Abstract P204: Acute Kidney Injury Prior To Pregnancy Induces Renal And Endothelial Dysfunction Which Predisposes Pregnant Rats To Adverse Pregnancy Outcomes

Abstract

Clinical data report an increase in adverse pregnancy outcomes in women with a history of AKI despite clinical recovery prior to pregnancy. We developed a rat model of pregnancy post-AKI in which female Sprague-Dawley (SD) rats recover normal creatinine clearance 30 days post-AKI, however, exhibit endothelial dysfunction, elevated plasma creatinine and fetal growth restriction (FGR) during pregnancy compared to sham. We hypothesized that AKI-induced endothelial dysfunction predisposes pregnant rats to adverse pregnancy events including renal dysfunction and FGR, and further, that sildenafil will ablate endothelial dysfunction and prevent AKI-induced FGR. Female SD rats were randomized to 45-minute warm bilateral renal ischemia reperfusion or sham (N=6-8/grp) and 15 days post-surgery were put on vehicle or sildenafil chow (50 mg/kg/day) and mated 30 days post sham/AKI surgery. Gestational day 1 (GD1) was determined via vaginal smear. Plasma and 24-hour urine collection, vascular and renal injury were analyzed in pre-pregnancy (30 days post-AKI/Sham) or late pregnancy (GD20). Although previous cohorts show creatinine clearance normalizes 30 days post-AKI, urine kidney injury marker-1 (KIM-1) was greater in AKI rats compared to sham after 30 days (580±169 pg/24hrs vs 257±17, P=0.09) which remained elevated at GD20 of pregnancy (283±28 vs 216±12, P=0.06). Mason Trichrome revealed increases in glomerular (0.93±0.08 vs 0.04±0.04 score, *P<0.05) and tubular fibrosis (1.7±0.19 vs 0.0±0.0, *P<0.05) in post-AKI pregnant rats at GD20 compared to sham. Endothelial-dependent relaxation to acetylcholine (ACh) in 3 rd order mesenteric arteries, measured by wire myography, was impaired in both 30-day post-AKI rats (concentration-response, 1nM-10μM, 2-w ANOVA, RM, *P<0.05) and in post-AKI GD20 groups (*P<0.05) compared to respective shams. Sildenafil treatment restored endothelial function at GD20 (P>0.05) and restored pup weights in post-AKI pregnant GD20 rats (1.18g±0.23 g vs 2.11±0.19, *P<0.05). Collectively, these data indicate that AKI induces endothelial dysfunction in female rats predisposing them to adverse renal adaptations and FGR in pregnancy, which is potentially prevented by improvement of endothelial function with sildenafil.