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Prevalence and pathogenesis of SHPT in CKD

Prevalence and pathogenesis of SHPT in CKD

SHPT in CKD

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

Prevalence of SHPT in CKD

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

Figure 1. Prevalence of abnormal PTH, calcium and phosphorus levels by CKD stage3
graph

Cross-sectional analysis of baseline data from 5,255 patients with CKD.

Adapted from Levin A et al. 2007.3

 

Pathogenesis of SHPT in CKD

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

  • A decrease in 25(OH)D, 1,25(OH)2D and calcium levels
  • An increase in phosphorus concentrations

These changes result in excessive secretion of PTH.1,6

Figure 2. Disturbances in mineral metabolism with progression of CKD7
graph

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

Figure 3. Pathogenesis of SHPT1,6,12,13
graph

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

 

Elevated phosphorus and FGF-23 levels

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:

  • Upregulation of fibroblast growth factor-23 (FGF-23), which exacerbates 1,25(OH)2D deficiency by downregulating 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for 1,25(OH)2D synthesis.12 FGF-23 also upregulates 24-hydroxylase (CYP24A1), the enzyme that catabolises both 25(OH)D and 1,25(OH)2D12,15
  • Precipitation of calcium ions with phosphorus to form an insoluble complex, thus further decreasing serum calcium concentrations.14 This process also increases the risk of extraskeletal calcification14
 

Vitamin D deficiency

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

 

Learn more about the role of vitamin D in SHPT

 
Abbreviations and references

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.

  1. Cunningham J et al. Clin J Am Soc Nephrol. 2011;6:913–21.
  2. Moe S et al. Kidney Int. 2006;69:1945–53.
  3. Levin A et al. Kidney Int. 2007;71:31–8.
  4. Geng G et al. Osteoporos Int. 2019;30:2019–25.
  5. Sprague SM et al. Exp Rev Endocrinol Metab. 2017;12(5):289–301.
  6. Rodriguez M et al. Am J Renal Physiol. 2005;288:F253–64.
  7. Wolf M. JASN. 2010;21(9):1427–35.
  8. Xu Y et al. Clin Kidney J. 2021;sfab006.
  9. Castro RH et al. Poster C-1002 presented at: European Congress of Radiology (ECR) 2011; 2011 March 3–7; Vienna, Austria.
  10. Fukuda N et al. J Clin Invest. 1993;92:1436–43.
  11. Gogusev J et al. Kidney Int. 1997;51:328–36.
  12. Friedl C et al. Int J Nephrol Renovascular Dis. 2017;10:109–22.
  13. Wu W et al. Exp Dermatol. 2018;27:1201–09.
  14. Tomasello S. Diabetes Spectrum. 2008;21(1):19–25.
  15. Holick MF et al. J Clin Endocrinol Metab. 2011;96:1911–30.