Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?

Abstract

SUMMARY Considerable advances have been made in the understanding of the pathogenesis and treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). These include the discovery that the calcium-sensing receptor has an important role in the regulation of parathyroid gland function, the development of calcimimetics to target this receptor, the recognition that vitamin D receptor activation has important functions beyond the regulation of mineral metabolism, the identification of the phosphaturic factor fibroblast growth factor 23 and the contribution of this hormone to disordered phosphate and vitamin D metabolism in CKD. However, despite the availability of calcimimetics, phosphate binders, and vitamin D analogs, control of SHPT remains suboptimal in many patients with advanced kidney disease. In this Review, we explore several unresolved issues regarding the pathogenesis and treatment of SHPT. Specifically, we examine the significance of elevated circulating fibroblast growth factor 23 levels in CKD, question the proposition that calcitriol deficiency is truly a pathological state, explore the relative importance of the vitamin D receptor and the calcium-sensing receptor in parathyroid gland function and evaluate the evidence to support the treatment of SHPT with calcimimetics and vitamin D analogs. Finally, we propose a novel treatment framework in which calcimimetics are the primary therapy for suppressing parathyroid hormone production in patients with end-stage renal disease.

Fibroblast Growth Factor-23 in Early Chronic Kidney Disease

“…Our data are in favor of the hypothesis that the FGF-23-bonekidney axis might be the effector of a "phosphate trade-off" that compensates for the limited renal phosphate excretion caused by the reduced nephron mass (10). In this view, reduced renal phosphate excretion leads to increased FGF-23 secretion from the bone.…”

“…The discovery of FGF-23 and the elucidation of its function as a phosphaturic (8) and 1,25(OH) 2 VitD counter-regulatory hormone (3,8,9) provides a new conceptual framework for the understanding of the pathogenesis of secondary hyperparathyroidism (sHPT) (10). According to this new paradigm for the pathogenesis of sHPT, a primary decrease in renal phosphate excretion due to the loss of functioning kidney mass leads to increased FGF-23 secretion from bone; increased FGF-23 levels act on the kidney to inhibit phosphate reabsorption and to suppress 1,25(OH) 2 VitD levels.…”

Vitamin D Affects Survival Independently of Vascular Calcification in Chronic Kidney Disease

“…In contrast to 25D, circulating levels of 1,25D chiefly depend on the ability of renal 1-␣ hydroxylase to convert 25D into 1,25D. This ability is decreased by (1) a reduction in the nephron mass, and (2) the hyperphosphatemia-induced increase in levels of the phosphaturic hormone FGF-23, which both inhibits the production of 1,25D and increases its degradation (33). Thus, as renal failure progresses and renal production of 1,25D decreases, 25D availability may constitute a rate-limiting step in the production of 1,25D by nonrenal tissues, where it may act either in autocrine or paracrine pathways (6).…”

Decreases in PTH in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism

“…Long-term disorders of bone-mineral metabolism can be seen as a systemic condition (chronic kidney disease-related mineral and bone disorders [CKD-MBD]) (8), and the prognosis for dialysis patients might be improved if SHPT is controlled (8,9). MBD is controlled by treatment with phosphate binders, vitamin D analogs, and calcimimetics, which are usually given in combination (10). In Japan, the calcimimetic agent cinacalcet hydrochloride has been manufactured and marketed by Kyowa Hakko Kirin Co., Ltd. since January 2008.…”