The objective the proposed studies is to better define the factors that may predispose the obese patient and the cyclosporine A (Cys A) treated patient to F-induced nephrotoxicity. Ultimately, an understanding of the predisposing factors and identification of potentially detrimental interactions should prevent toxicity in the human clinical setting. Fischer 344 rats will be used as models of human obesity, chronic renal insufficiency and renal transplantation. Studies will determine if differences in serum F- concentrations following fluorinated anesthetic exposure in the rat model of obesity with or without mild or severe chronic renal insufficiency (CRI) could be related to intrinsic differences in F-elimination. To accomplish this, the F- distribution and elimination pharmacokinetics in obese and non-obese rats with CRI will be determined following bolus i.v. F- administration and chronic F- administration in drinking water. The apparent steady state serum F- concentration, renal and non-renal F- clearances will be calculated. Additional studies will determine whether the elimination of ISO or HAL is different among the rat models of obesity and CRI and possibly contributes to the observed differences in serum F- concentrations. Anesthetic uptake, disposition and elimination will be determined for chronic and acute exposures to ISO or HAL. ISO will be studied as it is the most commonly used volatile anesthetic in the U.S. with the potential to produce F--induced nephrotoxicity. HAL will be studied to determine, by comparison with ISO, the role of solubility in anesthetic elimination in obesity. As more transplant patients will be seen for surgery, both related and unrelated to transplantation, they comprise a significant population possibly at risk of F- induced nephrotoxicity. The potential for interaction between the nephrotoxins F- and Cys A has not been investigated. Studies are designed to determine the interaction of acute and chronic Cys A treatment and ISO anesthesia in renal transplantation. A renal transplantation model will reproduce the human clinical situation where ischemia and denervation are intrinsic to the transplantation surgery. The model consists of a unilateral nephrectomy and ischemia and renal denervation of the remaining kidney. Chronically or acutely Cys A-treated rats will be exposed to anesthetizing concentrations of ISO and serum F- and renal function and pathology will be determined.
