A Novel Treatment for Preeclampsia

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. Karumanchi and co-workers in break-through research starting with a landmark paper in JCI in 2003 (1) demonstrated that soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Other key publications from Karumanchi's group are listed at this link.

Very preterm preeclampsia  (<32 weeks) is associated with the greatest risk because the infant mortality rate is 70 times higher than at term. As well, circulating sFlt-1 in very preterm preeclampsia is at a very high level. Delivery of the placenta remains the only effective means to treat preeclampsia. Attempts to remove toxic circulating factors, either through hemodialysis or plasmapheresis, have been unsuccessful in preeclampsia.

Ravi Thadhani and colleagues in their paper in Circulation (2), hypothesized that since circulating sFlt-1 represents <20% of the total body sFlt-1 burden a selective adsorption column would create a concentration gradient and augment its removal.

The paper comprises of a series of experiments: first, they demonstrate that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. Next, 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels are then enrolled in a pilot study in a pilot study to examine whether a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. And, lastly, they perform multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth.

I invited Ravi Thadhani, who has led the clinical discovery and development of sFlt-1, to discuss the study that he published in Circulation. Ravi is Director of Clinical Research in the Renal Unit at the Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. His Harvard Catalyst Profile is available at the following link.

COMMENTARY

Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Preeclampsia is one of the most common medical complications of pregnancy and is associated with significant risk for maternal and fetal morbidity and mortality. Although the pathogenesis of preeclampsia remains unknown, elevated levels of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) may contribute to the pathogenesis of preeclampsia. Therapies targeting circulating sFlt-1 may alleviate the progression of preeclampsia and potentially prolong pregnancy in women presenting with very preterm (gestational age 32 weeks) preeclampsia.

We have been working on therapies targeted against sFlt-1 for nearly a decade, and while the biology is supportive, moving this concept to the clinic to actually treat women with preeclampsia has not been straightforward for obvious reasons. Our challenge was to administer an effective therapy, and importantly ensure safety for both mother and baby. We thought rather than administering a biological agent to neutralize maternal circulating sFlt-1, why not take a "nephrology" approach and remove sFlt-1 using an extracorporeal adsorption column. We have been administering dialysis and pheresis to pregnant women for years, so theoretically this should work. An adsorption column would augment its removal from maternal circulation, and importantly allow us to titrate the dose and immediately terminate the treatment should any adverse consequences become evident. We specifically tested clinically available negatively charged dextran sulfate columns, which would in theory exploit the positive charge of circulating sFlt-1. All along safety was our primary concern.

After a year of ex-vivo work (e.g., to determine which adsorption column could remove sFlt-1 from blood), we prepared for our first-in-human studies in Germany. We chose Germany because both the device and the expertise to use the device were readily available there, and the blood test to screen for elevated sFlt-1 levels in maternal blood (entry criteria) was also easily available there. We purchased insurance, obtained ethics/IRB approval, purchased the needed equipment and columns, and modified the procedure (e.g., citrate > heparin anticoagulation, changed flow rates) so as to accommodate pregnant women. Our initial challenges were many, but the teams we assembled were terrific and motivated.

Our design was to first test this treatment in 5 women with very preterm preeclampsia (presenting <32 weeks of gestation) to obtain initial safety and dose-response information. We showed with a single treatment that we could reduce maternal sFlt-1 levels in a dose-dependent fashion -- longer the duration of treatment, further the reduction of maternal sFlt-1 levels. The most common side effect was a drop in blood pressure, which was observed in the first 15-30 minutes in most women. This reversed with saline in all women. We then asked our DSMB for permission to treat women more than once. With permission, we treated 3 more women with very preterm preeclampsia. With 2-4 extra treatments, we were able to prolong pregnancy for an extra 15, 19, and 23 days. We also showed that each treatment resulted in lowering of urine protein excretion, which was promising. Finally, we did not want to significantly lower blood pressure given the risk for impairing fetal growth, so we titrated our treatments so that only minimal changes in blood pressure were observed. In all women given multiple courses, the treatments were well tolerated and there was evidence of fetal weight gain.

Every extra day and week a preterm fetus remains in utero, the lower the immediate and long-term complications of preterm birth. Importantly, we compared the prolongation of pregnancy with our treatments with contemporaneous controls, but this was not a randomized trial, hence we could not say for sure our treatments extended pregnancy. We are certainly encouraged by these initial results, but we have much to do. We are currently trying to obtain funding for additional studies, including a randomized trial, and in parallel performing in vitro and ex vivo studies to improve the precision and safety of our intervention.  

References

1. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003 Mar;111(5):649-58. PubMed PMID: 12618519; PubMed Central PMCID: PMC151901.

2. Thadhani R, Kisner T, Hagmann H, Bossung V, Noack S, Schaarschmidt W, Jank A, Kribs A, Cornely OA, Kreyssig C, Hemphill L, Rigby AC, Khedkar S, Lindner TH, Mallmann P, Stepan H, Karumanchi SA, Benzing T. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011 Aug 23;124(8):940-50. Epub 2011 Aug 1. PubMed PMID: 21810665.