The applicant is a Diplomate of the American Board of Internal Medicine, with five years of postgraduate training in internal medicine and nephrology. For the past two years he has been a recipient of a National Kidney Foundation Fellowship Grant. This proposal is an extension of the work performed as a NKF Fellow. Cisplatin is a wisely used chemotherapeutic agent in the treatment of solid tumors. The chief limit to its greater efficacy is its dose related nephrotoxicity. Co-administration of cisplatin with various agents can reduce the severity of renal failure. Until a more basic understanding of the mechanism by which cisplatin reduces GFR is obtained it may not be possible to more effectively prevent the renal failure. Following a single 5mg/kg dose of cisplatin in the rat, glomerular filtration begins to fall over the next 48-72 hours. Using micropuncture, we plan to measure the glomerular hydro-os-motic forces in the Munich-Wistar rat 72 hours following cisplatin. We can then quantitate the changes in renal resistance, trans-glomerular hydrostatic pressure difference, and glomerular capillary ultrafiltration coefficient to the observed fall in GFR. These studies performed in rats pretreated with mannitol, furosemide or hypertonic saline will allow us to test directly the ways in which these agents ameliorate the renal failure. Additional studies in hydrated and non-hydrated cisplatin rats treated with various inhibitors of prostaglandin synthesis will assess the role of prostaglandins in producing or modifying the reduced GFR. We will test the role of the tubulo-glomerular feedback system in contributing to the reduced GFR. We will determine whether abnormal responses to vasoconstrictors or changes in renal perfusion pressure precede the fall in GFR, and whether such changes are important in determining the level to which the GFR falls. We will also determine whether such response are specific for the adrenergic system, renin-angiotensin system, or are prostaglandin dependent. All work will be performed in a fully equipped micropuncture laboratory in a medical school Department of Medicine. The applicant's sponsor is a recognized authority in renal physiology, micropuncture, and cisplatin nephrotoxicity. The Division of Nephrology is comprised of experienced faculty committed to research, teaching and excellence in clinical medicine. This proposal will provide the applicant with an appropriate mix of independent research, supervision and peer review to help him develop into an experienced, independent investigator.
| Winston, J A; Feingold, R; Safirstein, R (1989) Glomerular hemodynamics in cyclosporine nephrotoxicity following uninephrectomy. Kidney Int 35:1175-82 |
