Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

Abstract

We enrolled 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension from a cohort of women receiving care at Brigham and Women's Hospital from March 2012 through March 2013. Institutional review board approval was obtained through the Partners Human Research Committee, and subjects gave informed consent. All procedures followed were in accordance with institutional guidelines. Methods Abstract-Kidney injury with proteinuria is a characteristic feature of preeclampsia, yet the nature of injury in specific regions of the nephron is incompletely understood. Our study aimed to use existing urinary biomarkers to describe the pattern of kidney injury and proteinuria in pregnancies affected by severe preeclampsia. We performed a case-control study of pregnant women from Brigham and Women's Hospital from 2012 to 2013. We matched cases of severe preeclampsia (n=25) 1:1 by parity and gestational age to 2 control groups with and without chronic hypertension. Urinary levels of kidney injury molecule-1 and complement components (C3a, C5a, and C5b-9) were measured by enzyme-linked immunosorbent assay, and other markers (albumin, β2 microglobulin, cystatin C, epithelial growth factor, neutrophil gelatinase-associated lipocalin, osteopontin, and uromodulin) were measured simultaneously with a multiplex electrochemiluminescence assay. Median values between groups were compared with the Wilcoxon signed-rank test and correlations with Spearman correlation coefficient. Analysis of urinary markers revealed higher excretion of albumin and kidney injury molecule-1 and lower excretion of neutrophil gelatinase-associated lipocalin and epithelial growth factor in severe preeclampsia compared with chronic hypertension and healthy controls. Among subjects with severe preeclampsia, urinary excretion of complement activation products correlated most closely with kidney injury molecule-1, a specific marker of proximal tubule injury (C5a: r=0.60; P=0.001; and C5b-9: r=0.75; P<0.0001). Taken together, we describe a pattern of kidney injury in severe preeclampsia that is characterized by glomerular impairment and complement-mediated inflammation and injury, possibly localized to the proximal tubule in

The complement system and adverse pregnancy outcomes

“…On the other hand, both severe preeclampsia and lupus have been associated with increased terminal complement activation as measured by plasma and urine biomarkers C5a and sC5b-9 (Burwick et al, 2013; Chiu et al, 1998; Gou et al, 2013). In preeclampsia, urinary excretion of sC5b-9 correlates most closely with kidney injury molecule 1 (KIM-1), a marker of proximal tubule injury (Burwick et al, 2014b). Extrinsic C5 activation by serine proteases in the coagulation cascade may also contribute to increased levels of C5a and sC5b-9 in severe preeclampsia (Amara et al, 2010; Burwick et al, 2014a; Huber-Lang et al, 2006).…”

Role of IgM and angiotensin II Type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat

“…Multiple studies demonstrated significantly enhanced systemic complement system activation in preeclamptic pregnancies compared to normal pregnancies (Derzsy et al, 2010; Regal et al, 2015a). Both the placenta and kidney also showed evidence of increased local complement activation in preeclampsia, coincident with up-regulation of message for complement regulators but no evidence of changes in regulator expression using immunohistochemistry have been reported (Burwick et al, 2014; Buurma et al, 2012; Lokki et al, 2014; Penning et al, 2015). However, the event or events that initiate complement activation in preeclampsia are unknown.…”

Pathological significance of urinary complement activation in diabetic nephropathy: A full view from the development of the disease

“…However, the exact significance and underlying mechanism are far from clear. Increased urinary complement activation products (CAPs) have been reported in proteinuric kidney diseases including DN [6][7][8][9][10][11][12] . However, the exact significance of urinary CAPs in DN is still unclear.…”