{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T03:48:16Z","timestamp":1785037696599,"version":"3.55.0"},"reference-count":67,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2705101"],"award-info":[{"award-number":["2022YFC2705101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Despite observational links between glucagon\u2010like peptide\u20101 receptor agonists (GLP\u20101RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP\u20101RAs on chronic kidney disease (CKD) and related renal outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Using large\u2010scale Genome \u2010 Wide Association Study (GWAS) data, we applied two\u2010sample Mendelian randomisation (MR) to estimate the causal effects of GLP\u20101RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome \u2010 Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort\u2010specific studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Positive control analyses revealed that genetically predicted GLP\u20101R activation was associated with reduced levels of HbA1c (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20094.93E\u221215) and blood glucose (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20099.73E\u22125), as well as a decreased risk of T2DM (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20092.45E\u22124) and DN (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20096.35E\u22124), fully validating the reliability of the genetic instruments. Genetic proxies for GLP\u20101R activation lowered risks of CKD (odds ratio [OR]\u2009=\u20090.83,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20099.22E\u22129), immunoglobulin A nephropathy (IgAN) (OR\u2009=\u20090.70,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20092.11E\u22123) and kidney function preservation (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.01,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20099.11E\u22123), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high\u2010density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides robust genetic evidence for repurposing GLP\u20101RAs in CKD and IgAN through anti\u2010inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70144","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T06:15:50Z","timestamp":1758780950000},"page":"7395-7407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genetic evidence for repurposing GLP\u20101 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti\u2010inflammatory pathways beyond glycaemic control"],"prefix":"10.1111","volume":"27","author":[{"given":"Xueying","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders Ministry of Education Key Laboratory of Child 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China"},{"name":"Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders Ministry of Education Key Laboratory of Child Development and Disorders  Chongqing China"},{"name":"Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0456-9304","authenticated-orcid":false,"given":"Haiping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders Ministry of Education Key Laboratory of Child Development and 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