The role of nutritional vitamin D in chronic kidney disease-mineral and bone disorder in children and adults with chronic kidney disease, on dialysis, and after kidney transplantation-a European consensus statement

Abstract

Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels >75 nmol/l (>30 ng/ml). Although vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (>150-200 nmol/l, or 60-80 ng/ml) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD.

Keywords: chronic kidney disease–mineral and bone disorder; kidney transplantation; parathyroid hormone; renal osteodystrophy; vitamin D.

Graphical Abstract

Figure 1:

Overview of vitamin D metabolism. Vitamin D is supplied through ultraviolet radiation of the skin or through diet. Two hydroxylation steps are necessary for activation into the active hormone, first by CYP2R1 in the liver to 25 hydroxyvitamin D [25(OH)D], and then by CYP27B1 in the kidneys or other tissues to 1,25 dihydroxy vitamin D [1,25(OH)2D]. Hepatic hydroxylation may be affected by energy metabolism, with reduced efficacy seen in diabetes mellitus and obesity. Renal CYP27B1 is under strict hormonal control by hormones governing mineral metabolism (parathyroid hormone, PTH and fibroblast growth factor 23, FGF23), with negative feedback from 1,25(OH)2D itself. In contrast, extrarenal CYP27B1 activity seems to be substrate dependent and stimulated by conditions of inflammation.

Figure 2:

Renal vitamin D metabolism and primary regulators of 1α-hydroxylase and 24-hydroxylase enzymes. Vitamin D metabolites circulate bound to proteins, mainly vitamin D protein. The 25-hydroxyvitamin D-DBP complex enters the proximal tubular cells from the glomerular filtrate through a megalin/cubulin-mediated transport. 1α-Hydroxylase (encoded by CYP27B1) is a cytochrome P450 enzyme that catalyzes the hydroxylation of 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D [1,25(OH)2D; the active form of vitamin D]. 24-hydroxylase (encoded by CYP24A1) catalyzes the 24-hydroxylation of 25(OH)D and 1,25(OH)2D to their inactive 24-metabolites. Factors that regulate each enzyme are depicted in the figure. Renally produced 1,25(OH)2D serves autocrine (genomic and non-genomic), paracrine and endocrine functions. Abbreviations: FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; DBP, Vitamin D binding protein; Ca, calcium; Phos, Phosphate; VDRE, vitamin D responsive element; VDR, vitamin D receptor; RXR, retinoid X receptor.

Figure 3:

Extrarenal vitamin D metabolism and primary regulators of 1α-hydroxylase and 24-hydroxylase enzymes. Free circulating 25-hydroxyvitamin D enters the cells through diffusion. Factors that regulate extrarenal CYP27B1 and CYP24A1 are depicted in the figure. Extrarenally produced 1,25(OH)2D mainly serves autocrine (genomic and non-genomic) and paracrine functions, but may also spill over the circulation and thus confer endocrine actions. Abbreviations: 24,25(OH)2D, 24,25-dihydroxyvitamin D; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; DBP, Vitamin D binding protein; VDRE, vitamin D responsive element; VDR, vitamin D receptor; RXR, retinoid X receptor.

Figure 4:

Association between predicted levels of 25(OH)D, based on genetic determinants, and all-cause and cause-specific mortality. Figure from a Mendelian randomizataino study utilizing the UK Biobank [155]. Arrows indicate the median baseline level in the VITamin D and OmegA-3 TriaL (VITAL) [151]. CV = Cardiovascular (divide by 2.5 to convert from nmol/l to ng/ml).

Figure 5:

25(OH)D response of 16 study arms from randomized controlled trials of nutritional vitamin D in adults with CKD where the outcome was change in PTH levels (divide by 2.5 to convert from nmol/l to ng/ml). Studies included: Alvarez et al., 2012 [92]; Marckmann et al., 2012 [95]; Westerberg et al., 2018 [96]; Yadav et al., 2018 [97]; Kumar et al., 2017 [98]; Dogan et al., 2008 [99]; Chandra et al., 2008 [100]; Matuszkiewicz-Rowinska et al., 2021 [102]; Alshahawey et al., 2021 [104]; Zheng et al., 2018 [105]; Zheng et al., 2016 [106]; Massart et al., 2014 [108]; Li et al., 2014 [109]; Hewitt et al., 2013 [110]; Delanaye et al., 2013 [111].

Figure 6:

25(OH)D response of five study arms from randomized controlled trials of nutritional vitamin D in adults with CKD where doses to maintain 25(OH)D levels were investigated (divide by 2.5 to convert from nmol/l to ng/ml). Data for the initial period where higher doses of vitamin D were used in some of these studies are excluded for illustration purposes only. Studies included: Alvarez et al., 2012 [92]; Li et al., 2014 [109]; Hewitt et al., 2013 [110]; Mager et al., 2016 [208]. (Note: Mager et al., 2016 included patients with CKD G1–2.)