Vitamin D: an important treatment for secondary hyperparathyroidism in chronic kidney disease?

Abstract

Secondary hyperparathyroidism (SHPT) is one of the most common complications of chronic kidney disease (CKD). Vitamin D levels begin to decrease in the early stages of CKD, and these vitamin D-related changes play a central role in the occurrence and development of SHPT. Vitamin D-based drugs, which inhibit parathyroid hormone secretion either directly or indirectly, are commonly used to treat SHPT. However, vitamin D-based drugs can also lead to a dysregulated balance between serum calcium and phosphorus, as well as other adverse reactions. Over the past several decades, researchers have conducted in-depth studies on the pathogenesis of SHPT, developed new vitamin D-based drugs, and explored combinatory methods to improve treatment efficacy for the disease. Here, we review vitamin D metabolism, the diagnosis of vitamin D deficiency in patients with CKD, the pathogenesis of SHPT, the pharmacological effects of vitamin D drugs, and the benefits and side effects of using vitamin D to treat SHPT.

Keywords: Chronic kidney disease; Complication; Mechanism; Secondary hyperparathyroidism; Treatment; Vitamin D.

Fig. 1

Catabolism and actions of vitamin D. Photosynthesis in the epidermis and dietary intake are the primary sources of vitamin D. Vitamin D is first catalyzed by 25-hydroxylase in the liver to produce 25(OH)D, and then activated by 1α-hydroxylase in the kidney to produce 1,25(OH)₂D. CYP2R1 is the major enzyme responsible for vitamin D 25-hydroxylation in the liver, and CYP27B1 is the major 1α-hydroxylase that catalyzes the production of 1,25(OH)₂D. CYP24A1 can hydroxylate 1,25(OH)₂D into 1,24,25(OH)₂D, thereby degrading 1,25(OH)₂D. Vitamin D exerts its biological effects via VDR. 1,25(OH)₂D can pass through cellular membranes and bind to VDR. VDR binds to retinol X receptor (RXR) to form the heterodimer VDR/RXR, and VDR/RXR then binds to the DNA sequence of vitamin D response elements (VDREs) in target genes to regulate genetic expression

Fig. 2

SHPT pathogenesis in CKD patients. Hyperphosphatemia, hypocalcemia, and vitamin D deficiency secondary to decreased renal function all stimulate PTH synthesis and secretion. Concurrent down-regulated expression of CaSR and VDR in parathyroid tissue makes the organ lose its sensitivity and responsivity to serum calcium and active vitamin D levels. Thus, negative feedback responses (e.g., inhibition of PTH secretion) are compromised, which results in parathyroid hyperplasia. In addition, CKD patients tend to have significantly increased FGF23 levels. When FGF23 acts on the parathyroid gland, it can directly reduce PTH levels. However, in CKD, FGF23 receptor expression in tissues decreases, resulting in resistance to FGF23 and meaning that FGF23 cannot inhibit high PTH levels. Increased FGF23 can also indirectly increase PTH synthesis by reducing the synthesis of active vitamin D