Terminal Complement Activation in Preeclampsia

Abstract

OBJECTIVE: To evaluate whether C5b-9 concentrations in blood and urine are increased in preeclampsia with severe features. METHODS: The Complement and Preeclampsia in the Americas study is a prospective, multicenter case–control study performed at six centers in Colombia from November 2015 to July 2016. The case group included women with preeclampsia with severe features, and the control group included women who were healthy or had chronic hypertension, gestational hypertension, or preeclampsia without severe features. We enrolled two women in the control group for every woman in the case group. Soluble C5b-9 concentrations were measured by enzyme-linked immunosorbent assays in blood and urine. The primary outcome was C5b-9 concentrations in women in the case group compared with all women in the control group, and the secondary outcome was C5b-9 levels in women in the case group compared with individual control subgroups. Differences were assessed by test of medians, and associations were further evaluated by receiver operating characteristic curve analysis and logistic regression with α=0.05. RESULTS: Three hundred fifty-two patients were enrolled. Plasma C5b-9 concentrations did not differ significantly between women in the case group and those in the control group, but urine C5b-9 concentrations were higher in women in the case group (median [interquartile range] 9.9 [1.6–43.7] vs 1.8 [0.54–4.1] ng/mL, P<.001). In subgroup analysis, plasma C5b-9 concentrations were increased in women in the case group compared with healthy women in the control group (median [interquartile range] 2,778 [1,633–4,230] vs 1,374 [1,064–2,332] ng/mL, P<.001), and urine C5b-9 concentrations were increased in women in the case group compared with all control subgroups (P<.001). Using receiver operating characteristic analysis, urine C5b-9 concentrations differentiated preeclampsia with severe features from hypertensive women in the control group (area under the receiver operating characteristic curve 0.74, 95% CI 0.68–0.80). Urine C5b-9 22 ng/mL or greater (range 0–158.4 ng/mL) was the optimal cut point for diagnosis of preeclampsia with severe features with adjusted odds ratio of 10.0 (95% CI 3.5–28.8, P<.001). CONCLUSION: Urinary excretion of terminal complement effector C5b-9 is higher in women with preeclampsia with severe features compared with women with other hypertensive disorders of pregnancy and women without hypertension.

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…Finally, Lokki et al noted that areas of C3b deposition were positively correlated with C1q and negatively with Factor H, a regulatory factor of the alternative pathway (147). The over-activation of the complement system in EOPE is reinforced by the rise in the plasma concentration of C5b-9, which is indicative of terminal activation (148). C-reactive proteins of the system, specifically, C3a, have also been found circulating in high concentration within the amniotic fluid in EOPE (149).…”

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

“…Complement activation is associated with renal dysfunction, and there is an accumulation of markers of complement activation, such as C4d and C1q in PE; hence, the inhibition of complement activation may be helpful in controlling the renal manifestations of PE [ 121 ]. Increased urinary C5b-9 levels in PE women were found to be potential biomarkers that distinguish PE from other hypertensive disorders [ 122 , 123 ]. A study on the HTR-8/SVneo cell line showed C5a induced higher levels of sFlt-1 transcription [ 124 ].…”

Late first trimester circulating microparticle proteins predict the risk of preeclampsia < 35 weeks and suggest phenotypic differences among affected cases

“…There is precedent for complement involvement in preeclampsia pathophysiology. Other authors have noted an association between early-onset/severe preeclampsia and complement function [64][65][66] . Our observations suggest that it may be possible to identify a sub-category of cases of preeclampsia with a dominant complement-associated phenotype at the end of the first trimester.…”