The goal of this project is to improve the detection and characterization of various renal diseases by the development of new radioactive agents and new non-invasive radioisotopic methods. They will be evaluated chiefly in models of human renal diseases in rats compared with controls. Existing clinical techniques using a gamma camera and dedicated computer can provide only qualitative images of the kidneys and stimates of glomerular filtration rates (GFR) and effective renal plasma flow (ERPF). This project will explore other aspects of renal function. Hemostatic abnormalities are thought to play an important role in the progression of several important renal diseases, particularly diabetes mellitus and membranoroliferative glomerulonephritis. In rat models of these human diseases, we will assess the survival and renal uptake of radiolabeled platelets and determine whether or not """"""""antiplatelet therapy"""""""" with aspirin and dipyridamole will arrest the deterioration renal function compared with untreated animals. New radiopharmaceuticals we plan to develop include (1) analogs of mercaptoacetyltriglycine (MAG3) for chelation with Tc-99m as a substitute for I-131 hippuran with a comparable high renal extraction efficiency and (2) small macromolecules such as dextran and lysozyme coupled with cationic polyethyleneimines or labeling with Tc-99m and In-111. We will explore the application of these cationic macromolecules to demonstrate the decrease in the normal anionic charge of the glomerular basement membrane (GBM) which occurs early in several important renal diseases. We will assess the distribution of these radiolabeled macromolecules in rat models of these human diseases compared with conventional renal radiodiagnostic agents such as Tc-99m DTPA and I-131 hippuran. We propose to study the altered clearance and organ distribution of renal adiodiagnostic agents in pre-renal azotemia induced by interleukin-2 in rats. Because of the abnormal capillary permeability and resultant fluid shift from plasma volume to extravascular spaces, conventional measurements of GFR and ERPF by single injection of c-99m DTPA and I-131 hippuran respectively are rendered invalid. Hence, these agents will be administered by continuous infusion and I-125 albumin will be administered to provide an """"""""index of capillary permeability"""""""" for the major organs. Intraventricular injections of radiolabeled microspheres will be used to measure the changes in blood low to the major organs in this toxic state. The nephrotoxicity of high- and low-molality intravascular radiographic contrast media will be compared in rats with two models of induced renal lesions--unilateral ischemia, and bilateral tubular dysfunction induced wit platinol.
