Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis

the Accelerating Medicines Partnership in RA/SLE network

doi:10.1172/jci.insight.172569

Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis

the Accelerating Medicines Partnership in RA/SLE network

Bar-Ilan University - Azrieli Faculty of Medicine

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

12 Scopus citations

Abstract

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL- 16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

Original language	English
Article number	e172569
Journal	JCI insight
Volume	9
Issue number	2
DOIs	https://doi.org/10.1172/jci.insight.172569
State	Published - 23 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024, Fava et al.

Funding

We would like to thank the patients who participated in this study and the scientists and clinical sites in the AMP in RA/SLE. We thank Felipe Andrade and René Ferretti for their critical review of the interpretation of the results. This work was supported by the AMP RA/SLE network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol Myers Squibb, GlaxoSmithKline, Lupus Foundation of America, Lupus Research Alliance, Janssen, Merck Sharp & Dohme Corp., NIH National Institute of Allergy and Infectious Diseases, NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals International Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. See Supplemental Acknowledgments for a list of members of the AMP RA/SLE network. This work was supported by NIH grants UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694, UM2-AR067678, and AR074096. The Oklahoma Rheumatic Disease Research Cores Center is funded by NIH P30AR073750. The Hopkins Lupus Cohort is funded by NIH R01 AR069572. AF is supported by NIH R01 DK134625, the Jerome L. Greene Foundation, the Plank Scholarship, and the Lupus Foundation of America G-2104-01274.

Funders	Funder number
National Institutes of Health	AR074096, P30AR073750, UM2-AR067678, UH2-AR067691, UH2-AR067681, UH2-AR067694, UH2-AR067690, UH2-AR067677, UH2-AR067688, UH2-AR067689, UH2-AR067679, UH2-AR067685, R01 AR069572, R01 DK134625, UH2-AR067676
Lupus Foundation of America	G-2104-01274
Jerome L. Greene Foundation

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10.1172/jci.insight.172569

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title = "Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis",

abstract = "Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL- 16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.",

author = "{the Accelerating Medicines Partnership in RA/SLE network} and Andrea Fava and Jill Buyon and Laurence Magder and Jeff Hodgin and Avi Rosenberg and Demeke, {Dawit S.} and Rao, {Deepak A.} and Arnon Arazi and Celia, {Alessandra Ida} and Chaim Putterman and Anolik, {Jennifer H.} and Jennifer Barnas and Maria Dall{\textquoteright}Era and David Wofsy and Richard Furie and Diane Kamen and Kenneth Kalunian and James, {Judith A.} and Joel Guthridge and Atta, {Mohamed G.} and Trujillo, {Jose Monroy} and Derek Fine and Robert Clancy and Belmont, {H. Michael} and Peter Izmirly and William Apruzzese and Daniel Goldman and Berthier, {Celine C.} and Paul Hoover and Nir Hacohen and Soumya Raychaudhuri and Anne Davidson and Betty Diamond and Michelle Petri",

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AU - Fava, Andrea

AU - Buyon, Jill

AU - Magder, Laurence

AU - Hodgin, Jeff

AU - Rosenberg, Avi

AU - Demeke, Dawit S.

AU - Rao, Deepak A.

AU - Arazi, Arnon

AU - Celia, Alessandra Ida

AU - Putterman, Chaim

AU - Anolik, Jennifer H.

AU - Barnas, Jennifer

AU - Dall’Era, Maria

AU - Wofsy, David

AU - Furie, Richard

AU - Kamen, Diane

AU - Kalunian, Kenneth

AU - James, Judith A.

AU - Guthridge, Joel

AU - Atta, Mohamed G.

AU - Trujillo, Jose Monroy

AU - Fine, Derek

AU - Clancy, Robert

AU - Belmont, H. Michael

AU - Izmirly, Peter

AU - Apruzzese, William

AU - Goldman, Daniel

AU - Berthier, Celine C.

AU - Hoover, Paul

AU - Hacohen, Nir

AU - Raychaudhuri, Soumya

AU - Davidson, Anne

AU - Diamond, Betty

AU - Petri, Michelle

PY - 2024/1/23

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N2 - Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL- 16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

AB - Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL- 16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

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Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis

Abstract

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