{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:28:31Z","timestamp":1790692111883,"version":"4.1.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20\u201340% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for <jats:italic>CFH<\/jats:italic> and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the <jats:italic>CFHR5<\/jats:italic> gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.<\/jats:p>","DOI":"10.3389\/fgene.2021.529236","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T07:44:47Z","timestamp":1621496687000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy"],"prefix":"10.3389","volume":"12","author":[{"given":"Gabriella","family":"Guzzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salima","family":"Sadallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Fodstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Venetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Rotman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Teta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Gauthier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pantaleo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Superti-Furga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Pascual","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4261","DOI":"10.1182\/blood-2009-05-223834","article-title":"Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical haemolytic uremic syndrome","volume":"114","author":"Abarrategui-Garrido","year":"2009","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1001\/jamainternmed.2019.0600","article-title":"Evaluating a new international risk-prediction tool in IgA nephropathy","volume":"179","author":"Barbour","year":"2019","journal-title":"JAMA Intern. Med"},{"key":"B3","first-page":"694","article-title":"Les depots intercapillaires d'IgA-IgG","volume":"74","author":"Berger","year":"1968","journal-title":"J. Urol. Nephrol"},{"key":"B4","unstructured":"2021"},{"key":"B5","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1056\/NEJMra020109","article-title":"IgA nephropathy","volume":"347","author":"Donadio","year":"2002","journal-title":"N. Engl. J. Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/S0140-6736(10)60670-8","article-title":"Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis","volume":"376","author":"Gale","year":"2010","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1093\/ndt\/gfs441","article-title":"C3 glomerulonephritis and CFHR5 nephropathy","volume":"28","author":"Gale","year":"2013","journal-title":"Nephrol. Dial. Transplant"},{"key":"B8","unstructured":"2021"},{"key":"B9","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/ng.787","article-title":"Genome-wide association study identifies susceptibility loci for IgA nephropathy","volume":"43","author":"Gharavi","year":"2011","journal-title":"Nat. Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4685","DOI":"10.1073\/pnas.1219260110","article-title":"Dimerization of complement factor H-related proteins modulates complement activation in vivo","volume":"110","author":"Goicoechea de Jorge","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B11","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.molimm.2018.06.008","article-title":"Developments in anti-complement therapy; from disease to clinical trial","volume":"102","author":"Harris","year":"2018","journal-title":"Mol. Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1517\/17530059.2013.856878","article-title":"Biomarkers in IgA nephropathy: relationship to pathogenetic hits","volume":"7","author":"Hastings","year":"2013","journal-title":"Expert Opion. Med. Diagn"},{"key":"B13","doi-asserted-by":"publisher","first-page":"101331","DOI":"10.1016\/j.smim.2019.101331","article-title":"Complement dysregulation in glomerulonephritis","volume":"45","author":"Kaartinen","year":"2019","journal-title":"Semin. Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e1002765","DOI":"10.1371\/journal.pgen.1002765","article-title":"Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis","volume":"8","author":"Kiryluk","year":"2012","journal-title":"PLoS Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"98","DOI":"10.5414\/CN107854","article-title":"Association of C1q deposition with renal outcomes in IgA nephropathy","volume":"80","author":"Lee","year":"2013","journal-title":"Clin. Nephrol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1681\/ASN.2014101000","article-title":"Current understanding of the role of complement in IgA nephropathy","volume":"26","author":"Maillard","year":"2015","journal-title":"J. Am. Soc. Nephrol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.ekir.2017.11.015","article-title":"Progressive IgA nephropathy is associated with low circulating mannan-binding lectin-associated serine protease-3 (MASP-3) and increased glomerular factor-H related protein-5 (FHR5) deposition","volume":"29","author":"Medjeral-Thomas","year":"2017","journal-title":"Kidney Int Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1038\/sj.ki.5002185","article-title":"Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels","volume":"71","author":"Moldoveanu","year":"2007","journal-title":"Kidney Int"},{"key":"B19","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1159\/000485194","article-title":"Atypical hemolytic uremic syndrome associated with complement factor H Mutation and IgA nephropathy: a case report successfully treated with eculizumab","volume":"138","author":"Nakamura","year":"2018","journal-title":"Nephron"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.1093\/ndt\/gfr664","article-title":"IgA nephropathy recurs early in the graft when assessed by protocol biopsy","volume":"27","author":"Ortiz","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1046\/j.1523-1755.2001.00006.x","article-title":"Kidney transplantation in patients with IgA mesangial glomerulonephritis","volume":"60","author":"Ponticelli","year":"2001","journal-title":"Kidney Int"},{"key":"B22","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1097\/00007890-198204000-00006","article-title":"Fate of four cadaveric donor renal allografts with mesangial IgA deposits","volume":"33","author":"Sanfilippo","year":"1982","journal-title":"Transplantation"},{"key":"B23","first-page":"182","article-title":"Complement depletion abolishes IgA-mediated glomerular inflammation in rats","volume":"2","author":"Stad","year":"1994","journal-title":"Exp. Nephrol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1681\/ASN.2011050464","article-title":"The pathophysiology of IgA nephropathy","volume":"22","author":"Suzuki","year":"2011","journal-title":"J. Am. Soc. Nephrol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1046\/j.1523-1755.63.6s.2.x","article-title":"Incidence of latent mesangial IgA deposition in renal allograft donors in Japan","volume":"63","author":"Suzuki","year":"2003","journal-title":"Kidney Int"},{"key":"B26","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.molimm.2019.07.017","article-title":"The role of complement in IgA nephropathy","volume":"114","author":"Tortajada","year":"2019","journal-title":"Mol. Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1053\/j.ajkd.2012.02.329","article-title":"Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency","volume":"60","author":"Vernon","year":"2012","journal-title":"Am. J. Kidney Dis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2894","DOI":"10.1681\/ASN.2015010012","article-title":"Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy","volume":"27","author":"Zhai","year":"2016","journal-title":"J. Am. Soc. Nephrol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.kint.2018.02.023","article-title":"Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy","volume":"94","author":"Zhu","year":"2018","journal-title":"Kidney Int"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.529236\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T15:29:24Z","timestamp":1623857364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.529236\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,20]]},"references-count":29,"alternative-id":["10.3389\/fgene.2021.529236"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.529236","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,20]]},"article-number":"529236"}}