A patient with chronic kidney disease stage 5 develops renal osteodystrophy characterised by high bone turnover (secondary hyperparathyroidism). Which is the correct sequence of pathophysiological events leading to elevated PTH?

• A Reduced GFR → phosphate retention → elevated serum phosphate → binds and lowers ionised Ca²⁺ + suppresses 1α-hydroxylase (reducing calcitriol) + directly stimulates PTH synthesis via PTH-FGF23 axis; hypocalcaemia and low calcitriol both stimulate parathyroid gland PTH secretion and hyperplasia ✓
• B Reduced GFR → metabolic acidosis → bone buffering releases Ca²⁺ → hypercalcaemia suppresses PTH → compensatory hypersecretion occurs after prolonged hypercalcaemia
• C Reduced GFR → hypermagnesaemia → inhibition of CaR on parathyroid cells → paradoxical PTH increase despite normal Ca²⁺
• D Reduced GFR → elevated Klotho (soluble) → blocks FGF23 receptors on the parathyroid → parathyroid escapes FGF23-mediated suppression → elevated PTH

Explanation

In CKD: (1) Phosphate retention (reduced renal excretion) raises serum phosphate, which directly lowers ionised Ca²⁺ by forming CaP complexes. (2) Reduced functional renal cortex (proximal tubule) decreases CYP27B1 (1α-hydroxylase) activity, reducing calcitriol (1,25-dihydroxyvitamin D3) production. (3) FGF23 (elevated early in CKD to drive phosphaturia) also directly suppresses 1α-hydroxylase further. Low calcitriol removes its inhibitory effect on PTH gene expression (calcitriol normally binds VDR in parathyroids to suppress PTH transcription). (4) Hypocalcaemia + reduced calcitriol both chronically stimulate parathyroid cell PTH secretion and gland hyperplasia → secondary hyperparathyroidism. Option D is reversed: soluble Klotho is reduced in CKD (not elevated), which is part of what blunts the FGF23 response.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.