Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression
Introduction: Cellular senescence is characterized by generally irreversible cell cycle arrest and changes in secretory activity, with senescent renal epithelia proposed as drivers of kidney fibrosis. The lack of noninvasive biomarkers represents an obstacle to the design of human trials of senescen...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024925002608 |
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| author | David P. Baird Maximilian Reck Ross Campbell Marie-Helena Docherty Piotr P. Janas Tilly Mason Zenuida Mortuza Matthieu Vermeren Andy Nam Wei Yang Nathan Schurman Claire Williams Jamie P. Traynor Patrick B. Mark Katie J. Mylonas Jeremy Hughes Laura Denby Bryan R. Conway David A. Ferenbach |
| author_facet | David P. Baird Maximilian Reck Ross Campbell Marie-Helena Docherty Piotr P. Janas Tilly Mason Zenuida Mortuza Matthieu Vermeren Andy Nam Wei Yang Nathan Schurman Claire Williams Jamie P. Traynor Patrick B. Mark Katie J. Mylonas Jeremy Hughes Laura Denby Bryan R. Conway David A. Ferenbach |
| author_sort | David P. Baird |
| collection | DOAJ |
| description | Introduction: Cellular senescence is characterized by generally irreversible cell cycle arrest and changes in secretory activity, with senescent renal epithelia proposed as drivers of kidney fibrosis. The lack of noninvasive biomarkers represents an obstacle to the design of human trials of senescent cell–depleting medications. Methods: Proteomic analysis was performed on urine from patients with chronic kidney disease (CKD) alongside immunofluorescence staining of paired kidney biopsies (n = 51). Enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence staining were performed in a second cohort of matched urine and kidney biopsies (n = 53). Spatial transcriptomic analysis was performed on kidney tissue from benign and fibrotic kidney disease (n = 13). Clusterin and senescence markers were analyzed in vitro by quantitative polymerase chain reaction (PCR) in irradiated human renal epithelia. Urinary biomarker concentrations were quantified by ELISA (n = 322) to assess their ability to predict patient outcomes (end-stage kidney disease or > 40% renal functional loss). Results: P21+Ki67- epithelial senescence correlated with age and inversely with renal function. Urinary clusterin-to-creatinine ratio (uCCR) correlated tightly with P21+Ki67- epithelial senescence in both matched urine and kidney biopsy cohorts (rho > 0.5, P < 0.001) and predicted levels of senescence after adjusting for other variables. Clusterin was upregulated transcriptomically in CDKN1A (p21) expressing epithelia in vitro and in vivo. An elevated uCCR predicted adverse renal end points in a cohort of patients with CKD after adjusting for baseline estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), age, systolic blood pressure, and sex. Conclusion: uCCR represents a surrogate for histologic quantification of p21+Ki67- senescent renal epithelia and predicts outcomes in human kidney disease independent of existing clinical risk factors. |
| format | Article |
| id | doaj-art-d2a26e159f814b64b95e56888c0ec455 |
| institution | OA Journals |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj-art-d2a26e159f814b64b95e56888c0ec4552025-08-20T02:35:19ZengElsevierKidney International Reports2468-02492025-07-011072344235610.1016/j.ekir.2025.04.035Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease ProgressionDavid P. Baird0Maximilian Reck1Ross Campbell2Marie-Helena Docherty3Piotr P. Janas4Tilly Mason5Zenuida Mortuza6Matthieu Vermeren7Andy Nam8Wei Yang9Nathan Schurman10Claire Williams11Jamie P. Traynor12Patrick B. Mark13Katie J. Mylonas14Jeremy Hughes15Laura Denby16Bryan R. Conway17David A. Ferenbach18Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UK; Correspondence: David P. Baird, Centre for Inflammation Research, Institute for Regeneration and Repair, 4-5 Little France Crescent, Edinburgh EH16 4UU, UK.Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKBruker Spatial Biology, Seattle, Washington, USABruker Spatial Biology, Seattle, Washington, USABruker Spatial Biology, Seattle, Washington, USABruker Spatial Biology, Seattle, Washington, USASchool of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UKSchool of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKCentre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKCentre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UKCentre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, UKIntroduction: Cellular senescence is characterized by generally irreversible cell cycle arrest and changes in secretory activity, with senescent renal epithelia proposed as drivers of kidney fibrosis. The lack of noninvasive biomarkers represents an obstacle to the design of human trials of senescent cell–depleting medications. Methods: Proteomic analysis was performed on urine from patients with chronic kidney disease (CKD) alongside immunofluorescence staining of paired kidney biopsies (n = 51). Enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence staining were performed in a second cohort of matched urine and kidney biopsies (n = 53). Spatial transcriptomic analysis was performed on kidney tissue from benign and fibrotic kidney disease (n = 13). Clusterin and senescence markers were analyzed in vitro by quantitative polymerase chain reaction (PCR) in irradiated human renal epithelia. Urinary biomarker concentrations were quantified by ELISA (n = 322) to assess their ability to predict patient outcomes (end-stage kidney disease or > 40% renal functional loss). Results: P21+Ki67- epithelial senescence correlated with age and inversely with renal function. Urinary clusterin-to-creatinine ratio (uCCR) correlated tightly with P21+Ki67- epithelial senescence in both matched urine and kidney biopsy cohorts (rho > 0.5, P < 0.001) and predicted levels of senescence after adjusting for other variables. Clusterin was upregulated transcriptomically in CDKN1A (p21) expressing epithelia in vitro and in vivo. An elevated uCCR predicted adverse renal end points in a cohort of patients with CKD after adjusting for baseline estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), age, systolic blood pressure, and sex. Conclusion: uCCR represents a surrogate for histologic quantification of p21+Ki67- senescent renal epithelia and predicts outcomes in human kidney disease independent of existing clinical risk factors.http://www.sciencedirect.com/science/article/pii/S2468024925002608agingbiomarkerscellular senescencechronic kidney diseaseclusterinfibrosis |
| spellingShingle | David P. Baird Maximilian Reck Ross Campbell Marie-Helena Docherty Piotr P. Janas Tilly Mason Zenuida Mortuza Matthieu Vermeren Andy Nam Wei Yang Nathan Schurman Claire Williams Jamie P. Traynor Patrick B. Mark Katie J. Mylonas Jeremy Hughes Laura Denby Bryan R. Conway David A. Ferenbach Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression Kidney International Reports aging biomarkers cellular senescence chronic kidney disease clusterin fibrosis |
| title | Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression |
| title_full | Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression |
| title_fullStr | Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression |
| title_full_unstemmed | Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression |
| title_short | Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression |
| title_sort | urinary clusterin is a biomarker of renal epithelial senescence and predicts human kidney disease progression |
| topic | aging biomarkers cellular senescence chronic kidney disease clusterin fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2468024925002608 |
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