Purpose: Unraveling the mechanisms leading to clinically active calcium oxalate (CaOx) stone disease and the development of effective medical therapies to treat it have been hampered by the lack of appropriate animal models. To address this problem we developed a model of hyperoxaluria and calcium oxalate crystal deposition by implanting osmotic minipumps subcutaneously into male rats, that is minipump induced hyperoxaluria and crystal deposition in rats. Materials and Methods: Male Harlan-Sprague Dawley rats (225 to 290 gm) were implanted subcutaneously with 1-week 2 ml osmotic minipumps containing 1.5 M potassium oxalate (360 muM KOx/24 hours, [KOx-trt], 11) or phosphate buffered saline (PBS-trt, 9) on days 1 and 7. The 24-hour urine collections were performed on days 0, 4, 7, 11 and 14. Data were analyzed by ANOVA and Tukey's HSD. Urinary crystals were analyzed by light microscopy. Kidneys were harvested on day 14 and processed for light and polarizing microscopy, and RNA analysis. Results: Mean overall creatinine excretion +/- SEM (PBS-trt 107 +/- 7 and KOx-trt 123 +/- 6 muM/24 hours, p > 0.07) and day 14 serum creatinine (PBS-trt 83 +/- 4 and KOx-trt 83 +/- 5 muM, p greater than or equal to 0.9) were similar in the 2 treatment groups. Overall urinary volume (PBS-trt 11.3 +/- 0.8 and KOx-trt 18.0 +/- 1.5 ml/24 hours, p less than or equal to 0.001) and oxalate (OX) excretion (PBS-trt 9.2 +/- 0.6 and KOx-trt 44 +/- 4.2 muM/24 hours, p less than or equal to 0.001) were higher in KOx-trt vs PBS-trt rats. In KOx-trt rats OX excretion on day 0 was significantly less than on any day after implantation (p less than or equal to 0.01). All KOx-trt rats excreted calcium oxalate dihydrate crystals by day 4 and had intrarenal deposits of bireftingent crystals by day 14. Overall the morphology of kidneys of OX rats was normal, although localized regions of inflammation and tubular debris were occasionally observed. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that the expression of 3 distress molecules tumor necrosis factor receptor, osteopontin and kidney injury molecule were up-regulated in KOx-trt kidneys. Conclusions: The model of minipump induced hyperoxaluria and crystal deposition in rats reliably induces hyperoxaluria, CaOx crystalluria and CaOx crystal deposition. These characteristics make it an appropriate model for investigations of the effects of OX on renal physiology as well as investigating the efficacy of new therapeutics.
