This proposal seeks to elucidate the pathophysiology of and evaluate novel therapy for pre-eclampsia toxemia (PET). This pregnancy-induced disease represents the commonest form of injury to glomerular endothelial cells in humans. We will examine 100 consecutive consenting patients with PET. Fifty healthy mothers will serve as controls. To avoid exposing the fetus to any hazards, studies involving pharmacological perturbations and renal biopsies will be performed in the early puerperium. We wish to test four main hypothesis. Hypothesis #1 is that PET lowers the GFR by depression of the ultrafiltration coefficient, Kf owing mainly to obliteration of endothelial fenestrae. A renal biopsy will be examined morphometrically to determine filtration surface area(s) and to compute the hydraulic permeability (k), using a novel hydrodynamic model of viscous flow. Hypothesis #2 is that depression of the transcapillary hydraulic pressure gradient (P) may aggravate hypofiltration. GFR, renal plasma flow (GFR) and oncotic pressure (pA) will be determined with optimal physiological techniques. A mathematical model of ultrafiltration will then be used to compute P from GFR, RPF, pA, S and k. 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 urinary excretion rate as a measure of nephrogenous production of NO, cGMP and ET-1. We will supplement this measure with an assessment of responsiveness of filtration dynamics in PET vs controls to acute blockade of NO synthesis by infusion of L-NMMA, and estimating levels in serum of the endogenous NO synthase inhibitor ADMA. 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 L-arginine supplementation will reverse pregnancy-associated hypoargininemia, and increase the L-arginine/ADMA plasma ratio. Thereby enhancing NO production and promoting recovery of glomerular injury. To test this hypothesis we will randomize 70 PET subjects to a controlled 10-15 day trial with L-arginine vs placebo. An evaluation of glomerular function and structure at the end of therapy on postpartum day 10 will be used to assess the efficacy of such therapy.
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