By: Nancy Yousry, PharmD Candidate c/o 2024

              Vitamin D is a multifaceted nutrient needed to maintain homeostasis and proper health. In addition to its role in building and maintaining healthy bones, vitamin D also regulates many important cellular functions in the body, serving as an anti-inflammatory, antioxidative, and neuroprotective agent.¹ In general, the two main sources for vitamin D supplementation are from diet and direct sunlight. Vitamin D can be found among foods in the pescetarian diet, including salmon, mackerel, and sardines. Certain foods can also be fortified with vitamin D, like orange juice and dairy products. Furthermore, the time of day, season, and geographical location serve as environmental factors that may influence the productivity of vitamin D.¹  

Regardless of its source, vitamin D is absorbed biologically inert and must undergo two hydroxylations to become active. The first hydroxylation occurs in the liver where vitamin D is converted into 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second hydroxylation occurs in the kidney, forming 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol, the physiologically active form of vitamin D.² However, in patients with renal disease, this conversion to calcitriol will be reduced. Chronic kidney disease (CKD) is a condition characterized by damage to the kidneys, resulting in a gradual loss of their ability to filter fluid and waste from the blood.³ Patients with renal disease have shown reduced activity of 1-α hydroxylase, the enzyme that converts calcidiol to calcitriol in the kidneys.⁴  

  Low serum concentrations of calcidiol in patients with CKD have been associated with a higher risk of all-cause mortality and a faster progression of kidney disease.⁴ Serum calcidiol levels less than 12 ng/mL are associated with vitamin D deficiency, levels between 12 to 20 ng/mL are insufficient for overall health, and levels greater than 20 ng/mL are sufficient.¹ Two forms of supplemental vitamin D currently exist for the correction of vitamin D deficiency. Patients can either use vitamin D2 (ergocalciferol), a plant-based sterol, or vitamin D3 (cholecalciferol), an animal-based sterol.¹ Although both cholecalciferol and ergocalciferol can be found as dietary supplements and in fortified foods, their efficacy may not be equal. 

A randomized, two-arm, parallel clinical trial, published in the British Journal of Nutrition, was conducted by Wetmore et al. to test the efficacy of different vitamin D formulations in CKD patients.⁵ The study included patients with an eGFR of < 60 ml/min per 1.73 m² and serum concentrations of calcidiol < 30 ng/ml. Exclusion criteria included dialysis dependence, presence of gastrointestinal disorders, liver cirrhosis, and current treatment with vitamin D.⁵ A total of 44 non-dialysis-dependent patients with stage 3-5 CKD were included and equally randomized into two treatments arms receiving either cholecalciferol 1250μg (50,000 IU) once weekly or ergocalciferol 1250μg (50,000 IU) once weekly.⁵ The primary outcome assessed the change of serum calcidiol concentrations over the 12-week treatment period.⁵ The investigators found that after 12 weeks of therapy, patients on cholecalciferol had a mean change in total calcidiol of 45.0 (Standard Deviation [SD] 16.5) ng/mL while patients on ergocalciferol saw a mean change of 30.7 (SD 15.3) ng/mL (P < 0.01).⁵ 

  Secondary outcomes of this trial included assessing changes in total calcidiol from baseline to week 18 and changes in parathyroid hormone (PTH).⁵ Regarding calcidiol, total change in serum concentrations seemed to be similar between the cholecalciferol and ergocalciferol groups from baseline to week 18, six weeks after stopping treatment. The mean change from baseline was 22.2 (SD 12.7) ng/mL for cholecalciferol and 17.6 (SD 8.9) ng/mL for ergocalciferol (p = 0.17).⁵ Regarding PTH, patients receiving cholecalciferol appeared to have a greater mean reduction in serum PTH compared to those receiving ergocalciferol. The mean change from baseline was -15.3 (SD 34.5) pg/mL for cholecalciferol and 2.3 (SD 38.3) pg/mL for ergocalciferol (p = 0.02).⁵ 

In summary, results from this randomized clinical trial by Wetmore et al. indicate that cholecalciferol was able to generate a greater initial increase in total serum calcidiol concentrations compared to ergocalciferol. However, the efficacy of cholecalciferol was deemed to be transient, as discontinuation of therapy for 6 weeks caused calcidiol concentrations to dramatically decline.⁵ To address vitamin D deficiency and insufficiency, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines do not suggest a preference between cholecalciferol and ergocalciferol. Instead, they recommend using general treatment strategies.⁶ The recommended dietary allowance for vitamin D is 10 μg (400 IU) for those up to 12 months of age, 15 μg (600 IU) for those between 1 to 70 years of age, and 20 μg (800 IU) for those over 70 years of age.¹ Although cholecalciferol may initially be superior to ergocalciferol in raising calcidiol serum levels, it is more important to stay adherent to vitamin D maintenance therapy in CKD patients to prevent possible complications from vitamin D deficiency. 

References

1. Vitamin D fact sheet for health professionals. National Institutes of Health Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/#en1. Last Updated 08/12/2022. 
2. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. 
3. Chronic kidney disease basics. Centers for Disease Control and Prevention. https://www.cdc.gov/kidneydisease/basics.html. Last Updated 02/28/2022. 
4. Melamed ML, Thadhani RI. Vitamin D therapy in chronic kidney disease and end stage renal disease. Clin J Am Soc Nephrol. 2012;7(2):358-65. doi: 10.2215/CJN.04040411  
5. Wetmore JB, Kimber C, Mahnken JD, Stubbs JR. Cholecalciferol v. ergocalciferol for 25-hydroxyvitamin D (25(OH)D) repletion in chronic kidney disease: a randomised clinical trial. Br J Nutr. 2016;116(12):2074-2081. doi: 10.1017/S000711451600427X 
6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and 7. Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl (2011). 2017;7(1):1-59. doi: 10.1016/j.kisu.2017.04.001  

Published by Rho Chi Post