NephMadness 2015: Championship Match: sFlt1 in Preeclampsia

Karumanchi-345x239S. Ananth Karumanchi, MD is a Professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. He currently works as an attending physician in the Nephrology Division at Beth Israel Deaconess Medical Center and also holds a second appointment as a Senior Scientist in the Department of Obstetrics and Gynecology. His current research focuses on the role of angiogenic growth factors and inhibitors in the pathogenesis of preeclampsia and other kidney diseases. Dr. Karumanchi’s research is currently funded by Howard Hughes Medical Institute, Gates Foundation, and the National Institutes of Health.

sFlt1 in Preeclampsia emerges from the Obstetric Nephrology region to face APOL1 in the championship match in NephMadness. The discovery of sFlt1s role in preeclampsia ushered a new era in the field. This is an invited commentary by Dr. Karumanchi who’s lab defined the role of sFlt1 in preeclampsia.

Preeclampsia, is one of the most common glomerular disorders that affects affects 5-10% of pregnancies throughout the world and is responsible for significant maternal and neonatal morbidity and mortality. Substantial evidence from human epidemiological studies, experimental studies in animals, and early therapeutic studies in humans suggest that soluble fms-like tyrosine kinase 1 (sFlt1), an anti-angiogenic protein made by the placenta is responsible for the hypertension, proteinuria, and glomerular endotheliosis, all key features of preeclampsia (ref).

sFlt1 acts as a vascular endothelial growth factor (VEGF) signaling inhibitor and induces vascular disease in organ beds such as glomerulus of the kidney that are dependent on VEGF for the maintenance of fenestrated endothelium (ref). Recently, sFlt1 and its ligand PlGF levels can be measured very rapidly on plasma or serum samples on automated platforms. Several large studies in humans have demonstrated that plasma/serum sFlt1 and PlGF levels can be used to differentiate preeclampsia from diseases that mimic preeclampsia such as chronic hypertension, gestational hypertension, chronic kidney disease, and gestational thrombocytopenia (ref). Moreover, plasma sFlt1 and PlGF levels among women with suspected preeclampsia predicts adverse maternal and perinatal outcomes in the preterm setting (ref). These angiogenic biomarkers outperform standard clinical diagnostic measures including blood pressure, proteinuria, uric acid, and others.

Human and animal studies have strongly suggested that targeting the sFlt1 pathway may be a viable strategy to prevent or treat preeclampsia. In small proof-of-concept human studies, depletion of sFlt1 using dextran sulfate apheresis appears to stabilize hypertension, improve proteinuria and prolong pregnancy without any major side effects (ref). Endothelial dysfunction, which has been linked to hypertension and atherosclerosis, persists in formerly preeclamptic women many years after an affected pregnancy. Using sFlt1 overexpression model in rodents it has been recently demonstrated that exposure to preeclampsia exacerbates vascular proliferative and fibrotic responses to future vascular injury (ref).

Taken together with human studies, these data suggest that vascular endothelial injury induced during preeclampsia promotes the progression of chronic kidney disease and cardiovascular disease both directly and synergistically with other risk factors such as obesity, hypertension and hyperlipidemia. In summary, these molecular discoveries that has provided a mechanistic explanation for preeclampsia will lead to improvement of care of patients suffering from preeclampsia and its devastating complications.

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