Supplementation eases inflammation, lowers cardiac risk, and improves glycemic controls
Deficiency in 25-hydroxyvitamin D [25(OH)D] is common in CKD. Although the endocrine functions of vitamin D in bone mineral metabolism are well known, the effects of autocrine and paracrine functions on insulin production and resistance, immunity, and CVD are receiving increased attention. Since an estimated 75% of “activated” vitamin D (1,25[OH]2D3) is produced in extra-renal sites close to where it is used for cellular “non-bone” functions, low serum levels of the required substrate 25(OH)D may negatively impact health outcomes particularly for people with CKD. The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in CKD recognize the need for further research in this area.
With natural food sources of vitamin D (D3, cholecalciferol) limited mainly to fatty fish and fish oils, the body's ability to convert ultra-violet B (UVB) rays from sunlight into pre-vitamin D provides its main supply. Factors impeding adequate 25(OH)D levels in CKD patients include reduced vitamin D3 in the skin as glomerular filtration rate (GFR) declines and as a result of aging; decreased activity and sunlight exposure resulting from fatigue and dialysis schedules; and higher melanin content in at-risk populations (African Americans, Hispanics). Foods commonly fortified with vitamin D (D2, ergocalciferol) such as milk and other dairy products are often restricted due to high phosphorus content, so supplementation with vitamin D is being investigated as a remedy for CKD patients.
Evidence of the possible benefits of ergocalciferol in dialysis patients is mounting. In a study by Shah et al. (Perit Dial Int. 2005;25:362-366), 29 peritoneal dialysis patients were examined with regard to serum 25(OH)D levels and effects of ergocalciferol supplementation. All but one patient were vitamin D deficient (less than 15 ng/mL [multiply by 2.496 to convert to nmol/L] and 25 had undetectable levels (less than 7 ng/mL). After receiving 50,000 IU of ergocalciferol weekly for four weeks, all were vitamin D replete except one patient who required an additional course. The investigators observed no significant change in serum calcium, phosphorus, and PTH. A retrospective study by my colleagues and me (J Ren Nutr. 2008;18:375-382) examined the prevalence of vitamin D deficiency in 344 maintenance hemodialysis patients and the effects of supplementation with ergocalciferol (50,000 IU/week for 24 weeks) for 25(OH)D levels less than 40 ng/mL. Ninety-two percent of patients were vitamin D deficient based on these criteria, with 80% less than 31 ng/mL and 24% below 11 ng/mL. Baseline subgroup analysis showed lower levels of 25(OH)D associated with higher glycosylated hemoglobin (HbA1c). Supplementation with ergocalciferol resulted in significant improvement in mean serum 25(OH)D from baseline (18.4 ng/mL) to six months (42 ng/mL), and improved glycemic control as reflected by lower mean HbA1c (6.9% vs. 6.4%).
Inflammation is a major non-nutritional contributor to hypoalbuminemia that is strongly associated with increased morbidity and mortality in stage 5 CKD. In a randomized double-blind clinical trial of vitamin D supplementation in 123 congestive heart failure patients by Schleithoff et al. (Am J Clin Nutr. 2006;83:754-759), anti-inflammatory cytokine interleukin 10 (IL-10) increased significantly in the group receiving 2,000 IU/day of cholecalciferol compared with those receiving none. The authors conclude that study results “indicate vitamin D can serve as an anti-inflammatory agent.”
Studies have linked vitamin D deficiency to an increased risk of CVD, the primary cause of mortality in stage 5 CKD. This increased risk may involve vitamin D receptors (VDRs) in smooth muscle cells and the role of vitamin D in reducing inflammation related to atherosclerosis.
A prospective cohort study by Wang et al. (Am J Clin Nutr. 2008;87:1631-1638) examined serum 25(OH)D levels in 230 peritoneal dialysis patients and followed them for three years comparing incidence of cardiovascular events (CVE) to baseline vitamin D. The authors report that low serum 25(OH)D (18.3 ng/mL or less) was associated with an increased risk of CVE. Furthermore, in a nested case-control study of 18,225 men in the Health Professionals Follow-up Study, Giovannucci et al. (Arch Intern Med. 2008;168:1174-1180) looked at MI risk associated with serum 25(OH)D levels and concluded that “low levels of 25(OH)D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.”
As new evidence emerges regarding the importance of vitamin D for “non-bone” functions, it is hoped that renal research will focus on the potential benefits of regularly monitoring serum 25(OH)D and supplementing as needed to maintain adequate levels in CKD patients.