Investigators have developed a new model to explore alterations in kidney function following acute kidney injury (AKI) in women with the goal of predicting and preventing pregnancy complications, according to a recently published report in the Journal of the American Society of Nephrology.1
“Studies in pregnant women to fully understand the early pathogenesis of pregnancy-related complications are difficult and severely lacking,” said corresponding author Ellen Gillis, PhD, a postdoctoral fellow at the Medical College of Georgia at Augusta University. “Identification of rodent models that mirror what we see in pregnant women can serve as useful tools to better explore the changes in renal function early in pregnancy. Now that we have identified this rodent model of pregnancy after renal injury, we can start to study these early time points, which are difficult to capture in pregnant women.”
Many women of childbearing age experience AKI and recover based on usual measures of kidney function, but problems with the mother or baby or both still occur. During pregnancy, maternal circulation must support fetal circulation so cardiac output increases, total body volume increases, and plasma volume increases, Dr Gillis explained. As a result, the kidneys have an increased load to filter. Plasma volume increases to ensure the high metabolic demands of both baby and mother are met, but the baby actually gets preferential protection, she said.
The incidence of AKI has been on the increase, and the COVID-19 pandemic appears to have accelerated the trend. “We know that AKI is common among hospitalized COVID patients, and we think the COVID-19 pandemic will increase the number of young women with AKI to make pregnancy after AKI a growing problem,” Dr Gillis said.
Two clinical studies looked at women years out from their AKI episode, with multiple assessments indicating their kidneys had recovered. Yet, the researchers found significant increases in problems with both mother and baby, including preeclampsia, low birthweight, and miscarriage.2,3 An animal model developed by Dr Gillis and her colleagues showed that throughout pregnancy, uterine artery resistance increased, uterine blood flow decreased, and the offspring were born smaller because they were not getting adequate nutrition. “It’s still early in our studies to fully understand the magnitude of our findings, but we hope to fill an important gap in the literature with our focus on recovery mechanisms after ischemia reperfusion injury in females and subsequent changes in renal function early in pregnancy,” Dr Gillis said.
In this model, pregnancy appeared to induce renal insufficiency, driving up levels of creatinine and urea in the blood. Plasma volume, which should double, increased some but not sufficiently, Dr Gillis said. It is unknown what the exact mechanism is and why plasma volume increase is insufficient, but it is theorized the kidneys simply cannot handle the volume. The researchers report there is crosstalk between the kidneys, uterus, and placenta that the previous insult to the kidney appears to change.
Dr Gillis’ team is now exploring whether regulatory T cells are part of the problem. “We have studies planned to examine potential mechanisms more in depth, and would also like to follow the studies out beyond pregnancy to see what the long-term effects are for the moms and pups,” Dr Gillis said.
Snigdha Reddy, MD, an assistant professor in the division of nephrology and hypertension at Wayne State University in Detroit, Michigan, said this new model may be highly beneficial for developing prevention strategies. It has been theorized that the stress of pregnancy was the driving force behind the evidence showing that women who recover from AKI have an increased risk of preeclampsia and poor fetal outcomes. The model may help better explain the pathogenesis and whether proactive steps could be taken. “This has been attributed to the loss of functional renal reserve in ‘stress’ states such as pregnancy,” Dr Reddy said. “Recognition of AKI in pregnant females is still under appreciated and there are delays in therapeutic management.”
Ziyad Al-Aly, MD, chief of research and development service at the VA Saint Louis Health Care System in Missouri, said there are more than 30 million people with COVID in the US and a great proportion are women of child bearing age. “Greater understanding of how COVID and its attendant consequences will impact long-term health among women of child bearing age and other population groups will be important,” Dr Al-Aly said. “The US has the highest maternal mortality rate among developed countries. This is very disappointing, and we must change that. Upstream drivers of maternal mortality in the US must be identified, and this problem should be tackled.”
Gillis EE, Brands MW, Sullivan JC, et al. Adverse maternal and fetal outcomes in a novel experimental model of pregnancy after recovery from renal ischemia-reperfusion injury. J Am Soc Nephrol. 2021;32:375-384. doi:10.181/ASN.2020020127.
Tangren JS, Wan MD, Adnan WAH, et al. Risk of preeclampsia and pregnancy complications in women with a history of acute kidney injury. Hypertension. 2018;72:451-459. doi:10.1161/HYPERTENSIONAHA.118.11161
Tangren JS, Powe CE, Ankers E, et al. Pregnancy outcomes after clinical recovery from AKI. J Am Soc Nephrol. 2017;28:1566–1574. doi:10.1681/ASN.2016070806