This proposal seeks to elucidate the pathophysiology of and evaluate novel therapy for pre-eclampsia toxemia (PET) and the HELLP syndrome. This pregancy-induced injury to glomerular endothelial cells represents the most common form of, and will be used as a prototypic model for, the hemolytic-uremic syndrome. We will examine 125 continuous consenting patients with PET, of whom half are predicted to manifest also the HELLP syndrome. Forty healthy mothers will serve as controls. To avoid exposing the fetus to any hazards, all studies will be performed in the early puerperium, beginning immediately after parturition. We wish to test four main hypotheses. Hypothesis #1 is that PET/HELLP lowers the GRF by depression of the ultrafiltration coefficient, owing mainly to endothelial cell swelling with obliteration of fenestrae. A renal biopsy will be performed to examine glomerular structure morphometrically, including fenestral number and radius by scanning electron microscopy. Filtration surface area (S) will be computed, and hydraulic permeability (k) estimated, using a novel hydrodynamic model of viscous flow. Hypothesis #2 is that depression of the transcapillary hydraulic pressure gradient may aggravate hypofiltration. GRF, renal plasma flow (RPF) and oncotic pressure will be determined with optimal physiological techniques. A mathematical model of ultrafiltration will then be used. Hypothesis #3 is that altered filtration dynamics and capacity are associated with deranged release of endothelial-derived vasoactive factors (EDVF), resulting in nitric oxide (NO) deficiency and endothelin-1 (ET-1) excess. We will use the excretion rate per ml GFR as a measure of nephrogenous production of NO, cGMP and ET-1. We will supplement this measure with corresponding determinations of plasma levels and the generation rate of each EDVF in vitro from umbilical cord vessels. We will also perform in situ hybridization of renal tissue to evaluate possible down- and upregulation of NO and ET-1, respectively from the amount and distribution of mRNA for NO synthase and ET converting enzyme. Hypothesis #4 is that enhancing NO production with L-arginine or blocking ET-1 with a receptor antagonist will enhance recovery of glomerular injury over the first four postpartum days. To test this hypothesis we will randomize successive groups of 60 PET subjects to a controlled trial with each agent vs a placebo. In addition to providing potential novel therapies, these perturbations will provide further insights into possible roles for NO and ET-1 excess in the genesis of PET/HELLP.
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