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

Abstract

Background-Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. 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. Removing sFlt-1 may benefit women with very preterm (Ͻ32 weeks) preeclampsia. Methods and Results-We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27ϩ4 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. Conclusions-This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting. (Circulation. 2011;124:940-950.)Key Words: angiogenic factor Ⅲ apheresis Ⅲ preeclampsia P reeclampsia is a devastating medical complication of pregnancy associated with significant maternal and fetal morbidity and mortality. 1 The risk is highest in very preterm (Ͻ32 weeks) preeclampsia when the infant mortality rate is 70 times higher than at term. 2,3 Delivery of the placenta remains the only effective means to treat preeclampsia. Randomized trials have tested nonspecific interventions including antihypertensive agents; however, the ability of these and other interventions to prevent or stabilize the clinical manifestations and prolong pregnancy in preterm preeclampsia is limited. 4 -6 The underlying pathogenesis of preeclampsia has remained elusive, hampering successful development of targeted interventions for the condition. Clinical Perspective on p 950The prevailing hypothesis suggests that preeclampsia involves a placental factor that circulates to distal organs and causes damage to the vasculature. 7 We and others have suggested that excess placental derived soluble fms-like tyrosine kinase 1 (sFlt-1) or the soluble vascular endothelial growth factor (VEGF) receptor 1, an alternatively spliced variant of VEGF receptor 1, mediates the signs and symptoms of preeclampsia, and elevated circulating levels are associated with clinical preeclampsia. 8 -11 Circulating sFlt-1 levels in very preterm preeclampsia are among the highest obs...

Urinary Plasmin Activates Collecting Duct ENaC Current in Preeclampsia

“…The cause of preeclampsia is thought to involve release of a soluble fms-like tyrosine kinase (a vascular endothelial growth factor receptor) from placenta leading to decreased bioavailability of circulating vascular endothelial growth factor and endothelial injury, decreased NO formation, vasoconstriction, and glomerular damage with endotheliosis. 11,12 Preeclamptic (PE) patients exhibit suppressed renin-angiotensin-aldosterone system activity, in particular aldosterone, 13,14 and avid NaCl retention. 15 Treatment with furosemide in preeclampsia yields less stimulation of plasma renin concentration.…”

Transforming Growth Factor – Β1 and Pre-Eclampsia: Perspectives for Novel Therapeutic Modalities

“…In line with this notion, a recent study suggested an apheresis based treatment for reduction of plasma levels of a placental protein Flt-1, whose elevated levels are detrimental for normal pregnancy [35]. The statement of Goske et al, raises hopes about enhanced treatment options for PE, relative to the present situation of administering drugs with potent side-effects.…”

Nouveaux regards sur la prééclampsie

“…Une autre piste pourrait être fournie par l'administration de nanoparticules ciblant le trophoblaste [45], qui pourrait véhiculer des siARN (en anglais, small interfering RNA) mimant l'action des miARN naturels. Récemment, il a été proposé de limiter la circulation de sFLT1 pour permettre une prolongation de la grossesse dans des conditions satisfaisantes de sécurité pour la mère et le foetus [46]. Jusqu'à présent, ces études ont concerné très peu de patientes.…”