Acute kidney injury causes subclinical renal and endothelial injury in female rats which predisposes to adverse outcomes of pregnancy

Clinical data report a 3-5-fold increase in adverse pregnancy outcomes, including preeclampsia and small for gestational age neonates, among women with a history of acute kidney injury (AKI) despite clinical recovery of renal function. We developed a rat model of pregnancy post-AKI: Sprague-Dawley (SD) rats undergo a bilateral renal-ischemia reperfusion and fully recover renal function as measured by creatinine clearance 30 days post-AKI. Rats are then mated and during pregnancy recovered AKI rats exhibit decreased creatinine clearance, increased uterine artery resistance, reduced plasma volume expansion, and decreased fetal growth compared to pregnant rats that received sham surgery. Healthy pregnancy demands robust renal and vascular adaptations. Whether subclinical renal and vascular injury persists following AKI in females, and whether this is exacerbated in pregnancy to drive the adverse pregnancy outcomes remains unknown. We tested the hypothesis that AKI results in subclinical renal and vascular injury that lingers into pregnancy. Female SD rats were randomized to 45-minute warm bilateral renal ischemia reperfusion or sham (N=6-8/grp) and renal and vascular injury assessments were made 30 days post-AKI/Sham (pre-pregnancy) or during pregnancy on gestational day 20 (GD20). Pre-pregnancy urine volume measured via metabolic cage was greater in post-AKI rats compared to sham (10±1 vs 21±2 ml/daily urine, p<0.05). Urinary kidney injury marker-1 (KIM-1) measured via ELISA 30 days post-AKI/Sham was greater in pre-pregnant AKI rats compared to sham (9685±871 vs. 6399±198 pg/24 hrs urine, p<0.05). Vascular function, measured via wire myography on 3rd order mesenteric arteries 30 days post-AKI/Sham, revealed decreased endothelial-dependent relaxation to acetylcholine (ACh) (concentration-response, 1 nM-10 μM, 2-way ANOVA, RM, *p<0.05). GD20 urine volume (31±5 vs 19±2 ml/daily urine, p<0.05) and KIM-1 levels (9125±673 vs 6380±297 pg/daily urine, p<0.05) were elevated in post-AKI pregnant rats compared to sham pregnant rats. Mason Trichrome renal staining revealed greater glomerular fibrosis (0.93±0.08 vs 0.04±0.04, *p<0.05) and tubular fibrosis (1.7±0.19 vs 0.0±0.0, *p<0.05) in post-AKI pregnant rats vs. sham pregnant. Ultrastructural changes to the kidneys were evaluated via electron microscopy and further revealed extensive brush border loss, loss of mitochondrial structure and mitochondrial swelling in post-AKI pregnant rats compared to sham pregnant. Endothelial-dependent relaxation to ACh was also lower (2-way ANOVA, *p<0.05), suggesting enhanced endothelial dysfunction in post-AKI pregnant rats vs. sham pregnant. Taken together, these data suggest that with a history of AKI, subclinical renal and vascular injury is present despite “recovery” of renal function using clinical definitions and may predispose to adverse pregnancy outcomes in pregnant women with a history of AKI. 1R01HL169576 4R00HL146948 1RO1DK134695 AHA967662. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.