Vitamin D Deficiency in Chronic Kidney Disease: Recent Evidence and Controversies

Abstract

Vitamin D (VD) is a pro-hormone essential for life in higher animals. It is present in few types of foods and is produced endogenously in the skin by a photochemical reaction. The final step of VD activation occurs in the kidneys involving a second hydroxylation reaction to generate the biologically active metabolite 1,25(OH)₂-VD. Extrarenal 1α-hydroxylation has also been described to have an important role in autocrine and paracrine signaling. Vitamin D deficiency (VDD) has been in the spotlight as a major public healthcare issue with an estimated prevalence of more than a billion people worldwide. Among individuals with chronic kidney disease (CKD), VDD prevalence has been reported to be as high as 80%. Classically, VD plays a pivotal role in calcium and phosphorus homeostasis. Nevertheless, there is a growing body of evidence supporting the importance of VD in many vital non-skeletal biological processes such as endothelial function, renin-angiotensin-aldosterone system modulation, redox balance and innate and adaptive immunity. In individuals with CKD, VDD has been associated with albuminuria, faster progression of kidney disease and increased all-cause mortality. Recent guidelines support VD supplementation in CKD based on extrapolation from cohorts conducted in the general population. In this review, we discuss new insights on the multifactorial pathophysiology of VDD in CKD as well as how it may negatively modulate different organs and systems. We also critically review the latest evidence and controversies of VD monitoring and supplementation in CKD patients.

Keywords: Vitamin D; Vitamin D deficiency; chronic kidney disease; proteinuria.

Figure 1

Vitamin D activation and metabolism. Adapted from Gois et al [3].

Figure 2

Representation of the tandem function of megalin and cubilin in renal uptake of 25(OH)-VD. (a) Filtered complexes of vitamin D binding protein (VDBP) and 25(OH)-VD are endocytosed by the proximal tubular epithelium via an endocytic receptor-mediated pathway recognizing VDBP. The VDBP is degraded in the lysosomes releasing 25(OH)-VD which is either secreted or hydroxylated in the mitochondria to 1,25(OH)₂-VD. Both 25(OH)-VD and 1,25(OH)₂-VD reenter the circulation bound to VDBP. (b) Postulated megalin and cubilin shedding in chronic kidney disease (CKD) perpetuating vitamin D deficiency (VDD) with subsequent lower 25(OH)-VD reuptake and intracrine 1,25(OH)₂-VD production in the renal proximal tubules.

Figure 3

Schematic model of the classical and non-classical effects of vitamin D. The compounds 25(OH)-VD and 1,25(OH)₂-VD circulate mainly bound to the vitamin D binding protein (VDBP). The endocrine effects of 1,25(OH)₂-VD are represented on the right. Different types of cells can present the machinery for 25(OH)-VD activation (left). In an autocrine and paracrine fashion, 1,25(OH)₂-VD regulates the transcription of pivotal proteins involved in several biological processes (left). RAAS = renin-angiotensin-aldosterone system. PTH = parathyroid hormone.