conventional vitamin D supplementation regimens in altering cardiac autonomic tone, as in the VITAH trial.
Evidence to date supports the safety profile of vitamin D therapy. Vitamin D deficiency is the norm in hemodialysis patients and as such, vitamin D supplementation should result in significant increase vitamin D levels. Secondly, given there is significant controversy regarding the target 25-hydroxyvitamin D level in both the general and chronic kidney disease population [
38,
39], we aimed to determine the effect of delivered dose of vitamin D, rather than level of vitamin D, on cardiac autonomic tone. Lastly, though there is significant practice variation, the activated and nutritional vitamin D doses chosen for the study reflect those recommended in and typically prescribed to the end-stage kidney disease population on hemodialysis [
38].
Despite the high prevalence of vitamin D deficiency in ESKD, current guidelines regarding correction of vitamin D status are widely acknowledged to be opinion-based and derived from biochemical endpoints [
38]. The nutritional vitamin D product (ergocalciferol) and dose proposed within this protocol is identical to that suggested by guidelines for treatment in the ESKD population [
38,
40]. Furthermore, treatment with other nutritional forms of vitamin D
3 at a dose of 15,000 IU/day × 1 month [
41] and 40,000 IU/day over 28 weeks, followed by 10,000 IU/day × 12 weeks [
42] has been shown to be safe. A main clinical concern with activated vitamin D supplementation in the ESKD population is hypercalcemia, hyperphosphatemia and reduction in parathyroid hormone levels. This protocol employs the lowest possible dose of activated vitamin D (alfacalcidiol) available to minimize significant fluctuations in these biochemical values, though the relative importance of these changes remains unquantified within the literature [
43].
In summary, the evidence to guide treatment that may minimize SCD and cardiovascular risk in ESKD is extremely limited. The VITamin D supplementation and cardiac Autonomic tone in Hemodialysis (VITAH) study is the first clinical trial to assess whether various vitamin D therapies, specifically ingestion of the combination of activated and nutritional vitamin D compared to activated vitamin D alone, influence cardiac autonomic tone and therefore cardiovascular risk in ESKD patients requiring hemodialysis.