A patient with chronic renal failure (GFR 15 mL/min) develops secondary hyperparathyroidism. Which sequence of pathophysiological events correctly explains elevated PTH in CKD?

• A Reduced GFR → increased calcium reabsorption → hypercalcemia suppresses PTH → reactive hypersecretion after normocalcemia is restored
• B Tubular phosphate reabsorption falls → hypophosphatemia → inhibits PTH secretion → secondary parathyroid hyperplasia
• C Reduced GFR → hyperphosphatemia → hyperphosphatemia directly stimulates PTH secretion; also reduced 1α-hydroxylase in kidney → reduced calcitriol → impaired intestinal Ca²⁺ absorption → hypocalcemia → stimulates PTH ✓
• D PTH hypersecretion in CKD is caused solely by deficient calcitriol without involvement of phosphate

Explanation

In CKD, multiple mechanisms drive secondary hyperparathyroidism: (1) Reduced GFR → phosphate retention → hyperphosphatemia. Phosphate directly stimulates PTH secretion and parathyroid cell proliferation. It also reduces ionized calcium (Ca²⁺ × PO4 product). (2) Loss of renal tubular 1α-hydroxylase activity → reduced 1,25(OH)2D3 (calcitriol) → impaired intestinal Ca²⁺ and phosphate absorption → hypocalcemia. Calcitriol also directly suppresses PTH gene transcription; its deficiency removes this suppression. (3) Resulting hypocalcemia directly stimulates calcium-sensing receptors (CaSR) to release PTH. FGF-23 (elevated early in CKD) also contributes by suppressing 1α-hydroxylase. All three mechanisms (hyperphosphatemia, low calcitriol, hypocalcemia) synergistically elevate PTH.

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

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