KL 14 Targeted therapies in preeclampsia

Preeclampsia is a devastating hypertensive complication of pregnancy for which there is no suitable treatment other than premature delivery of the fetus. Approximately 5% of pregnancies are affected, producing substantial maternal and fetal morbidity and mortality, including an increased risk of cardiovascular consequences later in life. Levine and colleagues ( NEJM , 2004) demonstrated over a decade ago that the presence of excess soluble FMS-like tyrosine kinase (sFlt-1), a splice variant of vascular endothelial growth factor, is predictive of preeclampsia in at-risk women. We subsequently hypothesized that antagonizing or removing excess circulating sFlt-1 will help prolong gestational duration and, in turn, markedly improve fetal outcomes. To avoid the risks of administering investigational pharmacologic agents to pregnant women, we devised a novel approach using extracorporeal apheresis to remove sFlt-1 (a positively-charged protein) from the maternal circulation in women with frank preeclampsia. Our multidisciplinary team designed and conducted two single-arm, proof-of-concept clinical studies to determine the feasibility of apheresis using dextran-sulfate adsorption (DSA) columns to remove sFlt-1 from maternal blood of women with very pre-term preeclampsia (defined as ⩾ 140 mmHg or ⩾ 90 mmHg, respectively, on 2 occasions at least 4 h apart; proteinuria (24-h total protein excretion of ⩾ 300 mg or ⩾ 2+ on dipstick testing), or ⩾ 0.35 g protein/gram creatinine). In both studies, delivery decisions were made by the treating Obstetrician/MFM based on maternal and fetal clinical parameters. Maternal blood sFlt-1 levels, BP, and proteinuria were monitored at study entry and during and after pheresis at frequent, pre-specified time points. Clinical parameters of maternal and fetal well-being were monitored throughout the pheresis intervention and following therapy. Gestational age at delivery and birth weight, fetal APGAR scores, and fetal outcomes including NICU admission and complications (e.g., ventilatory support) were documented. Eight women completed the first pilot study (Thadhani et al., Circulation , 2011) which utilized DL-75 DSA columns (without separating whole blood into red cells and plasma); 5 received single apheresis treatments; 3 received apheresis up to twice per week for 3 ( n = 2, one of whom gave birth to twins) or 4 ( n = 1) total treatments. The pheresis interventions stabilized maternal parameters without leaving any residual adverse effects. Maternal blood pressure was only transiently and not markedly decreased, sFlt-1 levels were lowered by 17–34%, and protein-to-creatinine levels rose and fell in conjunction with sFlt-1. The two patients with singleton fetuses who underwent more than one apheresis treatment had pregnancies prolonged by 15 days (2 treatments) and 23 days (4 treatments). The patient with twins had her pregnancy prolonged by 19 days (2 treatments), remarkable given that most twin pregnancies are not prolonged more than a few days with expectant management. In our second study (Thadhani, JASN , 2016), 11 women received a total of 17 apheresis treatments using a modified apheresis apparatus that first separated plasma from whole blood before passing through a plasma-specific DSA column, improving the efficiency of sFlt-1 removal, minimizing the need for therapeutic anticoagulation, and reducing potential immune cell activation. Six women were treated once, 4 were treated twice and 1 was treated 3 times). All experienced a reduction of sFlt-1 from 17,394 (range 7916–35,301) pg/mL to 14,265 (6446–26,259) pg/mL post-apheresis. The safety of this approach was again verified and, among women treated multiple times, pregnancy continued on average for 15 days (range 11–21). We are now planning additional studies aiming to ultimately conduct a randomized clinical trial that will compare this promising therapy with the currently flawed standard-of-care. Follow up approaches in developing therapies for preeclampsia include a specific antibody column that only removes sFlt-1 and administration of ligands that neutralize circulating sFlt-1.