The potentiation and alleviation of cyclosporin A nephrotoxicity in the Lewis rat
Cyclosporin A immunosuppression following organ transplantation is associated with a reversible nephrotoxicity as manifested by elevations in serum urea and creatinine concentrations and urinary N-acetyl-B-D-glucosaminidase activities. The metabolism of Cyclosporin A is primarily via the hepatic cytochrome P-450 mono-oxygenase system with previous studies having demonstrated that the short term co-administration of phenobarbitone, an inducer of this enzyme system, ameliorates this nephrotoxicity in the non-renal allografted rat. Initial studies demonstrated that the induction of Cyclosporin A nephrotoxicity in the Lewis rat followed by the co-administration of phenobarbitone in the long term abolished nephrotoxicity in the female whilst alleviating it in the male animal. In addition Cyclosporin A hepatotoxicity was also abolished in female rats co-treated with phenobarbitone. A rat renal transplantation model was successfully developed to allow the study of Cyclosporin A nephrotoxicity in the renal allografted animal. Initial studies demonstrated a protective effect of phenobarbitone against Cyclosporin A nephrotoxicity within the first 14 days of treatment in female, but not male allografted animals. These studies also demonstrated a greater susceptibility of the male renal allografted and surgically intact rat to Cyclosporin A induced nephrotoxicity. The effect of ischaemia and sympathetic nervous system denervation were investigated using a series of Lewis syngeneic renal transplanted animals. Histological examination revealed Cyclosporin A induced renal damage to be more marked in non-transplanted than transplanted kidneys. The results are discussed in relation to cold and warm ischaemia and also to the role of the sympathetic nervous and renin-angiotensin-aldosterone systems in the potentiation of Cyclosporin A induced nephrotoxicity. The effect of long term phenobarbitone treatment on Cyclosporin A induced deteriorations in renal and hepatic function was determined using the Lewis syngeneic transplant model. The effect of intraoperative liver ischaemia and diethyl ether anaesthesia on hepatic function and their potentiation of Cyclosporin A hepatotoxicity is also considered. Finally the role of surgical stress and reduction of renal mass by unilateral nephrectomy, on Cyclosporin A nephrotoxicity was studied revealing a protective effect of unilateral nephrectomy against nephrotoxicity in the female animal. Previous studies have demonstrated that reduction in renal mass results in glomerulosclerosis with a progressive impairment of renal function. The protective effect of unilateral nephrectomy reported here is discussed in relation to a Cyclosporin A induced reduction in glomerular filtration rate and subsequent protection against glomerulosclerosis.