Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression

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

doi:10.1016/j.ekir.2025.04.035

Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	2344-2356
Number of pages	13
Journal	Kidney International Reports
Volume	10
Issue number	7
Early online date	21 Apr 2025
DOIs	https://doi.org/10.1016/j.ekir.2025.04.035
Publication status	Published - Jul 2025

Keywords / Materials (for Non-textual outputs)

aging
biomarkers
cellular senescence
chronic kidney disease
clusterin
fibrosis

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10.1016/j.ekir.2025.04.035Licence: Creative Commons: Attribution (CC-BY)

Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease ProgressionFinal published version, 2.28 MBLicence: Creative Commons: Attribution (CC-BY)

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Baird, D. P., Reck, M., Campbell, R., Docherty, M.-H., Janas, P. P., Mason, T., Mortuza, Z., Vermeren, M., Nam, A., Yang, W., Schurman, N., Williams, C., Traynor, J. P., Mark, P. B., Mylonas, K. J., Hughes, J., Denby, L., Conway, B. R., & Ferenbach, D. A. (2025). Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression. Kidney International Reports, 10(7), 2344-2356. https://doi.org/10.1016/j.ekir.2025.04.035

@article{d4e8e86bd8ef42feb2dec6b3f95483c1,

title = "Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression",

abstract = "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. ",

keywords = "aging, biomarkers, cellular senescence, chronic kidney disease, clusterin, fibrosis",

author = "Baird, \{David P\} and Maximilian Reck and Ross Campbell and Marie-Helena Docherty and Janas, \{Piotr P\} and Tilly Mason and Zenuida Mortuza and Matthieu Vermeren and Andy Nam and Wei Yang and Nathan Schurman and Claire Williams and Traynor, \{Jamie P\} and Mark, \{Patrick B\} and Mylonas, \{Katie J\} and Jeremy Hughes and Laura Denby and Conway, \{Bryan R\} and Ferenbach, \{David A\}",

note = "{\textcopyright} 2025 International Society of Nephrology. Published by Elsevier Inc.",

year = "2025",

month = jul,

doi = "10.1016/j.ekir.2025.04.035",

language = "English",

volume = "10",

pages = "2344--2356",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier",

number = "7",

}

Baird, DP, Reck, M, Campbell, R, Docherty, M-H, Janas, PP, Mason, T, Mortuza, Z , Vermeren, M, Nam, A, Yang, W, Schurman, N, Williams, C, Traynor, JP, Mark, PB, Mylonas, KJ , Hughes, J , Denby, L , Conway, BR & Ferenbach, DA 2025, 'Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression', Kidney International Reports, vol. 10, no. 7, pp. 2344-2356. https://doi.org/10.1016/j.ekir.2025.04.035

TY - JOUR

T1 - Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression

AU - Baird, David P

AU - Reck, Maximilian

AU - Campbell, Ross

AU - Docherty, Marie-Helena

AU - Janas, Piotr P

AU - Mason, Tilly

AU - Mortuza, Zenuida

AU - Vermeren, Matthieu

AU - Nam, Andy

AU - Yang, Wei

AU - Schurman, Nathan

AU - Williams, Claire

AU - Traynor, Jamie P

AU - Mark, Patrick B

AU - Mylonas, Katie J

AU - Hughes, Jeremy

AU - Denby, Laura

AU - Conway, Bryan R

AU - Ferenbach, David A

PY - 2025/7

Y1 - 2025/7

N2 - 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.

AB - 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.

KW - aging

KW - biomarkers

KW - cellular senescence

KW - chronic kidney disease

KW - clusterin

KW - fibrosis

U2 - 10.1016/j.ekir.2025.04.035

DO - 10.1016/j.ekir.2025.04.035

M3 - Article

C2 - 40677355

SN - 2468-0249

VL - 10

SP - 2344

EP - 2356

JO - Kidney International Reports

JF - Kidney International Reports

IS - 7

ER -

Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

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Decoding senescent cell signalling pathways in tissue fibrosis

The discovery and validation of biomarkers of renal epithelial senescence in the human kidney

Selective targeting of GPR176 as a paradigm for the development of novel renal anti-fibrotic drugs

Cite this

Urinary Clusterin is a Biomarker of Renal Epithelial Senescence and Predicts Human Kidney Disease Progression

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Projects

Decoding senescent cell signalling pathways in tissue fibrosis

The discovery and validation of biomarkers of renal epithelial senescence in the human kidney

Selective targeting of GPR176 as a paradigm for the development of novel renal anti-fibrotic drugs

Cite this