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Question Breakdown
Scenario: A 62-year-old man with prior MI and hypertension has his diuretic dose increased. His serum calcium rises after the adjustment. Which nephron segment does this diuretic act on?
The key clue is hypercalcemia (↑ serum Ca²⁺) caused by a diuretic.
Answer: Distal Convoluted Tubule (DCT) — labeled "A" in the diagram
The diuretic is a thiazide (e.g., hydrochlorothiazide or chlorthalidone), and its primary site of action is the early distal convoluted tubule (DCT1).
Mechanism Explained
How thiazides work at the DCT:
Thiazides block the NCC (Na⁺/Cl⁻ cotransporter) on the apical membrane of DCT cells. This:
- Inhibits Na⁺ and Cl⁻ reabsorption → natriuresis and diuresis
- Increases Ca²⁺ reabsorption in the DCT → hypercalcemia / hypocalciuria
Why does Ca²⁺ go up?
The mechanism is indirect:
- Blocking NCC lowers intracellular Na⁺
- This enhances basolateral Na⁺/Ca²⁺ exchange (NCX1), pulling more Ca²⁺ out of the tubular lumen into blood
- PTH also regulates Ca²⁺ reabsorption at this segment, amplifying the effect
- Result: less Ca²⁺ in urine → more Ca²⁺ in serum
"Thiazide and thiazide-like diuretics decrease the Ca²⁺ content of urine by promoting the reabsorption of Ca²⁺ in the distal convoluted tubule where parathyroid hormone regulates reabsorption." — Lippincott Illustrated Reviews: Pharmacology
"The major site of action of thiazide and thiazide-like diuretics is the distal convoluted tubule (DCT), where they block coupled reabsorption of Na⁺ and Cl⁻... reducing the excretion of calcium." — Brenner and Rector's The Kidney
Clinical Context
| Feature | Thiazide diuretics |
|---|---|
| Site of action | Distal convoluted tubule (DCT) |
| Na⁺ effect | ↑ excretion |
| K⁺ effect | ↑ excretion (hypokalemia) |
| Ca²⁺ effect | ↓ excretion → ↑ serum Ca²⁺ |
| Mg²⁺ effect | ↑ excretion |
| Uric acid | ↓ excretion (hyperuricemia) |
| Use in this patient | Hypertension (especially post-MI) |
Compare to loop diuretics (e.g., furosemide): these act on the thick ascending limb of the loop of Henle and increase Ca²⁺ excretion (hypocalcemia). The opposite effect on calcium is a classic exam discriminator.
Summary
The correct answer is the Distal Convoluted Tubule (DCT) — segment "A".
The diuretic is a thiazide, which blocks the NCC cotransporter at the DCT, uniquely causing hypocalciuria and hypercalcemia — exactly what this patient's labs show. This is why thiazides are also used therapeutically in hypercalciuria and nephrolithiasis (calcium oxalate stones).
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