Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia.
A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for C4d, C1q, mannose-binding lectin, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d-a stable marker of complement activation-and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 mouse model of preeclampsia. The kidneys in the soluble fms-like tyrosine kinase 1-injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that soluble fms-like tyrosine kinase 1-injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia.
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Marlies
M
Penning
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.). j.s.chua@lumc.nl.
Jamie S
JS
Chua
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Cees
C
van Kooten
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Malu
M
Zandbergen
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Aletta
A
Buurma
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Joke
J
Schutte
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Jan Anthonie
JA
Bruijn
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Eliyahu V
EV
Khankin
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Kitty
K
Bloemenkamp
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
S Ananth
SA
Karumanchi
From the Department of Pathology (M.P., J.S.C., M.Z., A.B., J.A.B., H.B.), Department of Nephrology (C.v.K.), and Department of Obstetrics (K.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics & Gynecology, Isala Zwolle, Zwolle, the Netherlands (J.S.); and Howard Hughes Medical Institute and Department of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (E.V.K., S.A.K.).
Hans
H
Baelde
D000328:Adult; D000818:Animals; D015415:Biomarkers; D002908:Chronic Disease; D015935:Complement C4b / Q000032:analysis*; D011416:Complement Factor D / Q000032:analysis; D003171:Complement Pathway, Classical; D003165:Complement System Proteins / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006973:Hypertension / Q000276:immunology / Q000473:pathology; D007136:Immunoglobulins / Q000032:analysis; D007678:Kidney Glomerulus / Q000737:chemistry / Q000276:immunology*; D037241:Mannose-Binding Lectins / Q000032:analysis; D051379:Mice; D009426:Netherlands / Q000453:epidemiology; D010446:Peptide Fragments / Q000032:analysis*; D011225:Pre-Eclampsia / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D011247:Pregnancy; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000633:toxicity
D015415:Biomarkers; D007136:Immunoglobulins; D037241:Mannose-Binding Lectins; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d; D003165:Complement System Proteins; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D011416:Complement Factor D; C493491:complement factor D, mouse
C4d; complement; hypertension kidney; preeclampsia; proteinuria; sFlt-1