Characterizing the Development of Secondary Hyperparathyroidism and Vitamin D Resistance in Experimental Chronic Kidney Disease

Abstract

The parathyroid gland (PTG) responds to alterations in calcium and phosphate via secretion of parathyroid hormone (PTH) that acts on kidneys and bone to regulate mineral homeostasis. Hallmarks of chronic kidney disease (CKD) include increased retention of phosphate (PO4) and decreased renal production of 1,25-dihydroxyvitaminD3 (calcitriol) from its precursor, 25-hydroxyvitaminD3 (calcifediol). Hyperphosphatemia and vitamin D deficiency in CKD stimulate excessive production and secretion of PTH, generating maladaptive consequences to the structure and function of bone and blood vessels, pathologies that are associated with increase mortality in the CKD population.

Calcitriol is a mainstay therapy for the treatment of secondary hyperparathyroidism (SHPT) that develops in CKD. A major issue with therapy includes the development of calcitriol resistance and increased vascular calcification. Modifications to the PTG that hinder its sensitivity to calcium (Ca) and PO4 are hypothesized to be involved in the development of calcitriol resistance, renal osteodystrophy, and vascular calcification in SHPT which is associated with increased risk of bone fracture and cardiovascular burden. The research contained herein, involving in vivo animal studies as well as in vitro isolated PTG studies, sought to characterize the development of calcitriol resistance and SHPT in CKD, particularly with regard to changes in response mediated by excess PO4.

The major findings indicate that high dietary PO4 attenuates calcitriol mediated suppression of PTH to acute and chronic treatment of calcitriol. Calcitriol treatment (CTx) in both CKD and non-CKD animals showed reduced gland responsiveness and persistent lowering of basal PTH secretion in vitro.

Overall the findings emphasize the clinical significance of PO4 restriction for enhancing the effectiveness of strategies that target PTH lowering and suggest caution in the use of calcitriol for the treatment of SHPT. A common approach for management of calcitriol resistance is to increase doses of calcitriol during therapy. This should be avoided as prolonged treatment appears to be able to persistently impact PTG response to alterations in Ca and PO4 both in non-CKD and experimental CKD animals resulting in impaired mineral homeostasis.