Pathophysiology and therapies of CKD-associated secondary hyperparathyroidism

Abstract

Uremic secondary hyperparathyroidism (SHP) refers to the biochemical abnormalities that characterize CKD-MBD. However, historically parathyroid hormone (PTH) is identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism. SHP represents the adaptive response to several mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal dysregulations. Among classic factors involved in the pathogenesis of SHP, phosphate, calcium, and calcitriol have a prominent role. The discovery of new pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) including fibroblast growth factor-23 (FGF23) and klotho provides new hypothesis and perspectives to our understanding of this complex metabolic disturbance. Recently more than serum phosphate a critical role in regulating FGF23 synthesis and the progression of CKD is ascribed to phosphate pool, reflected by production of glycerol-3-phosphate and the formation of excessive CPP-2. Finally, also skeletal resistance to PTH action, due to dysregulation of the Wnt-β-catenin system and intestinal dysbiosis, affecting the PTH actions on bone are causal factor of SHP. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient. This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.

Keywords: CKD-MBD; FGF23; Phosphate pool; Secondary Hyperparathyroidsm (SHP); glycerol-3-phosphate (G3P); intestinal dysbiosis.

Figure 1:

Novel pathogenic mechanisms of secondary hyperparathyroidism. In CKD, nephron loss results in elevated serum phosphate (Pi) pool and increased phosphate concentration in the remaining nephrons (PiU). Serum phosphate load promotes the formation of type 1 and type 2 CPPs, which stimulate the production of FGF23. Elevated phosphate levels within individual nephrons increase glycerol-3-phosphate production (G3-P) and decrease tubular expression of klotho, both enhancing FGF23 synthesis. Upregulation of FG23 suppresses renal production of calcitriol, resulting in hypocalcaemia and increased PTH secretion. Further, FGF23 increases intratubular phosphate concentrations while simultaneously lowering systemic serum phosphate pools. The sustained elevation of serum phosphate directly stimulates PTH synthesis.