Complement Activation and Thrombotic Microangiopathies.

Adult Antibodies, Monoclonal, Humanized / therapeutic use Atypical Hemolytic Uremic Syndrome / drug therapy Complement Activation Complement Membrane Attack Complex / metabolism Female HELLP Syndrome / immunology Humans Male Pre-Eclampsia / drug therapy Pregnancy Thrombotic Microangiopathies / drug therapy

HELLP syndrome alternative antibodies atypical hemolytic uremic syndrome complement C9 complement activation complement membrane complement pathway complement system proteins eculizumab endothelial cells female fibrin fluorescent antibody technique humanized humans hypertension malignant monoclonal pre-eclampsia pregnancy recurrence thrombotic microangiopathies

Journal

Clinical journal of the American Society of Nephrology : CJASN

ISSN: 1555-905X

Titre abrégé: Clin J Am Soc Nephrol

Pays: United States

ID NLM: 101271570

Informations de publication

Date de publication:
06 12 2019

Historique:

received: 13 05 2019

accepted: 02 10 2019

pubmed: 7 11 2019

medline: 2 12 2020

entrez: 8 11 2019

Statut: ppublish

Résumé

Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome ( Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

Sections du résumé

BACKGROUND AND OBJECTIVES

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS

Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (

RESULTS

Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels.

CONCLUSIONS

The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

Identifiants

DOI: 10.2215/CJN.05830519 PMID: 31694864 PMC: PMC6895490

pubmed: 31694864

pii: 01277230-201912000-00010

doi: 10.2215/CJN.05830519

pmc: PMC6895490

doi:

Substances chimiques

Antibodies, Monoclonal, Humanized 0

Complement Membrane Attack Complex 0

eculizumab A3ULP0F556

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1719-1732

Commentaires et corrections

Type : CommentIn

Informations de copyright

Références

George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 371: 654–666, 2014 25119611

Sethi S, Fervenza FC: Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost 40: 416–421, 2014 24799306

Román E, Mendizábal S, Jarque I, de la Rubia J, Sempere A, Morales E, Praga M, Ávila A, Górriz JL: Secondary thrombotic microangiopathy and eculizumab: A reasonable therapeutic option. Nefrologia 37: 478–491, 2017

Cavero T, Rabasco C, López A, Román E, Ávila A, Sevillano Á, Huerta A, Rojas-Rivera J, Fuentes C, Blasco M, Jarque A, García A, Mendizabal S, Gavela E, Macía M, Quintana LF, María Romera A, Borrego J, Arjona E, Espinosa M, Portolés J, Gracia-Iguacel C, González-Parra E, Aljama P, Morales E, Cao M, Rodríguez de Córdoba S, Praga M: Eculizumab in secondary atypical haemolytic uraemic syndrome. Nephrol Dial Transplant 32: 466–474, 2017 28339660

Jokiranta TS: HUS and atypical HUS. Blood 129: 2847–2856, 2017 28416508

Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T: Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 36: 673–681, 2010 20865645

Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, Lieberman KV, Maringhini S, Pape L, Rees L, van de Kar NC, Vande Walle J, Ogawa M, Bedrosian CL, Licht C: Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int 89: 701–711, 2016 26880462

Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, Menne J, Minetti EE, Provôt F, Rondeau E, Ruggenenti P, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM: Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: A single-arm, open-label trial. Am J Kidney Dis 68: 84–93, 2016 27012908

Rodríguez de Córdoba S, Hidalgo MS, Pinto S, Tortajada A: Genetics of atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost 40: 422–430, 2014 24799305

Vieira-Martins P, El Sissy C, Bordereau P, Gruber A, Rosain J, Fremeaux-Bacchi V: Defining the genetics of thrombotic microangiopathies. Transfus Apheresis Sci 54: 212–219, 2016 27177491

Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G: Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5: 1844–1859, 2010 20595690

Asif A, Nayer A, Haas CS: Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: Case reports and a review of the evidence for treatment with eculizumab. J Nephrol 30: 347–362, 2017 27848226

Tufano A, Coppola A, Maruotti GM, Martinelli P, Cerbone AM, Di Minno G: HELLP syndrome and its relation with the antiphospholipid syndrome. Blood Transfus 12: 114–118, 2014 24333078

Egbor M, Johnson A, Harris F, Makanjoula D, Shehata H: Pregnancy-associated atypical haemolytic uraemic syndrome in the postpartum period: A case report and review of the literature. Obstet Med 4: 83–85, 2011 27582861

Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN: Drug-induced thrombotic microangiopathy: A systematic review of published reports. Blood 125: 616–618, 2015 25414441

Morton JM, George JN: Microangiopathic hemolytic anemia and thrombocytopenia in patients with cancer. J Oncol Pract 12: 523–530, 2016 27288467

Song D, Wu LH, Wang FM, Yang XW, Zhu D, Chen M, Yu F, Liu G, Zhao MH: The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther 15: R12, 2013 23320601

Rodríguez-Pintó I, Espinosa G, Cervera R: Catastrophic APS in the context of other thrombotic microangiopathies. Curr Rheumatol Rep 17: 482, 2015 25604575

Mathew RO, Nayer A, Asif A: The endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy. J Am Soc Hypertens 10: 352–359, 2016 26778772

Dhakal P, Bhatt VR: Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy? Bone Marrow Transplant 52: 352–356, 2017 27775697

Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K: De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (Orlando) 32: 58–68, 2018 29157988

Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, Tripodo C, Bettoni S, Donadelli R, Valoti E, Tedesco F, Amore A, Coppo R, Ruggenenti P, Gotti E, Remuzzi G: Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124: 1715–1726, 2014 25037630

Galbusera M, Noris M, Gastoldi S, Bresin E, Mele C, Breno M, Cuccarolo P, Alberti M, Valoti E, Piras R, Donadelli R, Vivarelli M, Murer L, Pecoraro C, Ferrari E, Perna A, Benigni A, Portalupi V, Remuzzi G: An Ex Vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome. Am J Kidney Dis 74: 56–72, 2019 30851964

Gavriilaki E, Yuan X, Ye Z, Ambinder AJ, Shanbhag SP, Streiff MB, Kickler TS, Moliterno AR, Sperati CJ, Brodsky RA: Modified Ham test for atypical hemolytic uremic syndrome. Blood 125: 3637–3646, 2015 25862562

Ades EW, Candal FJ, Swerlick RA, George VG, Summers S, Bosse DC, Lawley TJ: HMEC-1: Establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 99: 683–690, 1992 1361507

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A: Fiji: An open-source platform for biological-image analysis. Nat Methods 9: 676–682, 2012 22743772

Subías Hidalgo M, Martin Merinero H, López A, Anter J, García SP, Ataúlfo Gonzalez-Fernández F, Forés R, Lopez-Trascasa M, Villegas A, Ojeda E, Rodríguez de Córdoba S: Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment. Immunobiology 222: 363–371, 2017 27644115

Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa L, Espinosa M, Grinyó JM, Macía M, Mendizábal S, Praga M, Román E, Torra R, Valdés F, Vilalta R, Rodríguez de Córdoba S: An update for atypical haemolytic uraemic syndrome: Diagnosis and treatment. A consensus document. Nefrologia 35: 421–447, 2015 26456110

Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, Coppo R, Emma F, Johnson S, Karpman D, Landau D, Langman CB, Lapeyraque AL, Licht C, Nester C, Pecoraro C, Riedl M, van de Kar NC, Van de Walle J, Vivarelli M, Frémeaux-Bacchi V; HUS International: An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31: 15–39, 2016 25859752

Volokhina EB, van de Kar NC, Bergseth G, van der Velden TJ, Westra D, Wetzels JF, van den Heuvel LP, Mollnes TE: Sensitive, reliable and easy-performed laboratory monitoring of eculizumab therapy in atypical hemolytic uremic syndrome. Clin Immunol 160: 237–243, 2015 26111482

Ardissino G, Tel F, Sgarbanti M, Cresseri D, Giussani A, Griffini S, Grovetto E, Possenti I, Perrone M, Testa S, Paglialonga F, Messa P, Cugno M: Complement functional tests for monitoring eculizumab treatment in patients with atypical hemolytic uremic syndrome: An update. Pediatr Nephrol 33: 457–461, 2018 29046944

Wehling C, Amon O, Bommer M, Hoppe B, Kentouche K, Schalk G, Weimer R, Wiesener M, Hohenstein B, Tönshoff B, Büscher R, Fehrenbach H, Gök ÖN, Kirschfink M: Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders. Clin Exp Immunol 187: 304–315, 2017 27784126

Puissant-Lubrano B, Puissochet S, Congy-Jolivet N, Chauveau D, Decramer S, Garnier A, Huart A, Kamar N, Ribes D, Blancher A: Alternative complement pathway hemolytic assays reveal incomplete complement blockade in patients treated with eculizumab. Clin Immunol 183: 1–7, 2017 28647502

Burwick RM, Fichorova RN, Dawood HY, Yamamoto HS, Feinberg BB: Urinary excretion of C5b-9 in severe preeclampsia: Tipping the balance of complement activation in pregnancy. Hypertension 62: 1040–1045, 2013 24060886

Guseh SH, Feinberg BB, Dawood HY, Yamamoto HS, Fichorova RN, Burwick RM: Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia. Am J Reprod Immunol 73: 437–444, 2015 25521546

Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350: 672–683, 2004 14764923

Wang W, Irani RA, Zhang Y, Ramin SM, Blackwell SC, Tao L, Kellems RE, Xia Y: Autoantibody-mediated complement C3a receptor activation contributes to the pathogenesis of preeclampsia. Hypertension 60: 712–721, 2012

Ma Y, Kong LR, Ge Q, Lu YY, Hong MN, Zhang Y, Ruan CC, Gao PJ: Complement 5a-mediated trophoblasts dysfunction is involved in the development of pre-eclampsia. J Cell Mol Med 22: 1034–1046, 2018 29168351

Andries G, Karass M, Yandrapalli S, Linder K, Liu D, Nelson J, Pawar R, Chugh S: Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab. Exp Hematol Oncol 6: 4, 2017 28101432

Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R: Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 373: 1032–1039, 2015 26352814

Vaught AJ, Gavriilaki E, Hueppchen N, Blakemore K, Yuan X, Seifert SM, York S, Brodsky RA: Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome. Exp Hematol 44: 390–398, 2016 26921648

Tsai HM: Does anticomplement therapy have a role in the management of malignant hypertension? J Clin Hypertens (Greenwich) 18: 359–360, 2016 26359936

Timmermans SAMEG, Abdul-Hamid MA, Vanderlocht J, Damoiseaux JGMC, Reutelingsperger CP, van Paassen P; Limburg Renal Registry: Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int 91: 1420–1425, 2017 28187980

Timmermans SAMEG, Abdul-Hamid MA, Potjewijd J, Theunissen ROMFIH, Damoiseaux JGMC, Reutelingsperger CP, van Paassen P; Limburg Renal Registry: C5b9 formation on endothelial cells reflects complement defects among patients with renal thrombotic microangiopathy and severe hypertension. J Am Soc Nephrol 29: 2234–2243, 2018 29858281

Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Brückner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M: Molecular intercommunication between the complement and coagulation systems. J Immunol 185: 5628–5636, 2010 20870944

Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD: Complement and coagulation: Strangers or partners in crime? Trends Immunol 28: 184–192, 2007 17336159

Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B: Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: Possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes 51: 1779–1784, 2002 12031965

Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, Lambris JD, Huber-Lang M: Interaction between the coagulation and complement system. Adv Exp Med Biol 632: 71–79, 2008 19025115

Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD: Interactions between coagulation and complement--their role in inflammation. Semin Immunopathol 34: 151–165, 2012 21811895

Keowmaneechai E, McClements DJ: Influence of EDTA and citrate on physicochemical properties of whey protein-stabilized oil-in-water emulsions containing CaCl 2 . J Agric Food Chem 50: 7145–7153, 200212428974

Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: their course and prognosis. Am J Med Sci 268: 336–345, 1974