{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T20:06:34Z","timestamp":1779221194481,"version":"3.51.4"},"reference-count":145,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:p>Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.<\/jats:p>","DOI":"10.1172\/jci188353","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T07:59:44Z","timestamp":1746086384000},"source":"Crossref","is-referenced-by-count":4,"title":["Chronic kidney disease enhances alternative pathway activity: a new paradigm"],"prefix":"10.1172","volume":"135","author":[{"given":"Diana I.","family":"Jalal","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA."},{"name":"Center for Access and Delivery Research and Evaluation, Iowa City VA Health Care System, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9062-3559","authenticated-orcid":true,"given":"Joshua M.","family":"Thurman","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, Colorado, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.H.","family":"Smith","sequence":"additional","affiliation":[{"name":"Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00820-6"},{"key":"B2","unstructured":"Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. US Department of Health and Human Services, Centers for Disease Control and Prevention; 2023. https:\/\/www.cdc.gov\/kidney-disease\/php\/data-research\/index.html"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.10.018"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.550"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.451"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041031"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.167.11.1122"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-52251-9"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1159\/000495818"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2009.10.047"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(00)70262-9"},{"issue":"23 suppl 1","key":"B12","first-page":"III27","article-title":"Role of endothelial dysfunction in atherosclerosis","volume":"109","author":"Davignon","year":"2004","journal-title":"Circulation"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.602532"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1159\/000324954"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1159\/000322106"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004080656"},{"issue":"4","key":"B17","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/joneph\/17.4.512","article-title":"Endothelial dysfunction and oxidative stress in chronic renal failure","volume":"17","author":"Ghiadoni","year":"2004","journal-title":"J Nephrol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00281.x"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2006.08.008"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2013.08.051"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2008.01.021"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.864801"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.678276"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012543.55874.47"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000095273.92468.D9"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfr081"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2008.00438.x"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100080"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.804294"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glq233"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005070693"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq076"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2337\/dc22-0866"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.5301\/jn.5000047"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020111607"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0415-5"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00775-0"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41642-7"},{"issue":"8","key":"B39","first-page":"4039","article-title":"Complement factor H-deficient mice develop spontaneous hepatic tumors","volume":"130","author":"Laskowski","year":"2020","journal-title":"J Clin Invest"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/srep31877"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nri2620"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104053441406"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.152.4.1102"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.154.3.856"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.11.003"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.11.5786"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.07.008"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019338108"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02664"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13168"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.01710216"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.10.005"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2012.63"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2015.08.006"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.2.786"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2013.08.004"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014101000"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.37"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.3.1517"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.67109.x"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1805857"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-019-1640-3"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.03.043"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.03.041"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1181"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908706116"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-0699"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.10.5450"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2024.05.015"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112020"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00604.2016"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.6308"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.10.3982"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830200808"},{"issue":"1","key":"B75","first-page":"9","article-title":"The third component of complement is transcribed and secreted by cultured human endothelial cells","volume":"129","author":"Warren","year":"1987","journal-title":"Am J Pathol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.144.10.3835"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1996.tb00710.x"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2013.280"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-02011-w"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60674-5"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109557"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110359"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110189"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501536102"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/ng1890"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-8-62"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl183"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.11.076"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.00681"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.05.033"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf2489"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13155"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1084\/jem.148.6.1498"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(93)23039-P"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1084\/jem.139.2.355"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198502143120702"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112434"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1988.214"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200112023"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114384"},{"issue":"3","key":"B101","first-page":"724","article-title":"Functional deficiency of complement factor D in a monozygous twin","volume":"58","author":"Kluin-Nelemans","year":"1984","journal-title":"Clin Exp Immunol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.007818"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-87710-0"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135758"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2022.07.035"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-004-0660-7"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1135490"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01145"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1038\/ng.787"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3118"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006931"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.02.023"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1219260110"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68280"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.4.2610"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.9.4702"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/17.5.745"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1991.298"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-022-03022-z"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.5551\/jat.12286"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1177\/08968608231198984"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013070795"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2009.08.003"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.845953"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504828200"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2008.09.018"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2020.10.015"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010080795"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-008-0031-z"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2008.01.027"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000269"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1001\/jama.297.16.1793"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1001\/archophthalmol.2008.551"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007080844"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfr022"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2022.03.014"},{"key":"B137","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.2.547"},{"issue":"6","key":"B138","first-page":"747","article-title":"Prelesional complement activation in experimental atherosclerosis. Terminal C5b-9 complement deposition coincides with cholesterol accumulation in the aortic intima of hypercholesterolemic rabbits","volume":"60","author":"Seifert","year":"1989","journal-title":"Lab Invest"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001504"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.10.028"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012111064"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000216071.87981.16"},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01524-6"},{"key":"B144","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2410316"},{"key":"B145","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(23)00315-0"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/188353\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T19:17:21Z","timestamp":1779218241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/188353"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,1]]},"references-count":145,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,3,25]]},"published-print":{"date-parts":[[2025,5,1]]}},"alternative-id":["10.1172\/JCI188353"],"URL":"https:\/\/doi.org\/10.1172\/jci188353","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,1]]},"article-number":"e188353"}}