Apheresis to Treat Preeclampsia: Insights, Opportunities and Challenges.

Preeclampsia, a hypertensive condition unique to pregnancy, remains a significant source ofmaternal and neonatalmorbidity andmortality. The general approach of aggressive antenatal surveillance, diagnosis, and delivery has historically improved outcomeswhenpreeclampsia presents at termornear term. In lowandmiddle-income countries, where an infrastructure of surveillance and management may not be readily available, preeclampsia at term remains a significant cause of morbidity andmortality. Preterm preeclampsia, while less common, remains a clinical problem without an effective approach. Although surveillance,diagnosis, anddelivery serve toprotect themother, morbidity is transferred to the neonate as a consequence of preterm delivery. Innovation outside the box is clearly needed. In this issue of JASN, Thadhani et al. report on an innovative approach that addresses a broad need for new ideas in the management of preeclampsia.1 Fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor of vascular endothelial growth factor (VEGR) exerts antiangiogenic activity by binding circulating VEGF and therefore inhibiting activity at the endothelial receptor site. In 2003, Maynard et al. demonstrated that preeclampsia is associated with elevated levels of sFlt-1 and decreased levels of free VEGF and that introduction of sFlt-1 into pregnant rats by viral transfection creates a high fidelity model of preeclampsia manifest by hypertension, proteinuria, fetal wastage, and glomerular endotheliosis.2 Subsequently, Levine et al. demonstrated in a population-based study that sFlt-1 was not only elevated in women with preeclampsia but was elevated weeks before clinical disease.3 These breakthrough investigations led to a body of work supporting the role of antiangiogenic factors and the associated degradation of endothelial health in pregnancy contributing to the propensity to develop preeclampsia. On the basis of compelling evidence that circulating sFlt-1 is a critical and potentially rate-limiting step in the pathobiology of preeclampsia, the investigators hypothesized that by reducing serum concentration, disease progression could be limited. An open pilot study of apheresis was performed using negatively charged columns to remove positively charged sFlt-1. Eleven pregnant women with preeclampsia diagnosed between 23 and 32 weeks’ gestation were studied. Women served as their own controls for physiologic changes associated with apheresis. Comparisons of maternal and neonatal outcomes were made with 22 womenwith preterm preeclampsia who did not receive apheresis. This trial clearly demonstrates the potential for apheresis of women with preterm preeclampsia to reduce mean sFlt-1 concentrations by 18% (range, 7%–28%). Is this modest but significant reduction in sFlt-1 concentration biologically significant? Treated women experienced a 44% reduction in protein to creatinine ratio. The rapid development of proteinuria in the context of new onset hypertension is a cardinal feature of preeclampsia. The rapid and substantial improvement in proteinuria clearly suggests beneficial biologic effects, presumably because of increased concentration of free VEGF at the glomerular interface. Sucha rapid improvement inproteinuria is surprisingand may well provide important insights into the mechanisms of disease. Are the results clinically significant? Delivery was delayed in the women treated with apheresis from 8 to 15 days compared with a delay in an untreated comparison group of 3 days. If this differenceisattributabletotreatment, it isclearlyclinically relevant. Achieving an additional week of gestational age in a premature infant at the gestational ages studied is important and, given the cost of care in the neonatal intensive care unit, probably costeffective. The results must be interpreted with caution.Without a randomized approach, one cannot expect equivalent patients in each group. Without a blinded approach, one cannot expect unbiased decision making regarding the timing of delivery, often on the basis of the well informed but subjective judgment of experienced obstetrical providers. Does apheresis benefit the neonate? Oxygen therapy was reduced from 11615 days in the comparison group without apheresis to 262 days in the aphesis cohort, clinically suggesting less pulmonary pathology. If apheresis reduced the neonatal alveoli exposure to the antiangiogenic effects of sFlt-1, these results would be biologically plausible. Alternatively, they could be the result of a prolongation of gestation. Enthusiasm isdampenedexaminingFigures 1–5, describing the clinical course of individual subjects receiving apheresis. Although acute reductions in sFlt-1 in response to apheresis are evident, the general rise in sFlt-1 concentrations over time Published online ahead of print. Publication date available at www.jasn.org.