Response of genetic hypercalciuric rats to a low calcium diet. A fundamental mechanism for hypercalciuria in genetic hypercalciuric rats appears due to a primary increase in intestinal calcium absorption. However previous studies could not exclude additional mechanisms to account for the hypercalciuria. To determine if enhanced bone mineral dissolution either as a primary abnormality or secondary to a defect in renal tubule calcium reabsorption is responsible for a component of the augmented calcium excretion we studied rats continually inbred for hypercalciuria. Nineteenth generation adult female idiopathic hypercalciuric (IH) and non-inbred control (Ctl) rats were fed 13 g/day of a normal calcium diet (0.6% calcium, NCD) for 10 days. Urine calcium excretion over the last seven days was greater in IH (34 ± 2 mg/7 day) than in Ctl (2.9 ± 0.3, P < 0.01) rats. Some rats in each group were continued on the same diet while others were fed a low calcium diet (0.02% calcium, LCD) for an additional 10 days; balance measurements were made over the final seven days. With LCD, urine calcium excretion was ∼8-fold higher in IH compared to Ctl (13 ± 2 mg/7 day vs. 1.6 ± 0.1, IH vs. Ctl, respectively, P < 0.01). In IH rats percent calcium absorption was greater (59 ± 3% vs. 45 ± 3, IH vs. Ctl, P < 0.01), however calcium retention was negative (-1.9 ± 2.0 mg/7 day vs. 6.5 ± 0.5, IH vs. Ctl, P < 0.01) compared to Ctl rats. The fall in urine calcium excretion when IH rats are fed LCD indicates that enhanced intestinal calcium absorption is a primary mechanism of the hypercalciuria. However, the continued hypercalciuria and negative calcium retention during LCD indicates that an additional mechanism of hypercalciuria leads to a loss of bone mineral. Whether this additional mechanism is a primary bone resorptive process or due to an inability to conserve urinary calcium remains to be determined.