A new model of nephrolithiasis involving tubular dysfunction/injury.

To better understand the pathogenesis of nephrolithiasis, we developed a new animal model that closely mimics human calcium oxalate stone disease. Rats were treated with a regimen that combines moderate hyperoxaluria (produced by 10 days of feeding with 3% ammonium oxalate) with mild proximal tubular injury/dysfunction (produced by 8 daily injections of gentamicin sulfate -40 mg./kg.). This combined treatment caused a marked increase in the incidence of calcium oxalate crystals and stones over that seen in animals treated with oxalate or gentamicin alone. Using a semiquantitative scoring system for estimating the abundance of crystals in coronal sections of kidneys, we found that 63% of animals receiving gentamicin plus oxalate showed "moderate" numbers of crystal, as compared to 8% of animals receiving oxalate alone; and the majority of the crystals occurred in the papilla, a pattern similar to that seen in human stone disease. Untreated rats and rats treated with gentamicin alone did not exhibit calcium oxalate crystals or stones. Despite the abundance of crystals and stones, animals receiving gentamicin plus oxalate retained relatively normal renal function as judged by creatinine clearance. Thus, the model has several advantages over preexisting models of nephrolithiasis. Crystal and stone deposition develop rapidly (within 14 days). The pattern of deposition resembles that seen in human stone disease and renal function remains relatively normal. These findings indicate that this model of nephrolithiasis may prove useful for studies of the pathogenesis of stone disease. Moreover, they suggest that renal tubular injury and/or dysfunction may produce conditions conducive to the formation and growth of calcium oxalate stones.