Drug induced nephrotoxicity is a limiting factor in the therapeutic use of many drugs; however, factors that determine the extent of change of renal function are poorly understood. The central hypothesis of this proposal is that a nephrotoxin induces a primary effect on renal function. This results, under certain circumstances, in activation of regulatory mechanisms to increase smooth muscle tone in afferent arterioles, in mesangial cells in the glomerulus and efferent arterioles to decrease glomerular filtration rate (GFR). Amphotericin B has been chosen as a model drug for investigation of the mechanisms basad on the investigators prior experience with this drug, the demonstration that acute and chronic changes in GFR by amphotericin B can be modified and evidence that the nephrotoxic response can be modified in patients receiving amphotericin B. Four groups of studies are proposed. First, the acute GFR response to amphotericin B will be studied in the in situ renal perfusion model, with, when appropriate, renal cortical microcirculation studies, to test the hypotheses that i) differential effects of amphotericin B on the afferent arteriole, glomerulus and efferent arteriole change with salt depletion and salt loading ii) the response to amphotericin B can be modulated by adenosine, angiotensin II, arachidonic acid metabolites, cAMP activity, and/or changes in intracellular calcium. Second, a model of chronic amphotericin B nephrotoxicity in the rat will be used to evaluate the hypothesis that factors that modify acute changes in the GFR response also modify the chronic response, and determine mechanisms contributing to the sustained reduction in GFR. These studies will also include an evaluation of tubular back leak and renal tissue uptake of amphotericin B. Based on the demonstration that amphotericin B reduces the glomerular ultrafiltration coefficient, a third series of experiments will investigate the hypothesis that amphotericin B can stimulate contraction in isolated cultured mesangial cells via release of vasoconstrictor hormones. The clinical relevance of the ability to modify amphotericin B will be investigated in a fourth series of studies in man. A double-blind, randomized study will compare the renoprotective effect of parenteral sodium chloride versus dextrose supplementation during chronic amphotericin B therapy. Study groups will include patients with mucocutaneous leishmaniasis in Lima, Peru, who provide an opportunity to evaluate non-immunocompromised patients with normal renal function in whom amphotericin B is used as mono-therapy, and patients on cancer chemotherapy receiving amphotericin B for suspected systemic mycosis. It is anticipated that a better understanding of the mechanisms of reduction of GFR by amphotericin B can be used to design additional strategies for reducing the nephrotoxicity for this drug.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Toxicology Subcommittee 2 (TOX)
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University of Pittsburgh
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