Vitamin D is an integral and vital part of the complex management of calcium, phosphate and parathyroid hormone homeostasis. In patients with chronic kidney disease (CKD) vitamin D insufficiency (25 hydroxyvitamin D (25(OH)D) < 30ng/mL) is extremely common and is estimated to affect 71–83% of patients with stage 3 or 4 CKD.[2,3]
The effectiveness of vitamin D treatment for secondary hyperparathyroidism (SHPT), an early indicator of MBD in CKD, is well known. Hormone replacement therapy with ‘active’ or ‘vitamin D receptor activator’ (VDRA) compounds are effective in correcting parathyroid hormone levels (PTH), as they directly target the vitamin D receptor. However, the recently observed lack of cardiovascular benefits but increased risk of hypercalcaemia in the OPERA and PRIMO trials highlights the need for careful risk/benefit assessment when using calcitriol or other VDRAs in pre-dialysis patients.[4,5]
When increased PTH levels are first detected, KDIGO treatment guidelines recommend the same vitamin D replacement strategies as those used for the general population, although it is recognized that this guidance was opinion based on the limited trials available.
The evidence that replacement therapy with nutritional vitamin D supplements lowers PTH is mixed, particularly in pre-dialysis patients. Such nutritional vitamin D supplements include ergocalciferol and cholecalciferol.
It also remains debatable whether the hydroxyvitamin D levels recommended for the general population are adequate for early correction of PTH levels in CKD settings. A target for 25(OH)D of >30ng/mL is suggested by the KDOQI 2003 guidelines, although some analysts have used a value of <20ng/mL to define deficiency., Other questions that remain include:
- whether continued vitamin D therapy results in continued impact on SHPT, and
- at what point do increased vitamin D levels begin to lead to hypercalcemia or hyperphosphataemia?
In an effort to shed light on these uncertainties one study has found evidence for an optimal level of 25(OH)D. Data from over 14,000 patients showed a significant inverse relationship between PTH and 25(OH)D, which plateaued at between 42-48ng/mL in all 5 stages of CKD. Importantly, the authors also found no association between the higher 25(OH)D levels and either hyperphosphataemia or hypercalcemia.The potential importance of higher 25(OH)D levels is supported by the results of two studies in stage 3–4 CKD, in which correction of 25(OH)D levels above 30 ng/mL was also associated with a significant lowering of PTH levels.
While the data for nutritional vitamin D supplements is not definitive, and the use of hormone replacement therapy with active vitamin D may be revised in the future, current approaches to the management of vitamin D insufficiency may need to be revisited in pre-dialysis patients.
- Goldsmith DJA. Pro: Should we correct Vitamin D deficiency/insufficiency in chronic kidney disease patients with inactive forms of Vitamin D or just treat them with active Vitamin D forms? Nephrol Dial Transplant. 2016;31(5):698-705. doi:10.1093/ndt/gfw082.
- Sprague SM, Crawford PW, Melnick JZ, et al. Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease. Am J Nephrol. 2016;44(4):316-325. doi:10.1159/000450766.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385.
- Thadhani R, Wenger J, Tamez H, et al. Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease. 2012;307(7):674-684.
- Wang AY-M, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD–the OPERA trial. J Am Soc Nephrol. 2014;25(1):175-86. doi:10.1681/ASN.2013010103.
- KDIGO. KDIGO Clinical Practice Guideline for the diagnosis, evaluation, prevention and treatment of CKD-MBD. Kidney Int. 2009;76(August):Supplement 113.
- Agarwal R, Georgianos PI. Con: Nutritional Vitamin D replacement in chronic kidney disease and end-stage renal disease. Nephrol Dial Transplant. 2016;31(5):706-713. doi:10.1093/ndt/gfw080.
- Eknoyan G, Levin A, Levin NW. Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4):1-201. doi:10.1016/S0272-6386(03)00905-3.
- Ennis JL, Worcester EM, Coe FL, Sprague SM. Current recommended 25-hydroxyvitamin D targets for chronic kidney disease management may be too low. J Nephrol. 2016;29(1):63-70. doi:10.1007/s40620-015-0186-0.