Where are we now? Emerging opportunities and challenges in the management of secondary hyperparathyroidism in patients with non-dialysis chronic kidney disease

Abstract

Rising levels of parathyroid hormone (PTH) are common in patients with chronic kidney disease (CKD) not on dialysis and are associated with an elevated risk of morbidity (including progression to dialysis) and mortality. However, there are several challenges for the clinical management of secondary hyperparathyroidism (SHPT) in this population. While no recognised target level for PTH currently exists, it is accepted that patients with non-dialysis CKD should receive early and regular monitoring of PTH from CKD stage G3a. However, studies indicate that adherence to monitoring recommendations in non-dialysis CKD may be suboptimal. SHPT is linked to vitamin D [25(OH)D] insufficiency in non-dialysis CKD, and correction of low 25(OH)D levels is a recognised management approach. A second challenge is that target 25(OH)D levels are unclear in this population, with recent evidence suggesting that the level of 25(OH)D above which suppression of PTH progressively diminishes may be considerably higher than that recommended for the general population. Few therapeutic agents are licensed for use in non-dialysis CKD patients with SHPT and optimal management remains controversial. Novel approaches include the development of calcifediol in an extended-release formulation, which has been shown to increase 25(OH)D gradually and provide a physiologically-regulated increase in 1,25(OH)2D that can reliably lower PTH in CKD stage G3-G4 without clinically meaningful increases in serum calcium and phosphate levels. Additional studies would be beneficial to assess the comparative effects of available treatments, and to more clearly elucidate the overall benefits of lowering PTH in non-dialysis CKD, particularly in terms of hard clinical outcomes.

Keywords: Extended-release calcifediol; Non-dialysis chronic kidney disease; Parathyroid hormone; Secondary hyperparathyroidism; Vitamin D.

Conflict of interest statement

Markus Ketteler has received lecture fees and consulting honoraria from Amgen, Kyowa Kirin, Ono Pharmaceuticals, Vifor Fresenius Medical Care Renal Pharma and Vifor Pharma. Patrice Ambühl has no financial interests to declare.

© 2021. The Author(s).

Figures

Fig. 1

PTH levels independently predict A fracture, and B vascular events, and death in CKD Stage G3–G4 (Reprinted by permission from Springer Nature. Adapted from Geng S, et al. Osteoporos Int 2019;30:2019–2025 [2]). A Ten-year probability of fractures, based on baseline PTH levels. The hazards of fracture rose steadily with increasing PTH values. No significant difference was noted between the slope of the curve for fracture risk, when comparing odds of fracture in subjects with baseline PTH levels above and below a PTH value of 101 pg/mL. B Ten-year probability of vascular events and death, based on baseline PTH levels. The figure demonstrates that hazards of vascular events and death were lowest at PTH values of 69 and 59 ng/mL, respectively

Fig. 2

Role of Vitamin D in SHPT pathophysiology [6, 14]. a Vitamin D insufficiency stimulates PTH release which is exacerbated by renal impairment and impaired synthesis of active vitamin D in the kidney. b Declining glomerular filtration rate as CKD progresses leads to reduced phosphate clearance, increasing serum phosphate. c In response, FGF-23 is released from the bone. d FGF-23 down regulates CYP27B1 reducing renal 1-α-hydroxylase. Elevations in serum FGF-23 in CKD also lead to up-regulation of 25(OH)D and 1,25(OH)2D catabolism. e This leads to a decline in 25(OH)D and 1,25(OH)2D production, and as a result, reduced serum calcium levels. f Hypocalcaemia and 1,25(OH)2D deficiency in CKD patients result in the excessive PTH secretion and parathyroid gland hyperplasia that characterise SHPT

Fig. 3

Vitamin D metabolism [35, 43]. Vitamin D3 is generated in the skin under the influence of UV-B radiation, vitamin D2 and D3 are obtained from dietary sources by absorption through the intestine. In the liver, circulating vitamin D is converted to 25(OH)D by 25-hydroxylase (CYP2RI, CYP27A1). 25(OH)D is then converted to the active vitamin D metabolite, 1,25(OH)2D in the kidney and in extra-renal locations such as the parathyroid gland by the enzyme 1-α-hydroxylase (CYP27B1). 1-α-hydroxylase is regulated by several negative feedback mechanisms, including PTH, calcitonin, and FGF-23. Active vitamin D can be deactivated by 24-hydroxylase. The activity of 24-hydroxylase (CYP24A1) to degrade 25(OH)D and 1,25(OH)2D is governed by these negative feedback loops, and is a key determinant of the net amount of active vitamin D. Blue boxes represent where the therapeutic forms of vitamin D enter the metabolic pathway