Adverse Maternal and Fetal Outcomes in a Novel Experimental Model of Pregnancy after Recovery from Renal Ischemia-Reperfusion Injury

Ellen E. Gillis; Michael W. Brands; Jennifer C. Sullivan

doi:10.1681/ASN.2020020127

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Significance Statement

Increasing evidence suggests that patients have lingering subclinical damage after AKI, despite clinical recovery as defined by serum creatinine levels. Recent reports from clinical studies found that women with a history of AKI have poor maternal and fetal outcomes during pregnancy, suggesting that subclinical injury leaves these patients unable to cope with increased renal demands of pregnancy. In this study, which sought to establish an experimental animal model that recapitulates these findings, the authors demonstrate that female Sprague Dawley rats that experience biochemical resolution of surgically induced renal ischemia-reperfusion injury subsequently developed renal insufficiency during pregnancy and intrauterine growth restriction. This novel model may serve as a useful preclinical tool to address the critical gap in knowledge regarding the mechanisms by which AKI predisposes to adverse pregnancy outcomes.

Abstract

Background Recent clinical studies report that women with a history of AKI have an increased incidence of maternal and fetal adverse outcomes during pregnancy, despite fully recovering renal function prior to conception. The mechanisms contributing to such adverse outcomes in pregnancy after AKI are not yet understood.

Methods To develop a rodent model to investigate fetal and maternal outcomes in female animals with a history of AKI, we used ischemia-reperfusion injury as an experimental model of AKI in female Sprague Dawley rats. The 12-week-old animals underwent warm bilateral ischemia-reperfusion surgery involving clamping of both renal arteries for 45 minutes or sham surgery (control). Rats were allowed to recover for 1 month prior to mating. Recovery from ischemia-reperfusion injury was confirmed by measurements of plasma creatinine and urinary protein excretion. We assessed maternal and fetal outcomes during late pregnancy on gestational day 20.

Results After recovery from ischemia-reperfusion injury, compared with healthy sham-surgery controls, dams exhibited pregnancy-induced renal insufficiency with increases in plasma creatinine and urea, along with increased urinary protein excretion. Additionally, recovered ischemia-reperfusion dams experienced worse fetal outcomes compared with controls, with intrauterine growth restriction leading to higher rates of fetal demise and smaller pups.

Conclusions In this rat model, despite biochemical resolution of ischemia-reperfusion injury, subsequent pregnancy resulted in maternal renal insufficiency and significant impairments in fetal growth. This mirrors findings in recent reports in the clinical population, indicating that this model may be a useful tool to further explore the alterations in kidney function after AKI in women.

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