Genetic hypercalciuric stone-forming rats.

In humans, idiopathic hypercalciuria is associated with stone formation. In order to study the mechanisms that are responsible for excess urine calcium excretion, in ways that are difficult or impossible in humans, we have developed a rat model of hypercalciuria. Spontaneously hypercalciuric rats have been successively inbred for over 50 generations to produce a strain in which urine calcium excretion is over 10 times greater than that of controls, and all rats form kidney stones. Analysis of the model has revealed that the rats not only exhibit increased intestinal calcium reabsorption but an independent defect in renal tubular calcium resorption and an increased tendency for bone resorption. These findings closely parallel those in patients with idiopathic hypercalciuria. In the intestine, bone and kidney there is an increased number of vitamin D receptors which are hyperresponsive to 1,25-dihydroxyvitamin D3. Whether the increased number of vitamin D receptors is directly responsible for the hypercalciuria and whether the same abnormality is present in humans with idiopathic hypercalciuria is under investigation. Hypercalciuric rats appear to be an excellent model to provide insights into the mechanisms causing hypercalciuria, and to delineate treatments for stone disease.