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Characterised by increased plasma levels of parathyroid hormone (PTH) and parathyroid gland hyperplasia, secondary hyperparathyroidism (SHPT) is a maladaptive response to disrupted calcium, phosphorus and vitamin D homeostasis resulting from declining renal function.1
SHPT is a component of a broader systemic syndrome known as chronic kidney disease–mineral and bone disorder (CKD–MBD), which encompasses mineral, bone and calcific cardiovascular abnormalities that develop as a complication of CKD.2
SHPT is a common and serious complication of CKD.3,4 Its prevalence and severity increase with declining kidney function, with SHPT affecting up to 40% and 82% of patients with stage 3 and 4 CKD, respectively.3,5 Whilst abnormal PTH levels are more frequently observed from stage 3 CKD, SHPT can manifest as early as stage 2 (Figure 1).3
Cross-sectional analysis of baseline data from 5,255 patients with CKD.
Adapted from Levin A et al. 2007.3
As CKD progresses, the decline in renal function leads to a disruption of mineral and vitamin D homeostasis, as characterised by (Figure 2):1,6
These changes result in excessive secretion of PTH.1,6
The earliest alteration in mineral metabolism in CKD is an elevated FGF-23 level (1). This causes a decline in the level of 1,25(OH)2D (2), which leads to an increase in PTH secretion (3). All these changes occur prior to an elevation in the phosphate level (4). Colour-coded bands represent normal ranges.
Adapted from Wolf M 2010.7
Prolonged PTH elevations increase the risks of fractures,4,8 vascular calcification,1,9 cardiovascular disease4,8 and parathyroid gland hyperplasia,6 which can result in therapeutic resistance (Figure 3).6,10,11
Adapted from Cunningham J et al. 2011,1 Rodriguez M et al. 2005,6 Friedl C et al. 201712 and Wu W et al. 2018.13
As the glomerular filtration rate (GFR) declines to below 60 mL/min/1.73 m2, phosphorus excretion becomes altered in the nephron in CKD.14 The resulting elevations in serum phosphorus directly increase PTH levels1 and drive the progression of SHPT through indirect mechanisms, including:
Vitamin D deficiency is an important component in the pathogenesis of SHPT.1,12 In CKD, the reduction of functional renal mass is accompanied by a progressive loss of CYP27B1, which further exacerbates the reduction in 1,25(OH)2D synthesis.12
Declining renal 1,25(OH)2D synthesis has both an indirect and direct effect on PTH levels.14 A lack of 1,25(OH)2D binding to vitamin D receptors (VDRs) in the parathyroid glands disrupts the normal VDR-mediated downregulation of PTH levels.14 Decreased 1,25(OH)2D also acts indirectly by reducing intestinal calcium absorption, which lowers serum calcium levels and stimulates the release of PTH.1
1,25(OH)2D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; CKD: chronic kidney disease; CKD–MBD: chronic kidney disease–mineral and bone disorder; CYP24A1: cytochrome P450 family 24 subfamily A member 1; CYP27B1: cytochrome P450 family 27 subfamily B member 1; FGF-23: fibroblast growth factor-23; GFR: glomerular filtration rate; PO: phosphate; PTH: parathyroid hormone; sCa: serum calcium; SHPT: secondary hyperparathyroidism; sPO: serum phosphate; VDR: vitamin D receptor.
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