Low serum 1,25(OH)2D3 in end-stage renal disease: is reduced 1α-hydroxylase the only problem?

Low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) in end-stage renal disease (ESRD) is considered a consequence of elevated fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (CYP27B1). Current ESRD treatment strategies to increase serum calcium and suppress secondary hyperparathyroidism involve supplementation with vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of 25-hydroxyvitamin D (25(OH)D) deficiency as a contributor to low serum 1,25(OH)2D. We investigated the effects of vitamin D (cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum vitamin D metabolites (25(OH)D, 1,25(OH)2D3 and 24,25(OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active vitamin D analogues as part of routine ESRD care. 1,25(OH)2D3 levels were low at baseline (normal range: 60-120 pmol/L). Cholecalciferol supplementation normalised both serum 25(OH)D and 1,25(OH)2D3. Median serum 25(OH)D increased from 35.1 nmol/L (IQR: 23.0-47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5-143.3 nmol/L) (P < 0.001). Median serum 1,25(OH)2D3 and 24,25(OH)2D3 increased from 48.3 pmol/L (IQR: 35.9-57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3-6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1-130.6 pmol/L) and 12.3 nmol/L (IQR: 9-16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise 1,25(OH)2D3 in ESRD is maintained but is substrate dependent, and serum 25(OH)D was a limiting factor at baseline. Therefore, 1,25(OH)2D3 deficiency in ESRD is partly a consequence of 25(OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.

Prevalence and treatment of hypovitaminosis D in the haemodialysis population of Coventry.

Low serum 25(OH)D and associated bone and non-bone related problems are not well appreciated in end stage renal disease (ESRD). Vitamin D treatment strategies in the UK currently focus almost exclusively on calcitriol [1,25(OH)2D], alfacalcidol or paricalcitol. In ESRD hypovitaminosis D is associated with bone loss, muscle weakness, falls, fractures and increased inflammation. National guidelines changed in 2014 and now recommend the diagnosis and treatment of low serum 25(OH)D in all patients with glomerular filtration rate (GFR) less than 30ml/min/1.73m2. However as yet there are no standardized guidelines for dosage, frequency and monitoring in ESRD patients. Following a systematic review of the literature we developed a clinical guideline for cholecalciferol supplementation at University Hospitals of Coventry and Warwickshire, UK. The guideline recommends 40,000IU cholecalciferol weekly for patients with 25(OH)D <50nmol/L and 20,000IU weekly for patients with 25(OH)D 50-75nmol/L; to be continued long term unless levels increase to ≥150nmol/L. To date we have measured 25(OH)D levels in 385 in-center haemodialysis patients. Virtually all patients (95%) had serum 25(OH)D levels <75nmol/L (65% deficient, <30nmol/L; 30% insufficient, 30-74nmol/L). Only 5% of patients had optimal levels (≥75nmol/L). Our data indicates that hypovitaminosis D is prevalent in the haemodialysis population in Coventry and Warwickshire and this is likely to reflect UK haemodialysis patients, highlighting the need for a national supplementation guideline.