Individualised treatment effects of corticosteroids in IgA nephropathy
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: IgA nephropathy (IgAN) has diverse clinical presentations and responses to treatment. For systemic corticosteroids in particular, randomised controlled trials have reported conflicting effects, highlighting the need for individualised treatment strategies. METHODS: In this retrospective cohort study, we derived and validated a causal machine learning (ML) framework to estimate individualised corticosteroid treatment effects in IgAN. Eight international cohorts, including the VALIGA, CureGN, and NURTuRE-CKD repositories, comprising 1022 patients, were analysed (derivation, n = 464; validation, n = 558). We integrated baseline clinical data, histopathological classification scores (MEST-C), and deep learning-based histomorphological biomarkers (pathomics) from digitised kidney biopsies. The framework estimated the effect of systemic corticosteroids on the composite endpoint of a ≥50% decline in estimated glomerular filtration rate or kidney failure within five years of biopsy. FINDINGS: Across the overall study population, systemic corticosteroid therapy was not associated with a significant improvement in the composite outcome (p = 0·27). However, the causal ML framework revealed substantial treatment heterogeneity, identifying patients with high predicted benefit who achieved longer progression-free survival with corticosteroids (0·43 years, 95% CI 0·18-0·73, p < 0·01), while no benefit was observed in those with low predicted benefit (-0·005 years, 95% CI -0·3 to 0·22, p > 0·05). An individualised framework-guided treatment assignment was estimated to reduce systemic corticosteroid use by 60·7%. Pathomics facilitated the identification of interstitial inflammation and tubulitis as key features of corticosteroid response. INTERPRETATION: This study demonstrates that a causal ML framework integrating clinical, histopathological, and pathomics predictors can individualise treatment assignments for systemic corticosteroids in IgAN. This approach provides a blueprint for precision therapy in IgAN, supporting AI-enhanced clinical decision-making in the era of emerging targeted treatments. FUNDING: German Research Foundation; European Research Council; German Federal Ministry of Education and Research; German Innovation Fund of the Federal Joint Committee; Clinician Scientist Program of the Faculty of Medicine RWTH Aachen University.
Source: EBioMedicine
Authors: David L. Hölscher, Nikolas E.J. Schmitz, Leon Niggemeier, Pourya Pilva, Martin Strauch, Vladimir Tesar, Jonathan Barratt, Ian S.D. Roberts, Rosanna Coppo, Laura Barisoni, Motoko Yanagita, Ulas Alabalik, Andrew D. Rule, Jaidip M. Jagtap, Eliabe S. Abreu, Claudia Seikrit, Saskia von Stillfried, Maarten W. Taal, Philip A. Kalra, Juergen Floege, Rafael Kramann, Peter Boor, Roman D. Bülow, M.L. Russo, S. Troyanov, H.T. Cook, I.S.D. Roberts, V. Tesar, D. Maixnerova, S. Lundberg, L. Gesualdo, F. Emma, F. Diomedi, G. Beltrame, C. Rollino, A. Amore, R. Camilla, L. Peruzzi, M. Praga, S. Feriozzi, R. Polci, G. Segoloni, L. Colla, A. Pani, D. Piras, A. Angioi, G. Cancarini, S. Ravera, M. Durlik, E. Moggia, J. Ballarin, S. Di Giulio, F. Pugliese, I. Serriello, Y. Caliskan, M. Sever, I. Kilicaslan, F. Locatelli, L. Del Vecchio, J.F.M. Wetzels, H. Peters, U. Berg, F. Carvalho, A.C. da Costa Ferreira, M. Maggio, A. Wiecek, M. Ots-Rosenberg, R. Magistroni, R. Topaloglu, Y. Bilginer, M. D’Amico, M. Stangou, F. Giacchino, D. Goumenos, P. Kalliakmani, M. Papasotiriou, K. Galesic, C. Geddes, K. Siamopoulos, O. Balafa, M. Galliani, P. Stratta, M. Quaglia, R. Bergia, R. Cravero, M. Salvadori, L. Cirami, B. Fellstrom, H. Kloster Smerud, F. Ferrario, T. Stellato, J. Egido, C. Martin, J. Floege, F. Eitner, A. Lupo, P. Bernich, P. Menè, M. Morosetti, C. van Kooten, T. Rabelink, M.E.J. Reinders, J.M. Boria Grinyo, S. Cusinato, L. Benozzi, S. Savoldi, C. Licata, M. Mizerska-Wasiak, G. Martina, A. Messuerotti, A. Dal Canton, C. Esposito, C. Migotto, G. Triolo, F. Mariano, C. Pozzi, R. Boero, S. Bellur, G. Mazzucco, C. Giannakakis, E. Honsova, B. Sundelin, A.M. Di Palma, E. Gutiérrez, A.M. Asunis, J. Barratt, R. Tardanico, A. Perkowska-Ptasinska, J. Arce Terroba, M. Fortunato, A. Pantzaki, Y. Ozluk, E. Steenbergen, M. Soderberg, Z. Riispere, L. Furci, D. Orhan, D. Kipgen, D. Casartelli, D. Galesic Ljubanovic, H. Gakiopoulou, E. Bertoni, P. Cannata Ortiz, H. Karkoszka, H.J. Groene, A. Stoppacciaro, I. Bajema, J. Bruijn, X. Fulladosa Oliveras, J. Maldyk, E. Ioachim, N. Bavbek, C. Alpers, F. Berthoux, S. Bonsib, V. D’Agati, G. D’Amico, S. Emancipator, F. Emmal, F. Fervenza, S. Florquin, A. Fogo, M. Haas, P. Hill, R. Hogg, S. Hsu, T. Hunley, M. Hladunewich, C. Jennette, K. Joh, B. Julian, T. Kawamura, F. Lai, C. Leung, L. Li, P. Li, Z. Liu, A. Massat, B. Mackinnon, S. Mezzano, F. Schena, Y. Tomino, P. Walker, H. Wang, J. Weening, N. Yoshikawa, C.H. Zeng, S. Shi, C. Nogi, H. Suzuki, K. Koike, K. Hirano, T. Kawamura, T. Yokoo, M. Hanai, K. Fukami, K. Takahashi, Y. Yuzawa, M. Niwa, Y. Yasuda, S. Maruyama, D. Ichikawa, T. Suzuki, S. Shirai, A. Fukuda, S. Fujimoto, H. Trimarchi, Gerald Appel, Revekka Babayev, Ibrahim Batal, Andrew Bomback, Pietro Canetta, Brenda Chan, Vivette Denise D'Agati, Samitri Dogra, Hilda Fernandez, Gabriele Gaggero, Ali Gharavi, William Hines, Krzysztof Kiryluk, Satoru Kudose, Fangming Lin, Victoria Kolupaeva, Maddalena Marasa, Glen Markowitz, Mariela Navarro-Torres, Hila Milo Rasouly, Sumit Mohan, Nicola Mongera, Jordan Nestor, Jai Radhakrishnan, Maya Rao, Maya Sabatello, Simone Sanna-Cherchi, Dominick Santoriello, Miroslav Sekulic, Michael Barry Stokes, Natalie Uy, Natalie Vena, Benjamin Wooden, Bartosz Foroncewicz, Natalia Wiewiórska-Krata, Barbara Moszczuk, Krzysztof Mucha, Agnieszka Perkowska-Ptasińska, Elżbieta Ryszkowska, Francesca Lugani, Valerio Vellone, Diego Aviles, Tarak Srivastava, Alexander Katz, Sun-Young Ahn, Prasad Devarajan, Elif Erkan, Hillarey Stone, Sherene Mason, Liliana Gomez-Mendez, Larry Greenbaum, Chia-shi Wang, Hong (Julie) Yin, Jens Goebel, Donald Weaver, Jill Krissberg, Jerome Lane, Cindy Pan, Ellen Cody, Samantha Martinek-Bundt, Dawson Carmean, Mary Dreher, Mahmoud Kallash, John Mahan, Samantha Sharpe, William Smoyer, Laura Biederman, Amira Al-Uzri, Sandra Iragorri, Myda Khalid, Craig Belsha, Elizabeth Onugha, Michael Braun, A.C. Gomez, Tetyana Vasylyeva, Daniel Feig, Melisha Hannah, Aftab Chishti, Jon Klein, Chryso Katsoufis, Wacharee Seeherunvong, Michelle Rheault, Craig Wong, Qassim Abid, John Barcia, Agnes Swiatecka-Urban, Sharon Bartosh, Brian Stotter, Joseph Gaut, Louis-Philippe Laurin, Virginie Royal, Mathieu Latour, Natlie (Natacha) Patey, Anand Achanti, Milos Budisavljevic, Vishwajeeth Pasham, Cybele Ghossein, Yonatan Peleg, Salem Almaani, Isabelle Ayoub, Samir Parikh, Brad Rovin, Anjali Satoskar, Anthony Chang, Huma Fatima, Jan Novak, Matthew Renfrow, Dana Rizk, Dhruti Chen, Vimal Derebail, Ronald Falk, Keisha Gibson, Dorey Glenn, Susan Hogan, Koyal Jain, J. Charles Jennette, Vanessa Moreno, Amy Mottl, Caroline Poulton, Monica Reynolds, Manish Kanti Saha, Nicole E. Wyatt, Agnes Fogo, Neil Sanghani, Jason Kidd, Selvaraj Muthusamy, Rebecca Scobell, Michelle Denburg, Amy Kogon, Kevin Meyers, Madhura Pradhan, Raed Bou Matar, John O'Toole, John Sedor, Christine Sethna, Suzanne Vento, Mohamed Atta, Serena Bagnasco, Alicia Neu, John Sperati, Sharon Adler, Tiane Dai, Ram Dukkipati, Frederick Kaskel, Kaye Brathwaite, Kimberly Reidy, Laura Malaga-Dieguez, Katherine Tuttle, Richard Lafayette, Kamal Fahmeedah, Elizabeth Talley, Michelle Hladunewich, Rulan Parekh, Carmen Avila-Casado, Daniel Cattran, Heather Reich, Meherzad Kutky, Yelena Drexler, Alessia Fornoni, Jeffrey Hodgin, Andrea Oliverio, Jon Hogan, Lawrence Holzman, Matthew Palmer, Gaia Coppock, Michael Mortiz, Juhi Kumar, Charles Alpers, J. Ashley Jefferson, Kamal Sambandam, Bethany Roehm, Cynthia Nast, Jean Hou, Laura Barisoni, Crystal Gadegbeku, Abigail Smith, Brenda Gillespie, Bruce Robinson, Matthias Kretzler, Zubin Modi, Laura Mariani, Lisa M. Guay-Woodford, Maarten W. Taal, Paul Cockwell, Simon D.S. Fraser, Philip A. Kalra, Moin Saleem, David C. Wheeler, Rosanna Coppo, Sean Barbour, Jonathan Barratt, Ian S.D. Roberts, Juergen Floege, Vladimir Tesar, Roman D. Bülow, David L. Hölscher, Hong Zhang, Muh Geot Wong, Laura Barisoni, Mark Haas, Motoko Yanagita, Keiichi Kaneko, Takeo Koshida, Sigrid Lundberg
Institutions: Universitätsklinikum Aachen, Charles University, General University Hospital in Prague, National Health Service, University of Leicester, University Hospitals of Leicester NHS Trust, Oxford University Hospitals NHS Trust, Fondazione Ricerca Molinette, Ospedale Regina Margherita, Duke University, Kyoto University, Institute for the Advanced Study of Human Biology, Kyoto University, Dicle University, Mayo Clinic, University of Nottingham, University Hospitals of Derby and Burton NHS Foundation Trust, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funders: U.S. Department of Health and Human Services, AstraZeneca, Kidney Research UK, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, RWTH Aachen University, Gemeinsame Bundesausschuss, European Renal Association-European Dialysis and Transplant Association, European Research Council, Medizinische Fakultät, RWTH Aachen University, National Institute of Diabetes and Digestive and Kidney Diseases, H2020 European Research Council
Awards: G2669879858, G2820917408, G2823057324, G3952378347, G410390351, STOP-FSGS - Translationaler Forschungsverbund zur Verbesserung der Diagnostik und Therapie der FSGS, Histopathologische Bildanalyse und Analyse von pathogenen Signalwegen, G4317703243, KFO 5011: Integration neuer Methoden zur Verbesserung von translationaler Nierenforschung, AI-augmented, Multiscale Image-based Diagnostics of Chronic Kidney Disease, TRR 219: Mechanismen kardiovaskulärer Komplikationen bei chronischer Niereninsuffizienz, CUREGN 3.0 - Pediatric Nephrology Consortium - PCC, CureGN-3: UNCPCC, The Columbia PCC for CureGN: the Cure Glomerulonephropathy network, CureGN, CureGN-Penn PCC
OpenAlex ID: W7168248708