Academic Journal
Shared multicellular injury programs of acute and chronic kidney disease enable mechanistic patient stratification.
| Τίτλος: | Shared multicellular injury programs of acute and chronic kidney disease enable mechanistic patient stratification. |
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| Συγγραφείς: | 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. |
| Πηγή: | MedRxiv : the preprint server for health sciences [medRxiv] 2026 Mar 06. Date of Electronic Publication: 2026 Mar 06. |
| Τύπος έκδοσης: | Journal Article; Preprint |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Περίληψη: | 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. |
| References: | Bioinform Adv. 2022 Mar 08;2(1):vbac016. (PMID: 36699385) Crit Care. 2013 Feb 04;17(1):204. (PMID: 23394211) Intensive Care Med. 2015 Aug;41(8):1411-23. (PMID: 26162677) Am J Nephrol. 2016;44(4):289-299. (PMID: 27626625) Am J Pathol. 2025 Jan;195(1):7-22. (PMID: 39332674) J Transl Med. 2023 Feb 6;21(1):86. (PMID: 36747266) Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25026-25035. (PMID: 32958645) Front Cell Dev Biol. 2020 Aug 11;8:779. (PMID: 32850870) J Biol Eng. 2022 Aug 2;16(1):19. (PMID: 35918708) Crit Care Med. 2024 Jul 1;52(7):1127-1137. (PMID: 38869385) J Am Soc Nephrol. 2011 Jan;22(1):165-75. (PMID: 21071523) Diabetes. 2019 Dec;68(12):2301-2314. (PMID: 31578193) J Am Soc Nephrol. 2023 Apr 1;34(4):554-571. (PMID: 36735940) Diabetes. 2011 Sep;60(9):2354-69. (PMID: 21752957) Diabetes. 2025 Jun 1;74(6):998-1006. (PMID: 40036063) Kidney Int. 2018 May;93(5):1175-1182. (PMID: 29273332) Kidney Int. 2020 May;97(5):1017-1031. (PMID: 32245660) Am J Kidney Dis. 1996 May;27(5):640-6. (PMID: 8629622) Nat Commun. 2023 Jul 19;14(1):4140. (PMID: 37468493) Am J Pathol. 2010 Feb;176(2):594-607. (PMID: 20019191) J Am Soc Nephrol. 2017 Feb;28(2):678-690. (PMID: 27436854) Nat Biotechnol. 2010 May;28(5):478-85. (PMID: 20458318) Nat Rev Immunol. 2009 Oct;9(10):729-40. (PMID: 19730437) Kidney Int Suppl (2011). 2022 Apr;12(1):7-11. (PMID: 35529086) Elife. 2023 Nov 22;12:. (PMID: 37991480) Nature. 2021 Jan;589(7841):281-286. (PMID: 33176333) JAMA Netw Open. 2020 Apr 1;3(4):e202682. (PMID: 32282046) Kidney Med. 2025 Dec 12;8(2):101206. (PMID: 41623298) Nat Cell Biol. 2024 Sep;26(9):1613-1622. (PMID: 39223377) Am J Physiol Cell Physiol. 2026 Feb 1;330(2):C552-C569. (PMID: 41419123) Int J Mol Sci. 2020 Oct 22;21(21):. (PMID: 33105639) Nature. 2023 Jul;619(7970):585-594. (PMID: 37468583) Eur J Immunol. 2022 Jun;52(6):907-923. (PMID: 35334124) Nat Commun. 2024 Feb 12;15(1):1291. (PMID: 38347009) Am J Physiol Renal Physiol. 2004 Mar;286(3):F552-63. (PMID: 14600030) Nat Commun. 2021 Nov 4;12(1):6386. (PMID: 34737275) Curr Res Physiol. 2024 Nov 14;8:100133. (PMID: 39665027) Genome Biol. 2018 Feb 6;19(1):15. (PMID: 29409532) Crit Rev Clin Lab Sci. 2021 Aug;58(5):354-368. (PMID: 33556265) Am J Pathol. 2011 Sep;179(3):1243-56. (PMID: 21762674) J Biol Chem. 2019 Feb 8;294(6):1997-2008. (PMID: 30523158) Intensive Care Med. 2020 May;46(5):943-953. (PMID: 32025755) PLoS Med. 2022 Apr 6;19(4):e1003954. (PMID: 35385471) N Engl J Med. 2014 Jul 3;371(1):58-66. (PMID: 24988558) Pediatr Res. 2023 Aug;94(2):747-755. (PMID: 36864281) Nucleic Acids Res. 2011 Aug;39(15):e102. (PMID: 21646338) Genome Biol. 2022 Feb 1;23(1):42. (PMID: 35105358) Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2032-2045. (PMID: 28522654) Clin Chem. 2014 Jul;60(7):974-86. (PMID: 24829272) Nat Methods. 2020 Mar;17(3):261-272. (PMID: 32015543) Pediatr Nephrol. 2015 Aug;30(8):1317-26. (PMID: 25903639) Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1637-42. (PMID: 11172003) Kidney Int. 2021 Mar;99(3):498-510. (PMID: 33637194) Genome Biol. 2020 May 11;21(1):111. (PMID: 32393329) J Clin Invest. 2023 Mar 1;133(5):. (PMID: 36637914) J Biol Chem. 2018 Apr 20;293(16):5895-5908. (PMID: 29523688) Clin J Am Soc Nephrol. 2025 Jun 4;20(7):958-967. (PMID: 40493410) PLoS One. 2010 Dec 07;5(12):e15004. (PMID: 21165148) J Am Soc Nephrol. 2017 Oct;28(10):2961-2972. (PMID: 28646076) Nat Genet. 2024 Aug;56(8):1712-1724. (PMID: 39048792) Kidney Med. 2023 Aug 25;5(11):100719. (PMID: 37841418) Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021) Nat Rev Dis Primers. 2021 Jul 15;7(1):52. (PMID: 34267223) Lancet. 2025 Jan 18;405(10474):241-256. (PMID: 39826969) J Crit Care. 2024 Aug;82:154816. (PMID: 38678981) Nat Rev Genet. 2023 Aug;24(8):550-572. (PMID: 37002403) Sci Adv. 2022 Jun 10;8(23):eabn4965. (PMID: 35675394) J Am Soc Nephrol. 2017 Mar;28(3):785-801. (PMID: 27612995) Biochemistry. 1985 Sep 24;24(20):5480-6. (PMID: 4074709) Am J Physiol Renal Physiol. 2010 May;298(5):F1078-94. (PMID: 20200097) J Clin Invest. 2021 Feb 1;131(3):. (PMID: 33290282) JCI Insight. 2024 Apr 8;9(7):. (PMID: 38587072) Nat Commun. 2025 May 22;16(1):4745. (PMID: 40399382) Mod Pathol. 2016 Jul;29(7):671-84. (PMID: 27102348) BMC Nephrol. 2020 Jul 18;21(1):285. (PMID: 32682403) Inflamm Res. 2019 Feb;68(2):93-102. (PMID: 30456594) Mol Cancer Res. 2007 Aug;5(8):823-32. (PMID: 17699108) BMC Nephrol. 2022 Apr 7;23(1):137. (PMID: 35392844) Semin Nephrol. 2025 Nov;45(6):151663. (PMID: 40925758) PLoS One. 2012;7(12):e53439. (PMID: 23285295) J Am Soc Nephrol. 2024 Aug 1;35(8):1123-1126. (PMID: 39248631) J Diabetes Complications. 2012 Nov-Dec;26(6):546-53. (PMID: 22981148) Front Immunol. 2018 May 14;9:972. (PMID: 29867953) Kidney Int. 2015 Dec;88(6):1274-1282. (PMID: 26422503) Sci Transl Med. 2015 Dec 02;7(316):316ra193. (PMID: 26631632) Sci Rep. 2022 Oct 13;12(1):17147. (PMID: 36229504) Intensive Care Med. 2024 Sep;50(9):1426-1437. (PMID: 39115567) Kidney Int. 2024 Jun;105(6):1263-1278. (PMID: 38286178) Nucleic Acids Res. 2023 Nov 10;51(20):10934-10949. (PMID: 37843125) Exp Cell Res. 2012 Mar 10;318(5):464-77. (PMID: 22245584) Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F809-F821. (PMID: 32954852) Biochem Biophys Res Commun. 2006 Jan 27;339(4):1076-82. (PMID: 16338228) JAMA Intern Med. 2020 Mar 1;180(3):402-410. (PMID: 31985750) Am J Respir Crit Care Med. 2019 Apr 1;199(7):863-872. (PMID: 30334632) Mol Syst Biol. 2025 Aug;21(8):1030-1065. (PMID: 40473842) Kidney Int. 2024 Apr;105(4S):S117-S314. (PMID: 38490803) Cell Tissue Res. 2021 Aug;385(2):475-488. (PMID: 34027630) |
| Grant Information: | U01 DK114866 United States DK NIDDK NIH HHS; U01 DK133097 United States DK NIDDK NIH HHS; U01 DK114933 United States DK NIDDK NIH HHS; U01 DK114908 United States DK NIDDK NIH HHS; U01 DK133095 United States DK NIDDK NIH HHS; U01 DK114907 United States DK NIDDK NIH HHS; U24 DK114886 United States DK NIDDK NIH HHS; U01 DK133766 United States DK NIDDK NIH HHS; U01 DK114923 United States DK NIDDK NIH HHS; U01 DK133113 United States DK NIDDK NIH HHS; U01 DK133090 United States DK NIDDK NIH HHS; UH3 DK114915 United States DK NIDDK NIH HHS; U01 DK133768 United States DK NIDDK NIH HHS; UH3 DK114861 United States DK NIDDK NIH HHS; U01 DK133092 United States DK NIDDK NIH HHS; UH3 DK114937 United States DK NIDDK NIH HHS; U01 DK133081 United States DK NIDDK NIH HHS; UH3 DK114926 United States DK NIDDK NIH HHS; UG3 DK114861 United States DK NIDDK NIH HHS; U54 DK137328 United States DK NIDDK NIH HHS; U01 DK133091 United States DK NIDDK NIH HHS; U01 DK133093 United States DK NIDDK NIH HHS; U54 DK134301 United States DK NIDDK NIH HHS; U01 DK114920 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: 20260921 |
| Update Code: | 20260921 |
| PubMed Central ID: | PMC12976899 |
| DOI: | 10.64898/2026.03.05.26347522 |
| PMID: | 41822697 |
| Βάση Δεδομένων: | MEDLINE |
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