A 28-year-old man with a history of recurrent kidney stones presents with flank pain. Serum calcium is 10.2 mg/dL (normal), but 24-hour urine calcium is 450 mg/day (normal <300 mg/day). To determine the site of abnormal calcium reabsorption in the nephron, which investigation would be most appropriate?

Explanation

## Localization of Hypercalciuria via Fractional Excretion **Key Point:** Fractional excretion of calcium (FECa) and response to thiazide diuretics can differentiate the nephron segment responsible for abnormal calcium handling. ### Pathophysiology of Hypercalciuria Calcium reabsorption occurs in three main segments: 1. **Proximal convoluted tubule (PCT)** — 65% reabsorbed (paracellular, linked to sodium) 2. **Thick ascending limb (TAL)** — 25% reabsorbed (paracellular, voltage-driven) 3. **Distal convoluted tubule (DCT)** — 8–10% reabsorbed (transcellular, active transport via TRPV5) ### Diagnostic Approach Using FECa $$FECa = \frac{[Urine\,Ca] \times [Serum\,Cr]}{[Serum\,Ca] \times [Urine\,Cr]} \times 100$$ | **Type of Hypercalciuria** | **FECa** | **PTH** | **Thiazide Response** | **Defect Site** | |---|---|---|---|---| | **Absorptive** | High (>0.2%) | Normal | Excellent ↓ urine Ca | PCT (↑ intestinal absorption) | | **Renal leak** | Very high (>0.4%) | ↑ (secondary) | Excellent ↓ urine Ca | TAL/PCT (↓ reabsorption) | | **Resorptive** | High | ↑ (primary) | Poor response | Bone (PTH-mediated) | **High-Yield:** Thiazide diuretics block the Na-Cl cotransporter in the DCT, which indirectly enhances calcium reabsorption in the TAL (by reducing distal sodium delivery and maintaining the positive voltage gradient). This reduces urine calcium in absorptive and renal leak types but NOT in resorptive hypercalciuria (where PTH is primary driver). ### Clinical Pearl In this patient: - Normal serum Ca + high urine Ca = absorptive or renal leak hypercalciuria - FECa will be elevated (>0.2%) - Thiazide challenge will confirm the diagnosis and guide treatment (thiazides are first-line for absorptive and renal leak types) **Clinical Pearl:** Thiazide response is **pathognomonic** for defective renal calcium reabsorption (absorptive or renal leak), distinguishing these from primary hyperparathyroidism (resorptive type).