An injury of the renal tubule, characterized in part by backleak of glomerular filtrate across necrotic tubule epithelium, has been shown to be a major determinant of postischemic acute renal failure (ARF) in experimental animals. This proposal seeks to determine whether constituents of glomerular filtrate to which the tubule is normally impermeable also diffuse across the tubule wall in postischemic ARF in man. Total but transient renal ischemia (TRI) is commonly used to induce experimental ARF. We propose, therefore, to study patients in whom the aorta is occluded by a clamp above the level of the renal arteries during the performance of aortic surgery. Two, 24 and 96 hours following release of the clamp, inulin and dextran 40 will be infused; subsequently collected plasma and urine will be submitted to gel permeation chromatography (GPC) to ascertain the fractional clearance profile for dextrans relative to inulin (OD). We have previously observed that OD for fractions with radii (r) 20 to 30 Angstroms are frequently elevated above unity in patients with ARF, a finding that is best reconciled with backleak from the tubule of smaller inulin molecules (r=14 Angstroms) at a rate more rapid than that of the larger dextran molecules. We now propose to examine for this phenomenon in patients who develop ARF following aortic occlusion. A mass conservation model, which assumes that OD in Bowman's space in ARF is the same as that in non-azotemic postoperative controls, will be applied to the experimental findings to permit calculation of the fractional backleak of inulin and of individual dextran molecules of the ith radius. In a parallel series of studies of rodent ARF induced by TRI, we propose to characterize the permselective properties of the injured tubule by determining the fractional recovery in urine (following GPC) of dextran molecules (r=12 to 40 Angstrom) microinjected directly into the proximal tubule. A size-dependent backleak similar to that inferred from the indirect approach in man will enhance the analogy between postischemic rodent and human ARF. The potential to attenuate rodent ARF in the laboratory may then be expected to yield information pertinent to developing an effective therapeutic strategy for human ARF, which remains a highly lethal entity.
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