Correct Answer: D. It increases calcium reabsorption in the distal convoluted tubule, leading to a decrease in urinary calcium excretion.
Hydrochlorothiazide (HCTZ) is a thiazide diuretic that paradoxically reduces urinary calcium excretion despite being a diuretic. The mechanism is specific to the distal convoluted tubule (DCT), where thiazides block the Na-Cl cotransporter (NCC). This blockade causes mild volume depletion and hypokalemia, which triggers compensatory mechanisms: increased proximal tubular reabsorption of sodium and calcium (secondary to volume contraction), and enhanced calcium reabsorption in the DCT itself through increased activity of the basolateral Na-Ca exchanger. The net result is decreased urinary calcium (hypocalciuria), which reduces the driving force for calcium oxalate and calcium phosphate stone formation. This mechanism is why HCTZ is specifically recommended in Indian guidelines (and internationally) for recurrent calcium nephrolithiasis with hypercalciuria. The effect takes weeks to manifest clinically and is independent of the diuretic's blood pressure-lowering action. This is distinct from loop diuretics (furosemide), which increase urinary calcium and promote stone formation.
Why the other options are wrong
A. It directly dissolves existing calcium stones by altering urinary pH and increasing their solubility. — This is wrong because HCTZ does not dissolve pre-formed stones; it is preventive, not therapeutic for existing calculi. HCTZ does not significantly alter urinary pH. Dissolution of calcium stones requires alkalization (e.g., potassium citrate for calcium oxalate), not the mechanism of HCTZ. This option confuses stone dissolution with stone prevention. B. It increases the urinary excretion of citrate, which acts as a chelating agent. — This is wrong because HCTZ does not increase urinary citrate excretion; in fact, hypokalemia caused by HCTZ can reduce citrate excretion (citrate is reabsorbed in the proximal tubule when K+ is low). While citrate is indeed a stone inhibitor, this is not the mechanism of HCTZ. Potassium citrate supplementation increases citrate, not HCTZ. C. It increases the filtration of calcium at the glomerulus, thereby reducing serum calcium levels. — This is wrong because HCTZ does not increase glomerular filtration of calcium; it actually decreases urinary calcium by enhancing reabsorption. HCTZ does not significantly lower serum calcium in most patients. This option reverses the actual mechanism and confuses the site of action (glomerulus vs. DCT)—a classic NBE trap for students who know HCTZ is a diuretic but misunderstand its calcium-sparing effect.
High-Yield Facts
- Thiazide diuretics decrease urinary calcium (hypocalciuria) via enhanced DCT reabsorption, making them first-line for recurrent calcium nephrolithiasis with hypercalciuria.
- Loop diuretics (furosemide) increase urinary calcium (hypercalciuria) and promote stone formation—opposite effect to thiazides.
- Hypokalemia from HCTZ reduces urinary citrate excretion, which may paradoxically increase stone risk; potassium supplementation is often co-prescribed.
- HCTZ mechanism in DCT: NCC blockade → volume depletion → increased proximal Ca reabsorption + enhanced basolateral Na-Ca exchanger activity.
- Clinical timeline: HCTZ effect on stone prevention takes 4–6 weeks; serum calcium remains normal in most patients despite reduced urinary excretion.
Mnemonics
HCTZ ↓ Urine Ca (Thiazide Paradox) Hypovolemia → Calcium reabsorption ↑ in DCT → Zero calcium in urine (hypocalciuria). Remember: Thiazides are the only diuretics that reduce urinary calcium. Loop vs. Thiazide Calcium Effect Loop = Lose Ca (hypercalciuria, stone risk ↑). Thiazide = Trap Ca (hypocalciuria, stone risk ↓). Use when comparing diuretic classes in stone prevention.
NBE Trap
NBE pairs "diuretic" with "increased excretion" to trap students who assume all diuretics increase urinary losses of all solutes. HCTZ is the exception: it decreases urinary calcium despite being a diuretic—a counterintuitive mechanism that tests deeper understanding of renal physiology.
Clinical Pearl
In Indian clinical practice, a patient with recurrent calcium oxalate stones and hypercalciuria is started on HCTZ 25 mg daily with potassium supplementation (to prevent hypokalemia-induced citrate loss). Urine calcium drops from >300 mg/day to <200 mg/day within 4–6 weeks, significantly reducing stone recurrence risk—this is why HCTZ is preferred over loop diuretics in stone-forming patients.
_Reference: Guyton & Hall Physiology Ch. 27 (Renal Handling of Calcium); KD Tripathi Pharmacology Ch. 12 (Diuretics); Harrison Principles of Internal Medicine Ch. 279 (Nephrolithiasis)_