Hope of slowing the progression of renal disease has stimulated investigation into the mechanisms responsible for glomerular injury. A useful model is the rat subjected to partial nephrectomy. In this model, removal of a large portion of the renal mass results in elevation of the glomerular filtration rate in the remaining nephrons, due to increases in the glomerular capillary plasma flow rate and transcapillary hydraulic pressure gradient (delta P). These hemodynamic changes appear to be maladaptive, in that they are associated with progressive hypertension (HTN), proteinuria, and glomerular sclerosis. Therapeutic interventions which attenuate these hemodynamic changes (in particular, reduction in delta P) slow the progression of experimental renal disease. One factor which contributes to delta P is hematocrit; increasing hematocrit augments, and lowering of hematocrit lessens, systemic and glomerular HTN in rats with partial renal ablation. Patients with renal disease typically have low values for hematocrit. While anemia may have adverse systemic effects, correction of anemia often results in HTN. Anemia may in fact be a favorable renal adaptation, in that prevention of anemia in partially nephrectomized rats leads to aggravation of systemic and glomerular HTN, and acceleration of proteinuria and glomerular injury. This proposal will study the role of hematocrit and systemic and glomerular HTN in a number of experimental models of progressive renal disease. Renal disease is also accompanied by proteinuria. It has been suggested that interventions which reduce proteinuria do so by lowering delta P, but inability to measure delta P in humans has made interpretation of these observations difficult. Fractional clearance measurements of exogenous macromolecules provide an effective means of examining changes in proteinuria which accompany hemodynamic or structural changes. Using measurements of hemodynamic factors, including delta P, and fractional macromolecular clearances in the rat, we propose to derive methods for inferring delta P from hemodynamic parameters which can ultimately be applied in humans. Together, these approaches promise to provide important new strategies for the treatment of patients with renal disease, as well as useful methods for assessing efficacy of therapy.
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