This proposal seeks to elucidate the pathophysiology of and evaluate novel therapy for pre-eclamptic toxemia (PET). This pregnancy-induced disease represents the commonest form of injury to glomerular endothelial cells in humans. They 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. They wish to test four main hypotheses. 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 performed to examine glomerular structure morphometrically, including fenestral density and dimensions and scanning electron microscopy. The investigators are highly productive and are attempting to provide semi-quantitative information concerning the glomerular filtration barrier in an important clinical renal disease. 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 (delta P) may aggravate hypofiltration. GFR, renal plasma flow (RPF) and oncotic pressure (pi A) will be determined with optimal physiological techniques. A mathematical model of ultrafiltration will then be used to compute delta P from GFR, RPF, pi A, S, and k. Hypothesis #3 is that altered filtration dynamics and capacity are associated with deranged release of endothelial-derived vasoactive factors resulting in nitric oxide (NO) deficiency and endothelin-1 (ET-1) excess. They will use the urinary excretion rate as a measure of nephrogenous production of NO, cGMP, and ET-1. They will supplement this measure with an assessment of responsiveness of filtration dynamics in PET versus controls to acute blockade of NO synthesis by infusion of L-NMMA, and by estimating levels in serum of the endogenous NO synthase inhibitor, ADMA. They 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, they will randomize 70 PET subjects to a controlled 10-15 day trial with L-arginine versus 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.
| Lafayette, R A; Hladunewich, M A; Derby, G et al. (2011) Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia. Clin Nephrol 75:226-32 |
| Hladunewich, M A; Myers, B D; Derby, G C et al. (2008) Course of preeclamptic glomerular injury after delivery. Am J Physiol Renal Physiol 294:F614-20 |
| Hladunewich, M A; Derby, G C; Lafayette, R A et al. (2006) Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial. Obstet Gynecol 107:886-95 |
| Hladunewich, M A; Lafayette, R A; Derby, G C et al. (2004) The dynamics of glomerular filtration in the puerperium. Am J Physiol Renal Physiol 286:F496-503 |
| Lafayette, R A; Druzin, M; Sibley, R et al. (1998) Nature of glomerular dysfunction in pre-eclampsia. Kidney Int 54:1240-9 |
