S. Ananth Karumanchi, M.D.
Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-370D
Boston, MA 02215
Ananth Karumanchi received his medical degree in 1992 from the University of Madras, India. He then completed his residency in Internal Medicine at Henry Ford Hospital, Detroit, and a fellowship in Nephrology at the Beth Israel Deaconess Medical Center, Boston. He joined the faculty at the Beth Israel Deaconess Medical Center in 2001 as Attending Physician in Nephrology and is currently a Professor of Medicine at Harvard Medical School. He also holds a second appointment as a Senior Scientist with the Department of Obstetrics and Gynecology at the Beth Israel Deaconess Medical Center.
Research Interests: Angiogenic Factors in Health & Disease
Translational Research Preeclampsia (currently the major focus of my laboratory) - Preeclampsia (a pregnancy-specific hypertensive disorder), characterized by new-onset hypertension and proteinuria is associated with severe morbidity and mortality to the mother and the baby. Our laboratory has identified sFlt1, an antagonist of circulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), from preeclamptic placentas and has confirmed that it is released into the blood stream in vast excess in patients with preeclampsia. Exogenous administration of sFlt1 into pregnant rats reproduces the phenotype of preeclampsia, namely proteinuria, hypertension and glomerular endotheliosis, the classic histological renal lesion of preeclampsia. Work is in progress to understand the regulation of sFlt1 production by the cytotrophoblasts of the placenta. We are testing the effects of antagonizing excess sFlt1 with growth factors and small molecules in our animal model of preeclampsia with the goal of finding novel treatment options for this disease. Additionally, we are currently characterizing other gene products that are elevated in preeclampsia (such as soluble endoglin) and which may be synergistic to sFlt1 in the pathogenesis of preeclampsia.
Mechanisms of proteinuria. Our laboratory is interested in understanding the molecular mechanisms of proteinuria. Preliminary microarray data generated from podocytes grown in high and normal glucose (as a model for diabetic nephropathy) have revealed several novel targets and pathways. We are currently confirming the cell culture data in diabetic rats by in-situ hybridization. Newer in vitro assays to mimic in vivo proteinuria are currently in development. Transcriptional profiles of podocytes lacking nephrin (mutated in congenital Finnish nephritic syndrome) and LMX-1b (mutated in nail-patella syndrome) are in progress. Goals would be to identify common pathways that lead to proteinuria.
Clinical Research - We are evaluating the role of angiogenic proteins in the blood and urine of pregnant subjects for the prediction and diagnosis of preeclampsia. Prospective trials to test this hypothesis are in progress.
New and Noteworthy Publications:
Maynard SE, Min J, Merchan J, Lim KH, Li J, Mondal S, Libermann T, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental sFlt-1 may contribute to endothelial dysfunction, hypertension and proteinuria in preeclampsia. Journal of Clinical Investigation 2003, 111:649-658. This study identified the role of sFlt1 in preeclampsia phenotypes, with both bench and clinical data.
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani RI, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk for preeclampsia. New England Journal of Medicine 2004, 350:672-83. This manuscript demonstrates that altered levels of angiogenic factors (increased serum sFlt1 and decreased serum free PlGF) are were present weeks before onset of clinical symptoms of preeclampsia suggesting that they may useful as predictive biomarkers.
Venkatesha S, Toporsian M, Lam C, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke F, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Medicine, 2006, 12:642-49. This article identified the role of soluble endoglin (a novel anti-angiogenic factor) in the pathogenesis of preeclampsia.
Maharaj ASR, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC, Matharu KS, Karumanchi SA, D'Amore P. VEGF and TGF-? are required for the maintenance of the choroid plexus and ependyma. The Journal of Experimental Medicine, 2008, 205 491-501. This study in rats provides evidence that sFlt1 and soluble endoglin may induce reversible posterior leucoencephalopathy of eclampsia.
Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, Hacker MR, Rhee JS, Mitchell J, Mahmood F, Hess P, Farrell C, Koulisis N, Khankin EV, Burke SD, Tudorache I, Bauersachs J, del Monte F, Hilfiker-Kleiner D, Karumanchi SA, Arany Z. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.Nature. 2012 May 9;485(7398):333-8. PMCID: PMC3356917 In this manuscript, we provide evidence that PPCM is a vascular disease and that anti-angiogenic factors (such as sFlt1 and prolactin fragments that are associated with preeclampsia) may initiate PPCM in some women by interfering with cardiac vascular homeostasis.