MECHANISMS OF CYCLOSPORINE NEPHROTOXICITY

The long-term goal is to elucidate the mechanisms responsible for functional abnormalities present in the early phase of cyclosporine-induced nephrotoxicity (CIN). The specific aims are: 1. To determine if the renal vasoactive hormones (renin-angiotensin, prostaglandin, and kallikrein-kinin systems) and/or the sympathetic nervous system mediate the reduced rates of filtration (GFR) and renal blood flow (RBF) characteristic of CIN. 2. To determine whether the glomerular capillary ultrafiltration coefficient (Kf) is reduced in CIN. A rat model of early CIN with both functional and histomorphologic characteristics similar to those in humans will be used. Measurements will be made in awake, chronically cyclosporine treated animals of daily GRF by inulin clearance and renovasoactive hormone activities in blood and urine. Also, measurements of GFR by clearance and RBF by electromagnetic flow probe will be made in anesthetized control and acutely cyclosporine-treated rats, both before and after acute pharmacologic blockade of angiotensin II, renal kinins, and renal prostaglandins by infusions of saralasin, indomethacin or aprotinin. The contribution of the sympathetic nervous system will also be evaluated by acute renal denervation studies. GFR and RBF will also be studied in rats simultaneously treated with cyclosporine and a specific blocker for 7 days. The determinants of glomerular ultrafiltration will be measured with standard micropuncture methodology in the chronic model of CIN. Hydrostatic pressures will be measured in proximal tubules and efferent arterioles, as well as in stop-flow nephrons. Nephron filtration rates and protein concentrations in systemic and efferent arteriolar plasma will be measured; arteriolar resistances and Kf will be derived. The results of this project will elucidate the mechanisms responsible for the functional abnormalities in early CIN. This information may provide a scientific basis for the design of effective therapeutic interventions to treat and prevent the adverse effects of this increasingly utilized immunosuppressant.