Vitamin D and Cardiovascular Complications of CKD

CKD as a Global Health Problem and Its Association with Cardiovascular Disease The global prevalence of CKD is 13.4%, with 10.6% being stages 3–5 (1). Over the past 25 years CKD has become a more frequent cause of death and disability worldwide, both in developed and developing nations. According to the Global Burden of Disease Study, CKD rose up the ranks of cause of “years of lives lost” from 19th in 1990 to 16th in 2016, and is projected to become the fifth leading cause of “years of life lost” by 2040 (2). Most of the deaths in patients with CKD are due to cardiovascular causes. In a large, 3-year follow-up study, cardiovascular death rates increased from two per 100 patient-years in those with eGFR>60 ml/min per 1.73 m2 to 37 per 100 patient-years in those with eGFR<15 ml/min per 1.73 m2 (3). CKD and its complications utilize a major share of health care resources with a cost of £1.47 billion to the UK National Health Service in 2009–2010 and >$64 billion to US Medicare in 2015. CKD and Cardiovascular Risk Factors Control The benefits of traditional cardiovascular risk factor control demonstrated in the general population have met with limited success in patients with CKD. First, risk factors such as obesity and hypertension do not demonstrate a linear relationship with cardiovascular events in CKD. Second, cholesterol control has not been conclusively proven to be of benefit in patients with advanced CKD. In fact, two studies in patients on hemodialysis showed no benefit at all. The largest randomized trial of cholesterol control showed a reduction only in atherosclerotic events (4). Trials that target CKD-specific, nontraditional risk factors have also failed to show benefit. These include phosphate lowering with sevelamer, parathyroid hormone suppression with calcimimetics, uric acid lowering with febuxostat, and correction of anemia with erythropoietin. Vitamin D Therapy in CKD, Evidence So Far Vitamin D deficiency is common in patients with CKD, reflected as low 25-hydroxy and 1,25-dihydroxy vitamin D levels. Vitamin D deficiency has been associated with higher all-cause and cardiovascular mortality in patients with CKD, just as it does in the general population. Since the discovery of the role of the kidneys in activation of vitamin D in 1970 and associated bone disease, nephrologists have been keen on supplementing 1,25-dihydroxy vitamin D in patients with ESKD. Meta-analysis of observational studies has shown improvement of cardiovascular and all-cause mortality after treatment with vitamin D and its analogs in patients with CKD (5). However, adequately powered, randomized, controlled trials have not been conducted. Hence the impact of vitamin D therapy on cardiovascular health in patients with CKD is unknown. Use of Vitamin D in the General Population There has been considerable interest in studying the effect of vitamin D therapy on cardiovascular events in the past few decades. Observational studies suggest a relationship of vitamin D deficiency with cardiovascular disease, including carotid intima-media thickness, peripheral vascular disease, and cardiovascular death. Vitamin D supplementation improves BP and endothelial function (as measured by brachial artery flow-mediated dilatation), and reduces levels of inflammatory markers and lipids (particularly triglycerides) in the general population with or without vitamin D deficiency. Before 2017, prospective trials have examined the impact of vitamin D therapy on cardiovascular outcomes, but only as secondary end points, and used different doses of vitamin D. Only two studies included vitamin D–deficient participants, four out of 21 studies documented a >50% rise in vitamin D levels after supplementation, and none showed any effect on cardiovascular outcomes. In a prospective, randomized trial of 5101 unselected adult patients with baseline level of 66±26 nmol/L, vitamin D supplementation did not improve incident cardiovascular disease and death, or myocardial infarction, angina, heart failure, and arrhythmia (6). More recently, in 25,871 patients with baseline vitamin D concentration of 77 nmol/L, 2000 IU/daily of cholecalciferol did not improve cardiovascular outcomes (7). There was no difference between patients with vitamin D <50 nmol/L (n=2001) or >50 nmol/L (n=13,786). Impact of Vitamin D on Vascular Function in CKD The impact of vitamin D therapy on vascular structure and function in patients with CKD has been tested in several trials. We demonstrated improvement in brachial artery flow-mediated dilatation, from 3.1±3.3% to 6.1±3.7%, with 600,000 U of cholecalciferol in nondiabetic patients with CKD with baseline 25-hydroxy vitamin D level <75 nmol/L, over 16 weeks in a nonrandomized trial (8). Subsequently, we showed beneficial effects of nutritional vitamin D supplementation on brachial artery flow-mediated dilatation, markers of inflammation, arterial stiffness, parathyroid hormone, intracellular cell adhesion molecule, vascular cell adhesion molecule, and E-selectin in a randomized, placebo-controlled trial of 120 nondiabetic patients with stage 3–4 CKD and baseline vitamin D <75 nmol/L (9). In other randomized trials, pulse wave velocity improved after 6-month supplementation with 25-hydroxy vitamin D in 119 patients with an eGFR of 15–45 ml/min per 1.73 m2; and brachial artery flow-mediated dilatation improved with 12-week paricalcitol therapy in patients with CKD stages 3 and 4. On the other hand, two studies failed to find any change in flow-mediated dilatation and pulse wave velocity, respectively. Although the effects are inconsistent, a recent meta-analysis showed that vitamin D treatment led to an improvement of endothelial function. Impact of Vitamin D on Cardiac Structure and Function In two randomized, placebo-controlled studies, 1-year active vitamin D supplementation failed to improve cardiac structure and function in patients with CKD (10,11). One study demonstrated an improvement of left atrial volume, indicating a possible improvement in diastolic function, and small but significant improvement in the number of hospitalizations due cardiovascular events (11). Adequately powered studies with appropriate dose of 25-hydroxy vitamin D in deficient patients have not been conducted. Lessons from Vitamin D Trials in CKD These trials tell us that a number of issues need to be considered when designing future trials of vitamin D supplementation. Should we enroll all patients with CKD, or only those with vitamin D deficiency? Should patients with severe deficiency (<10 ng/ml) be excluded? What should be the dose and duration of vitamin D supplementation? And should there be a requirement to meet a target level? Randomized trials in patients with CKD without measurement of baseline vitamin D levels and randomized trials in the general population with baseline mean vitamin D level >50 nmol/L did not show benefits of vitamin D supplementation, whereas left ventricular structure and function improved in patients with heart failure with baseline levels of <50 nmol/L in the VitamIN D treatIng patients with Chronic heArT failurE (VINDICATE ) study (12). Hence it is logical to include patients with vitamin D levels <50 nmol/L in future studies. In the VINDICATE study, cholecalciferol 4000 U/d increased vitamin D level >100 nmol/L for 12 months without causing significant hypercalcemia, similar to our experience with 5000 U/d (9). Therefore this may be the appropriate dose for future studies. Conclusion Epidemiology suggests a link between of vitamin D deficiency with cardiovascular events in patients with CKD. Observational cohorts and small, randomized, placebo-controlled trials have shown some benefits with supplementation, whereas larger studies in the general population Vitamin D and Omega-3 Trial (VITAL) and in patients with CKD (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity [PRIMO], Effect of Paricalcitol on Left Ventricular Mass and Function in CKD [OPERA]) have not; hence expert guidelines such as those from Kidney Disease: Improving Global Outcomes and The National Institute for Health and Care Excellence do not recommend the use of vitamin D in patients with CKD to improve cardiovascular events (Figure 1) (7,10,11). To change practice, prospective, randomized, controlled trials are necessary with adequate dose and long enough duration in truly vitamin D–deficient patients with CKD.Figure 1.: The figure shows lack of strong evidence for vitamin D therapy to prevent cardiovascular disease in CKD. Although epidemiologic studies suggest a relationship between vitamin D deficiency and cardiovascular (CV) events, observational studies show improvement with supplementation, and randomized studies show improved vascular function with supplementation. There is no randomized trial evidence to justify supplementation in patients with CKD patients to improve cardiovascular function in regular clinical care.Disclosures Dr. Jha reports grants from Baxter Healthcare, grants from GSK, grants from NephroPlus, and grants from Zydus Cadilla, outside the submitted work. Dr. Banerjee has nothing to disclose.