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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK029985-05
Application #
3229181
Study Section
General Medicine B Study Section (GMB)
Project Start
1981-08-01
Project End
1989-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Squarer, A; Lemley, K V; Ambalavanan, S et al. (1998) Mechanisms of progressive glomerular injury in membranous nephropathy. J Am Soc Nephrol 9:1389-98
Ambalavanan, S; Fauvel, J P; Sibley, R K et al. (1996) Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy. J Am Soc Nephrol 7:290-8
Alejandro, V S; Nelson, W J; Huie, P et al. (1995) Postischemic injury, delayed function and Na+/K(+)-ATPase distribution in the transplanted kidney. Kidney Int 48:1308-15
Vinot, O; Bialek, J; Canaan-Kuhl, S et al. (1995) Endogenous ANP in postischemic acute renal allograft failure. Am J Physiol 269:F125-33
Alejandro, V; Scandling Jr, J D; Sibley, R K et al. (1995) Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft. J Clin Invest 95:820-31
Guasch, A; Myers, B D (1994) Determinants of glomerular hypofiltration in nephrotic patients with minimal change nephropathy. J Am Soc Nephrol 4:1571-81
Ting, R H; Kristal, B; Myers, B D (1994) The biophysical basis of hypofiltration in nephrotic humans with membranous nephropathy. Kidney Int 45:390-7
Myers, B D; Sommer, F G; Li, K et al. (1994) Determination of blood flow to the transplanted kidney. A novel application of phase-contrast, cine magnetic resonance imaging. Transplantation 57:1445-50
Drumond, M C; Kristal, B; Myers, B D et al. (1994) Structural basis for reduced glomerular filtration capacity in nephrotic humans. J Clin Invest 94:1187-95
Canaan-Kuhl, S; Venkatraman, E S; Ernst, S I et al. (1993) Relationships among protein and albumin concentrations and oncotic pressure in nephrotic plasma. Am J Physiol 264:F1052-9

Showing the most recent 10 out of 27 publications