Aligning with the NIH-NIDDK goal of ?advancing our understanding of the pathophysiology of sex differences in CKD and improving clinical care of women with CKD? outlined at the 2017 ?Sex and the Kidney: Sex Differences in Renal Disease? workshop, this proposal focuses on defining renal adaptation to pregnancy and strategies to identify women with CKD at high risk for pregnancy complications. Growing evidence suggests a strong link between kidney function and preeclampsia, yet significant gaps persist in our knowledge of renal adaptation in pregnancy.
Aim 1 A of this proposal utilizes existing data and blood samples from two large prospective longitudinal pregnancy cohorts to study pregnancy-associated changes in glomerular filtration markers in healthy and complicated pregnancies. Preliminary data suggests impaired glomerular hyperfiltration is associated with placental dysfunction, and in Aim 1B we will investigate metabolite and angiogenic pathways critical for placental development in women who fail to mount normal pregnancy-associated hyperfiltration. Studying over 3,000 pregnant subjects, this work will define gestational renal physiology in a diverse obstetric population and identify pathways linking kidney function and fetoplacental development that may be targeted to reduce preeclampsia in women with kidney disease.
In Aim 2, we will measure and study pre-conception renal functional reserve as a predictor of pregnancy-associated glomerular filtration and preeclampsia in women with kidney disease. Together, understanding the effects of renal adaptation and glomerular hyperfiltration before and during pregnancy will yield new metrics by which to evaluate and treat young women with kidney disease planning pregnancy. Dr. Tangren completed her medical degree at the University of Pennsylvania and her internal medicine and nephrology training at Brigham and Women?s Hospital and Massachusetts General Hospital. She recently completed a Master?s in Public Health at the Harvard T.H. Chan School of Public Health and holds a faculty appointment in the Massachusetts General Hospital Nephrology Division and Harvard Medical School. During this career development award, she will devote 75% of her time to focus on this research plan and complete didactic and hands-on training in physiologic investigation and metabolic pathway analysis through coursework and applied analytic experience. Dr. Tangren will benefit from the guidance of her primary mentor, Dr. Sushrut Waikar, an international leader in CKD epidemiology and biomarkers studies, and her co-mentor Dr. Ravi Thadhani, a clinical and translational preeclampsia investigator. Her training will be overseen by an advisory committee of senior scientists, Drs. Ellen Seely, Lesley Inker, and Jeffrey Ecker, with collective expertise in metabolism in pregnancy, glomerular filtration measurements and obstetrics research. She will work in collaboration with Dr. Eugene Rhee (kidney disease metabolomics) and Dr. Sophia Zhao (biostatistics). Dr. Tangren?s goal is to become an independent clinician-investigator with a research program focused on reproductive health in nephrology.
Preeclampsia is a leading cause of maternal morbidity and mortality and disproportionately affects women with chronic kidney disease (CKD), which afflicts 3-5% of women in their reproductive years in the United States. Despite overwhelming evidence on the link between kidney disease and preeclampsia, we have little understanding of normal and abnormal renal physiology in pregnancy. The current proposal is to study renal adaptation in pregnancy by performing novel assessments of kidney function, including the assessment of renal functional reserve and analysis of novel glomerular filtration markers, before and during pregnancy; knowledge gained from this proposal will help define the relationship between kidney function and fetoplacental development, ultimately leading to improved care for women with CKD and their offspring.
