Sub-clinical injury in AKI prior to pregnancy induces renal inflammation, renal fibrosis and suppresses the renin-angiotensin aldosterone system (RAAS) in female rats
Authors: Moronge Desmond , Mellott Elisabeth , Connor Gabrielle , Ayulo Victor , Gillis Ellen , Faulkner Jessica , Sullivan Jennifer 
Published: May 2023

Acute kidney injury (AKI), a sudden loss of kidney function, is responsible for 1 in 5 US hospitalizations. Although women are considered to be protected from AKI, they make up 40% of AKI patients. Recent clinical data report a 3-5-fold increase in adverse pregnancy outcomes among women with a history of AKI, despite apparent clinical recovery of renal function before pregnancy. These women have increased odds for developing preeclampsia and fetal growth restriction, via mechanisms unknown. To address this clinical issue, we developed a rat model of pregnancy post-AKI. We show that female Sprague-Dawley (SD) rats recover renal function as measured by creatinine clearance 30 days post-AKI. These rats exhibit decreased creatinine clearance, increased blood pressure, reduced plasma volume expansion and fetal growth restriction during pregnancy compared to sham rats. This study tested the hypothesis that AKI prior to pregnancy induces renal inflammation, fibrosis and dysregulates the renin-angiotensin aldosterone system (RAAS). Female SD rats were randomized to 45-minute warm sham or bilateral renal ischemia reperfusion (N=6/grp) and mated 30 days post sham/AKI surgery. Gestational day 1 (GD1) was identified through vaginal smear. Rats were placed in metabolic cages on GD19 for urine collection and euthanized on GD20. Urinary volume/day (30±5 vs 19±2 ml/day, P=0.08) and water intake (55±5 ml vs 41±1 ml, *P<0.05) increased in post-AKI pregnant rats compared to sham. In addition, urinary aldosterone levels measured by ELISA decreased in post-AKI pregnant rats compared to sham (188±34 pg/ml/day vs 312±35, *P<0.05). These data suggest disruption of fluid homeostasis and RAAS by pre-pregnancy AKI. Kidney injury marker-1 (KIM-1) measured via ELISA trended to increase in pre-pregnant AKI rats compared to sham at 30 days post AKI (580±169 pg/ml vs 257±17, P=0.09) and in pregnancy (283±28 vs 216±12 pg/ml, P=0.06), suggesting a lingering kidney injury despite creatinine clearance returning to sham levels. Mason Trichrome renal staining at GD20 revealed increases in both glomerular fibrosis (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 score, *P<0.05) in post-AKI pregnant rats compared to sham. T regulatory immune (Tregs) cell populations in blood and kidney were measured via flow cytometry on GD20. Blood Tregs (16195±2935 cells/ml vs 26740±2508, *P<0.05) as well as renal Tregs (1811±364 cells/gram kidney vs 3241±405.6, *P<0.05) decreased in post-AKI pregnant rats compared to sham, suggesting AKI prior to pregnancy increases renal inflammation. Taken together, these data suggest that history of AKI predisposes to pregnancy induced dysregulation of fluid hemodynamics, renal inflammation, renal fibrosis and sustained renal injury mediating adverse fetal and maternal outcomes.

R00 HL146948-03 to DM; AHA CDA858380 to JLF; AHA DIVSUP0224732 to DM

This is the full abstract presented at the American Physiology Summit 2023 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.