This project seeks to improve the detection and characterization of various renal diseases by the development of new radioactive diagnostic agents and methods. Existing techniques using a gamma camera and dedicated computer can provide only qualitative images of the kidneys and estimates of glomerular filtration rates (GFR) and effective renal plasma flow (ERPF). This project will explore other aspects of renal function. The new agents to be developed include (1) analogues of Tc-99m mercaptoacetyltriglycine, with a high renal extraction to replace I-131 Hippuran for estimation of ERPF, (2) cationic small macromolecules (dextran, inulin) labeled with In-111 or Tc-99m to reflect alterations in the normal anionic charge of the glomerular membrane before deterioration of GFR, (3) In-111 or Tc-99m lysozyme for quantitation of catabolism of low molecular proteins by renal tubular cells, and (4) labeled analogues of cationic drugs to compare their renal tubular transport with that of existing radioactive anions in models of tubular dysfunction. The biodistribution of these new agents will be compared with conventional renal radiodiagnostic agents by plasma clearance, urinary excretion and serial camera imaging in normal rats, rabbits, dogs and Rhesus monkey. Detailed organ distribution in rats will be determined by direct tissue assay after sacrifice at various time intervals. Labeled cationic small macromolecules will be tried to detect the loss of anionic glomerular membrane charge in streptozotocin-induced diabetes in rats and after intravascular iodinated contrast media. The efficacy of various agents, including labeled lysozyme, will be compared in rats for the detection of nephrotoxicity from cyclosporin A and cisplatin. Angiotensin-converting enzyme inhibitors (captopril and de-esterified enalopril) will be evaluated for detecting unilateral renovascular hypertension, before the injection of different radiodiagnostic agents, in the 2-kidney, 1-clip rat model.
