{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:51:48Z","timestamp":1785210708018,"version":"3.55.0"},"reference-count":52,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004528","name":"Maastricht Universitair Medisch Centrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004528","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011068","name":"Fondation Saint Luc","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011068","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006396","name":"Alexion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["kireports.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Kidney International Reports"],"published-print":{"date-parts":[[2021,4]]},"DOI":"10.1016\/j.ekir.2021.01.034","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T00:27:32Z","timestamp":1612571252000},"page":"1099-1109","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":24,"title":["Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes"],"prefix":"10.1016","volume":"6","author":[{"given":"Sjoerd A.M.E.G.","family":"Timmermans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.M.C.","family":"Damoiseaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Werion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris P.","family":"Reutelingsperger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Morelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"van Paassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ekir.2021.01.034_bib1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0140-6736(17)30062-4","article-title":"Haemolytic uraemic syndrome","volume":"390","author":"Fakhouri","year":"2017","journal-title":"Lancet"},{"key":"10.1016\/j.ekir.2021.01.034_bib2","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.2215\/CJN.02210310","article-title":"Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype","volume":"5","author":"Noris","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib3","doi-asserted-by":"crossref","first-page":"554","DOI":"10.2215\/CJN.04760512","article-title":"Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults","volume":"8","author":"Fremeaux-Bacchi","year":"2013","journal-title":"Clin J Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib4","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1056\/NEJMoa1208981","article-title":"Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome","volume":"368","author":"Legendre","year":"2013","journal-title":"N\u00a0Engl J Med"},{"key":"10.1016\/j.ekir.2021.01.034_bib5","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/ki.2014.423","article-title":"Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies","volume":"87","author":"Licht","year":"2015","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1053\/j.ajkd.2015.12.034","article-title":"Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial","volume":"68","author":"Fakhouri","year":"2016","journal-title":"Am J Kidney Dis"},{"key":"10.1016\/j.ekir.2021.01.034_bib7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00467-015-3076-8","article-title":"An international consensus approach to the management of atypical hemolytic uremic syndrome in children","volume":"31","author":"Loirat","year":"2016","journal-title":"Pediatr Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib8","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.kint.2016.10.005","article-title":"Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a \u201cKidney Disease: Improving Global Outcomes\u201d (KDIGO) Controversies Conference","volume":"91","author":"Goodship","year":"2017","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib9","doi-asserted-by":"crossref","first-page":"364","DOI":"10.2215\/CJN.05830518","article-title":"Complement gene variants and Shiga toxin\u2013producing Escherichia coli\u2013associated hemolytic uremic syndrome: retrospective genetic and clinical study","volume":"14","author":"Fremeaux-Bacchi","year":"2019","journal-title":"Clin J Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib10","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/j.1469-1809.2011.00671.x","article-title":"Age-related penetrance of hereditary atypical hemolytic uremic syndrome","volume":"75","author":"Sullivan","year":"2011","journal-title":"Ann Hum Genet"},{"key":"10.1016\/j.ekir.2021.01.034_bib11","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1182\/blood.2020006931","article-title":"Familial risk of developing atypical hemolytic-uremic syndrome","volume":"136","author":"Arjona","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib12","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1681\/ASN.2018020184","article-title":"C5b9 formation on endothelial cells reflects complement defects among patients with renal thrombotic microangiopathy and severe hypertension","volume":"29","author":"Timmermans","year":"2018","journal-title":"J\u00a0Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib13","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1161\/HYPERTENSIONAHA.119.13714","article-title":"Diagnostic and risk factors for complement defects in hypertensive emergency and thrombotic microangiopathy","volume":"75","author":"Timmermans","year":"2020","journal-title":"Hypertension"},{"key":"10.1016\/j.ekir.2021.01.034_bib14","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/j.1523-1755.2004.00835.x","article-title":"Signs and symptoms of thin basement membrane nephropathy: a prospective regional study on primary glomerular disease-The Limburg Renal Registry","volume":"66","author":"van Paassen","year":"2004","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib15","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0010208","article-title":"Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience","volume":"5","author":"Coppo","year":"2010","journal-title":"PLoS One"},{"key":"10.1016\/j.ekir.2021.01.034_bib16","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ki.2010.483","article-title":"The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report","volume":"80","author":"Levey","year":"2011","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib17","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1309\/AJCPXPD7ZQXNTIAL","article-title":"Effect of blood sampling, processing, and storage on the measurement of complement activation biomarkers","volume":"143","author":"Yang","year":"2015","journal-title":"Am J Clin Pathol"},{"key":"10.1016\/j.ekir.2021.01.034_bib18","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1182\/blood-2014-02-558296","article-title":"Dynamics of complement activation in aHUS and how to monitor eculizumab therapy","volume":"124","author":"Noris","year":"2014","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib19","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.kint.2019.04.011","article-title":"Defects in complement and \u201csecondary\u201d hemolytic uremic syndrome","volume":"96","author":"Timmermans","year":"2019","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"10.1016\/j.ekir.2021.01.034_bib21","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.4049\/jimmunol.1701695","article-title":"Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy","volume":"200","author":"Osborne","year":"2018","journal-title":"J\u00a0Immunol"},{"key":"10.1016\/j.ekir.2021.01.034_bib22","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1681\/ASN.2004050380","article-title":"Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome","volume":"16","author":"Dragon-Durey","year":"2005","journal-title":"J\u00a0Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib23","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1182\/blood.2020005171","article-title":"More about complement in the antiphospholipid syndrome","volume":"136","author":"Timmermans","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib24","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1182\/blood-2013-03-489245","article-title":"Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome","volume":"122","author":"Frimat","year":"2013","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib25","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ebiom.2016.02.011","article-title":"Complement activation in arterial and venous thrombosis is mediated by plasmin","volume":"5","author":"Foley","year":"2016","journal-title":"EBioMedicine"},{"key":"10.1016\/j.ekir.2021.01.034_bib26","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1093\/ndt\/gfaa050","article-title":"Chronic thrombotic microangiopathy in patients with a C3 gain of function protein","volume":"35","author":"Timmermans","year":"2020","journal-title":"Nephrol Dial Transplant"},{"key":"10.1016\/j.ekir.2021.01.034_bib27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1159\/000497779","article-title":"Mother and child reunion in \u201chypertensive\u201d end-stage renal disease: will they complement each other?","volume":"142","author":"Timmermans","year":"2019","journal-title":"Nephron"},{"key":"10.1016\/j.ekir.2021.01.034_bib28","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.1182\/blood-2013-12-547067","article-title":"Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP","volume":"123","author":"Cataland","year":"2014","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1053\/j.ajkd.2018.11.012","article-title":"An ex\u00a0vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome","volume":"74","author":"Galbusera","year":"2019","journal-title":"Am J Kidney Dis"},{"key":"10.1016\/j.ekir.2021.01.034_bib30","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.1182\/blood-2015-02-629683","article-title":"Modified Ham test for atypical hemolytic uremic syndrome","volume":"125","author":"Gavriilaki","year":"2015","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib31","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.99128","article-title":"Germline mutations in the alternative pathway of complement predispose to HELLP syndrome","volume":"3","author":"Vaught","year":"2018","journal-title":"JCI Insight"},{"key":"10.1016\/j.ekir.2021.01.034_bib32","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.exphem.2016.01.005","article-title":"Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome","volume":"44","author":"Vaught","year":"2016","journal-title":"Exp Hematol"},{"key":"10.1016\/j.ekir.2021.01.034_bib33","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1093\/ndt\/gfw314","article-title":"Atypical haemolytic uraemic syndrome and pregnancy: outcome with ongoing eculizumab","volume":"31","author":"Servais","year":"2016","journal-title":"Nephrol Dial Transplant"},{"key":"10.1016\/j.ekir.2021.01.034_bib34","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/bjh.16626","article-title":"The natural course of pregnancies in women with primary atypical haemolytic uraemic syndrome and asymptomatic relatives","volume":"190","author":"Timmermans","year":"2020","journal-title":"Br J Haematol"},{"key":"10.1016\/j.ekir.2021.01.034_bib35","doi-asserted-by":"crossref","first-page":"579418","DOI":"10.3389\/fmed.2020.579418","article-title":"Molecular studies and an ex\u00a0vivo complement assay on endothelium highlight the genetic complexity of atypical hemolytic uremic syndrome: the case of a pedigree with a null CD46 variant","volume":"7","author":"Piras","year":"2020","journal-title":"Front Med (Lausanne)"},{"key":"10.1016\/j.ekir.2021.01.034_bib36","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/ajt.12077","article-title":"Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome","volume":"13","author":"Le Quintrec","year":"2013","journal-title":"Am J Transplant"},{"key":"10.1016\/j.ekir.2021.01.034_bib37","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.kint.2016.12.009","article-title":"Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities","volume":"91","author":"Timmermans","year":"2017","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib38","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.kint.2019.05.014","article-title":"Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome","volume":"96","author":"Cavero","year":"2019","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib39","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.3324\/haematol.2019.216903","article-title":"Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome","volume":"104","author":"El Karoui","year":"2019","journal-title":"Haematologica"},{"key":"10.1016\/j.ekir.2021.01.034_bib40","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.2215\/CJN.00280117","article-title":"Hemolytic uremic syndrome in pregnancy and postpartum","volume":"12","author":"Bruel","year":"2017","journal-title":"Clin J Am Soc Nephrol"},{"key":"10.1016\/j.ekir.2021.01.034_bib41","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1111\/j.1600-6143.2008.02297.x","article-title":"Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation","volume":"8","author":"Le Quintrec","year":"2008","journal-title":"Am J Transplant"},{"key":"10.1016\/j.ekir.2021.01.034_bib42","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/j.kint.2019.01.023","article-title":"Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors","volume":"95","author":"Le Clech","year":"2019","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib43","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/ndt\/gfw453","article-title":"Eculizumab in secondary atypical haemolytic uraemic syndrome","volume":"32","author":"Cavero","year":"2017","journal-title":"Nephrol Dial Transplant"},{"key":"10.1016\/j.ekir.2021.01.034_bib44","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1046\/j.1523-1755.1999.00492.x","article-title":"Cyclosporine-associated thrombotic microangiopathy in renal allografts","volume":"55","author":"Zarifian","year":"1999","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib45","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.kint.2017.03.048","article-title":"The authors reply","volume":"92","author":"Timmermans","year":"2017","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib46","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/cpt.686","article-title":"Eculizumab dosing regimen in atypical HUS: possibilities for individualized treatment","volume":"102","author":"Volokhina","year":"2017","journal-title":"Clin Pharmacol Ther"},{"key":"10.1016\/j.ekir.2021.01.034_bib47","doi-asserted-by":"crossref","first-page":"4182","DOI":"10.1182\/blood-2011-10-383281","article-title":"A\u00a0prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function","volume":"119","author":"Roumenina","year":"2012","journal-title":"Blood"},{"key":"10.1016\/j.ekir.2021.01.034_bib48","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1093\/hmg\/ddaa114","article-title":"Effect of rare coding variants in the CFI gene on Factor I expression levels","volume":"29","author":"de Jong","year":"2020","journal-title":"Hum Mol Genet"},{"key":"10.1016\/j.ekir.2021.01.034_bib49","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1002\/eji.200939280","article-title":"Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I","volume":"40","author":"Nilsson","year":"2010","journal-title":"Eur J Immunol"},{"key":"10.1016\/j.ekir.2021.01.034_bib50","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ki.2009.472","article-title":"Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome","volume":"77","author":"Bienaime","year":"2010","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib51","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.kint.2017.07.015","article-title":"Complete functional characterization of disease-associated genetic variants in the complement factor H gene","volume":"93","author":"Merinero","year":"2018","journal-title":"Kidney Int"},{"key":"10.1016\/j.ekir.2021.01.034_bib52","doi-asserted-by":"crossref","first-page":"12966","DOI":"10.1073\/pnas.2135497100","article-title":"Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome","volume":"100","author":"Richards","year":"2003","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Kidney International Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S246802492100067X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S246802492100067X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T03:35:43Z","timestamp":1762832143000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S246802492100067X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":52,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["S246802492100067X"],"URL":"https:\/\/doi.org\/10.1016\/j.ekir.2021.01.034","relation":{},"ISSN":["2468-0249"],"issn-type":[{"value":"2468-0249","type":"print"}],"subject":[],"published":{"date-parts":[[2021,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes","name":"articletitle","label":"Article Title"},{"value":"Kidney International Reports","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ekir.2021.01.034","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 International Society of Nephrology. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}