Shared multicellular injury programs of acute and chronic kidney disease enable mechanistic patient stratification.
| Title: | Shared multicellular injury programs of acute and chronic kidney disease enable mechanistic patient stratification. |
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| Authors: | Fallegger R; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany.; Gomez-Ochoa SA; Heidelberg University Hospital, Department of General Internal Medicine and Psychosomatics, Heidelberg, Germany.; Boys C; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany.; Flores ROR; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, U.K.; Tanevski J; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany.; Pashos E; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States.; Feliers D; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States.; Piper M; Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States.; Schaub JA; Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA.; Zhou Z; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Mao W; Princeton Precision Health, Princeton University, Princeton, NJ 08544, USA.; Chen X; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY 10010, USA.; Sealfon RSG; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY 10010, USA.; Menon R; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Nair V; Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Eddy S; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Alakwaa FM; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Pyle L; University of Washington Medicine Diabetes Institute, Seattle, WA 98109, USA.; Choi YJ; University of Washington Medicine Diabetes Institute, Seattle, WA 98109, USA.; Bjornstad P; University of Washington Medicine Diabetes Institute and Seattle Children's Research Institute, Seattle, WA 98109, USA.; Alpers CE; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195.; Bitzer M; University of Michigan.; Bomback AS; Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA.; Caramori ML; Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, OH, USA.; Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, MN, USA.; Demeke D; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.; Fogo AB; Department. Of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Herlitz LC; Cleveland Clinic.; Kiryluk K; Department of Medicine, Division of Nephrology, Vagelos College of Physicians & Surgeons, Columbia University.; Lash JP; Department of Medicine, University of Illinois Chicago, Chicago, Illinois.; Murugan R; University of Pittsburgh.; O'Toole JF; Department of Kidney Medicine, Medical Specialties Institute, Cleveland Clinic & Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH.; Palevsky PM; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Parikh CR; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, US.; Rosas SE; Kidney and Hypertension Unit, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.; Rosenberg AZ; Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD, USA.; Sedor JR; Department of Kidney Medicine, Medical Specialties Institute, Cleveland Clinic & Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH.; Vazquez MA; Nephrology Division, University of Texas Southwestern Medical Center.; Waikar SS; Section of Nephrology, Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine.; Wilson FP; Clinical and Translational Research Accelerator, Department of Medicine, Yale School of Medicine, New Haven, CT.; Hodgin JB; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.; Barisoni L; Department of Pathology, Division of AI & Computational Pathology, Department of Medicine, Division of Nephrology, Duke University, Durham, NC, USA.; Himmelfarb J; Barbara T. Murphy Division of Nephrology, Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai.; Jain S; Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.; Kidney Translational Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.; Ju W; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Troyanskaya OG; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.; Princeton Precision Health, Princeton University, Princeton, NJ 08544, USA.; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY 10010, USA.; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.; Kretzler M; Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Co-senior authors: Matthias Kretzler, Michael T. Eadon, Julio Saez-Rodriguez.; Eadon MT; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Co-senior authors: Matthias Kretzler, Michael T. Eadon, Julio Saez-Rodriguez.; Saez-Rodriguez J; Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany.; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, U.K.; Co-senior authors: Matthias Kretzler, Michael T. Eadon, Julio Saez-Rodriguez. |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2026 Mar 06. Date of Electronic Publication: 2026 Mar 06. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants with AKI and CKD enrolled within the Kidney Precision Medicine Project (KPMP) and did so at the patient participant level. Using an unsupervised approach, we identified two multi-cellular programs associated with clinical and histopathological features of acute injury and chronic damage, respectively. We found that these programs are expressed across patients with AKI and CKD, supporting shared, rather than distinct, underlying molecular mechanisms. These programs capture tissue-level compositional changes towards adaptive and failed-repair states in tubular epithelial cells, as well as intra-cellular molecular changes characteristic of stress in all cell types. We identified subunits of the NFkB and AP-1 complexes, as well as members of the STAT family, as putative upstream regulators of the acute and chronic programs. We were able to map these continuous molecular measures of acute injury and chronic damage to urine and plasma protein profiles obtained at time of biopsy. These non-invasive protein signatures were predictive of renal outcomes in an independent cohort of 44 thousand participants from the UK biobank. In summary, unbiased identification of cellular programs in kidney disease biopsies defined molecular programs of injury cutting across conventional disease categorization and established a non-invasive molecular link to long term patient outcomes. |
| Competing Interests: | Conflict of interests EP, DF, MP were full-time employees of Pfizer. JSR reports in the last 3 years funding from GSK and Pfizer & fees/honoraria from Travere Therapeutics, Stadapharm, Astex Pharmaceuticals, Owkin, Pfizer, Vera Therapeutics, Grunenthal, Tempus and Moderna. Pfizer’s funding partially supported this work. SE reports funding from Nephcure, Astra Zeneca, Dimerix, Eli Lilly, Novo Nordisk, Sanofi, Travere Therapeutics, and Vera Therapeutics through the University of Michigan over the last 3 years. FPW reports research funding from NIDDK, Amgen, and Boeringher Ingelheim and consulting for WndrHlth. JRS reports consulting for Maze. SER reports research grant support from Bayer, AstraZeneca, Prokidney and NIDDK. consultant NovoNordisk and Travere. R. Murugan reports consulting from Vantive, Fresenius, and Grant funding from NIDDK. |
| Grant Information: | U01 DK114923 United States DK NIDDK NIH HHS; U01 DK114866 United States DK NIDDK NIH HHS; U01 DK133090 United States DK NIDDK NIH HHS; UH3 DK114861 United States DK NIDDK NIH HHS; U01 DK114933 United States DK NIDDK NIH HHS; U01 DK114908 United States DK NIDDK NIH HHS; U01 DK114907 United States DK NIDDK NIH HHS; U54 DK134301 United States DK NIDDK NIH HHS; U24 DK114886 United States DK NIDDK NIH HHS; UG3 DK114861 United States DK NIDDK NIH HHS; U54 DK137328 United States DK NIDDK NIH HHS |
| Contributed Indexing: | Keywords: acute kidney injury; chronic kidney disease; multi-cellular programs; single cell transcriptomics |
| Entry Date(s): | Date Created: 20260313 Date Completed: 20260318 Latest Revision: 20260517 |
| Update Code: | 20260517 |
| PubMed Central ID: | PMC12976899 |
| DOI: | 10.64898/2026.03.05.26347522 |
| PMID: | 41822697 |
| Database: | MEDLINE |
Journal Article; Preprint