Vitamin D and Secondary Hyperparathyroidism in Chronic Kidney Disease: A Critical Appraisal of the Past, Present, and the Future

Abstract

The association between vitamin D deficiency and especially critical shortage of active vitamin D (1,25-dihydroxyvitamin D, calcitriol) with the development of secondary hyperparathyroidism (sHPT) is a well-known fact in patients with chronic kidney disease (CKD). The association between sHPT and important clinical outcomes, such as kidney disease progression, fractures, cardiovascular events, and mortality, has turned the prevention and the control of HPT into a core issue of patients with CKD and on dialysis. However, vitamin D therapy entails the risk of unwanted side effects, such as hypercalcemia and hyperphosphatemia. This review summarizes the developments of vitamin D therapies in CKD patients of the last decades, from calcitriol substitution to extended-release calcifediol. In view of the study situation for vitamin D insufficiency and sHPT in CKD patients, we conclude that the nephrology community has to solve three core issues: (1) What is the optimal parathyroid hormone (PTH) target level for CKD and dialysis patients? (2) What is the optimal vitamin D level to support optimal PTH titration? (3) How can sHPT treatment support reduction in the occurrence of hard renal and cardiovascular events in CKD and dialysis patients?

Keywords: chronic kidney disease; chronic kidney disease–mineral and bone disorder; parathyroid hormone; secondary hyperparathyroidism; vitamin D; vitamin D insufficiency.

Figure 1

Possible reasons for vitamin D deficiency in chronic kidney disease (CKD). Adapted from Christensen et al. [10] and Nigwekar et al. [8].

Figure 2

Main pathways in which chronic kidney disease (CKD) leads to elevated parathyroid hormone (PTH) levels, causing secondary hyperparathyroidism (sHPT). Circled arrows indicate increases (↑)/decreases (↓). Adapted from Germain (2020) [13] and Leifheit-Nestler and Haffner (2021) [14]. CKD—chronic kidney disease, 25(OH)D—Calcidiol, 1,25(OH)₂D—Calcitriol, Ca—calcium, P—phosphorus, FGF23—Fibroblast growth factor-23, iFGF23—intact FGF23, PTH—parathyroid hormone, CYP27B1—1α-hydroxylase.

Figure 3

PubMed search results for “paricalcitol” (as of 24 May 2022; https://pubmed.ncbi.nlm.nih.gov/, accessed on 24 May 2022). The bin width is 1 year. Numbers on top of bars indicate counts.

Figure 4

PubMed search results from 2000 to 2022 for “CKD” and one of the following keywords, as of 25 May 2022: “Cardiovascular”, “Diabetic” or “Secondary hyperparathyroidism”; https://pubmed.ncbi.nlm.nih.gov/, accessed on 25 May 2022). Numbers on top of bars indicate counts.

Figure 5

Comparison of vitamin D replenishment treatments for non-dialysis chronic kidney disease patients with secondary hyperparathyroidism. Size and direction of circled arrows indicate the magnitude and effect (increase [↑]/decrease [↓]) of treatments on laboratory parameters. The immediate surge in vitamin D-levels by calcitriol bolus supplementation carries the risk of triggering vitamin D catabolism (dashed lines). VDR—vitamin D receptor, 24,25(OH)2D—24,25-dihydroxyvitamin D (inactive prohormone), 1,24,25(OH)3D—1,24,25 trihydroxyvitamin D (inactive hormone), Ca—calcium, P—phosphorus, FGF23—Fibroblast growth factor-23, PTH—parathyroid hormone, CYP27A1—25-hydroxylase, CYP27B1—1α-hydroxylase, CYP24A1—24-hydroxylase. Adapted from Cozzolino et al. [41], Christensen et al. [10], extended with data from Sprague et al. [42,68] and Fadda et al. [69].