{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:00:18Z","timestamp":1790874018941,"version":"4.1.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"abstract":"\n Key Points<\/jats:title>\n \n \n \n Elevated growth differentiation factor-15 was associated with higher CKD risk, whereas Mendelian randomization suggested a possible protective association with kidney function.<\/jats:p>\n <\/jats:list-item>\n \n Proteomics identified TNF receptor signaling, extracellular matrix organization, and leukocyte chemotaxis as candidate pathways.<\/jats:p>\n <\/jats:list-item>\n \n Growth differentiation factor-15 may serve as a prognostic biomarker, while its possible protective role and underlying mechanisms require further study.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n Growth differentiation factor-15 (GDF-15) has been implicated in adverse outcomes in cardiovascular disease and diabetes, highlighting its potential as a prognostic marker. However, its association with CKD development remains unclear. Therefore, we investigated the association between GDF-15 and incident CKD and explored potential causal mechanisms.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed 31,965 UK Biobank participants without preexisting CKD. The primary outcome was incident CKD, defined by diagnostic codes or an eGFR <60 ml\/min per 1.73 m\n 2<\/jats:sup>\n (eGFR-based CKD). Proteomics-based mediation and protein\u2013protein interaction analyses identified potential mediators linking GDF-15 to CKD. A bidirectional 2-sample Mendelian randomization (MR) analysis using genome-wide association study summary statistics evaluated the potential causal relationship between GDF-15 and eGFR.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In multivariable cause-specific analyses, higher GDF-15 levels were significantly associated with increased CKD risk (hazard ratios: Q2, 1.05 [0.87 to 1.26]; Q3, 1.21 [1.01 to 1.45]; Q4, 1.87 [1.56 to 2.26] versus Q1;\n P<\/jats:italic>\n for trend < 0.001). Similar results were observed for eGFR-based CKD. Mediation analysis identified candidate proteins potentially involved in TNF receptor signaling, extracellular matrix organization, and immune cell chemotaxis. MR analysis demonstrated a significant association between genetically predicted higher GDF-15 levels and higher eGFR (inverse-variance weighted coefficient, 0.003; 95% confidence interval, 0.001 to 0.004;\n P<\/jats:italic>\n = 0.004). Conversely, higher genetically predicted eGFR was associated with lower GDF-15 levels (inverse-variance weighted coefficient, \u22121.238; 95% confidence interval, \u22121.591 to \u22120.886;\n P<\/jats:italic>\n < 0.001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n This study provides evidence supporting the role of GDF-15 as a prognostic biomarker for CKD and MR analyses provide suggestive evidence of a possible protective association of GDF-15 with kidney function. Further studies are needed to explore the mechanistic pathways and therapeutic implications of GDF-15 in kidney diseases.<\/jats:p>\n <\/jats:sec>","DOI":"10.2215\/cjn.0000001177","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:01:13Z","timestamp":1787673673000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Levels of Growth Differentiation Factor-15 and Adverse Kidney Outcomes"],"prefix":"10.2215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-2823","authenticated-orcid":false,"given":"Hee Byung","family":"Koh","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-8473","authenticated-orcid":false,"given":"Hyo Jeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8764-7995","authenticated-orcid":false,"given":"Seok-Jae","family":"Heo","sequence":"additional","affiliation":[{"name":"Statistician Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4636-5745","authenticated-orcid":false,"given":"Cheol Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6305-452X","authenticated-orcid":false,"given":"Hyung Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-0928","authenticated-orcid":false,"given":"Young Su","family":"Joo","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-6379","authenticated-orcid":false,"given":"Tae Ik","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-8982","authenticated-orcid":false,"given":"Jung Tak","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9183-4507","authenticated-orcid":false,"given":"Tae-Hyun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-Wook","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-5635","authenticated-orcid":false,"given":"Seung Hyeok","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"10225","key":"B1-20261001","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the global burden of disease study 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