Megalin is an endocytic receptor abundantly expressed in proximal tubular epithelial cells and other calciotropic extrarenal cells expressing vitamin D metabolizing enzymes, such as bone and parathyroid cells. The receptor functions in the uptake of the vitamin D-binding protein (DBP) complexed to 25 hydroxyvitamin D₃ (25(OH)D₃), facilitating the intracellular conversion of precursor 25(OH)D₃ to the active 1,25 dihydroxyvitamin D3 (1,25(OH)₂D₃). The significance of renal megalin-mediated reabsorption of 25(OH)D₃ and 1,25(OH)₂D₃ has been well established experimentally, and other studies have demonstrated relevant roles of extrarenal megalin in regulating vitamin D homeostasis in mammary cells, fat, muscle, bone, and mesenchymal stem cells. Parathyroid gland megalin may regulate calcium signaling, suggesting intriguing possibilities for megalin-mediated cross-talk between calcium and vitamin D regulation in the parathyroid; however, parathyroid megalin functionality has not been assessed in the context of vitamin D. Within various models of chronic kidney disease (CKD), megalin expression appears to be downregulated; however, contradictory results have been observed between human and rodent models. This review aims to provide an overview of the current knowledge of megalin function in the context of vitamin D metabolism, with an emphasis on extrarenal megalin, an area that clearly requires further investigation.

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker C-reactive protein. Included trials were heterogeneous with regards to outcomes, and the majority studied small participant populations with a relatively short follow-up. We conclude that vitamin D supplementation corrects vitamin D deficiency and is safe and well-tolerated in humans with ESKD. However, it is not clear from clinical trials conducted to date that a causal pathway exists between 25(OH)D and pleiotropic effects that is responsive to vitamin D treatment.