Defect In Calcium Reabsorption Research Articles

Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease.

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2-null mice have hypercalciuria due to a primary defect in renal tubule calcium transport and papillary nephrocalcinosis that resembles the intratubular plugs in kidney stone formers. Our findings suggest that a proximal tubule defect in calcium reabsorption predisposes to papillary calcification, providing support for the vas washdown hypothesis. Claudin-2-null mice were also found to have increased net intestinal calcium absorption, but reduced paracellular calcium permeability in the colon, suggesting that this was due to reduced intestinal calcium secretion. Common genetic variants in the claudin-2 gene were associated with decreased tissue expression of claudin-2 and increased risk of kidney stones in 2 large population-based studies. Finally, we describe a family in which males with a rare missense variant in claudin-2 have marked hypercalciuria and kidney stone disease. Our findings indicate that claudin-2 is a key regulator of calcium excretion and a potential target for therapies to prevent kidney stones.

Hypercalciuria and Hematuria

Hypercalciuria in children is diagnosed when the urinary calcium excretion is greater than 4.0 mg/kg in 24 hours, the ratio of urinary concentration of calcium to creatinine (UCa/UCr) is greater than 0.20, and there is normal serum calcium. Hypercalciuria may be the result of increased intestinal absorption of calcium (absorptive hypercalciuria) or an impaired proximal tubular defect in calcium reabsorption (renal hypercalciuria). Oral calcium load tests will differentiate the two types of hypercalciuria. Elevated fasting UCa/UCr with normal levels of parathormone (PTH) or urinary cyclic-AMP indicates renal hypercalciuria. After an oral calcium load, the UCa/UCr ratio will be greater than normal in absorptive hypercalciuria. However, Hymes and Warshaw suggest that both subtypes may coexist in some patients.