LAUSR

Nature reviews | Nephrology Claudins are tight junction proteins that regulate the paracellular transport of solutes across epithelial layers. New findings demonstrate a role for the cationselective protein claudin 2 in regulating proximal tubule (Pt) calcium reabsorption and the formation of kidney stones. “Our premise, that it is defects in Pt calcium handling that lead to papillary calcification and hence kidney stone disease, represents a paradigm shift in thinking about tubular calcium handling, as the scientific community has previously focused on the distal tubule as the gatekeeper for calcium excretion,” explains alan Yu. “we are not the first to postulate the importance of the Pt in this process, but our study really strengthens this argument.” to assess the role of claudin 2 in calcium handling, Yu and colleagues looked at claudin 2-deficient mice. these mice were found to have hypercalciuria as a result of defective renal tubular calcium reabsorption and increased intestinal calcium absorption. the researchers also observed papillary nephrocalcinosis, with deposits resembling intratubular plugs. this resemblance prompted the researchers to examine genetic data, leading to the identification of common CLDN2 variants that were associated with decreased issue expression of claudin 2 and moderately associated with kidney stone disease risk in two large populationbased studies. in one family, they identified a rare missense variant of CLDN2 that was associated with hypercalciuria and kidney stone disease. Yu plans to further investigate the mechanisms by which claudin 2 affects calcium handling but say these insights could have consequences for treatment. “Our study suggests that interventions that increase Pt calcium reabsorption, and hence reduce calcium delivery to the papilla, might be effective at reducing stone incidence,” he says. Susan J. Allison S TO N E D I S E A S E