Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis

Laura H. Mariani, Sean Eddy, Fadhl M. AlAkwaa, Phillip J. McCown, Jennifer L. Harder, Viji Nair, Felix Eichinger, Sebastian Martini, Adebowale D. Ademola, Vincent Boima, Heather N. Reich, Jamal El Saghir, Bradley Godfrey, Wenjun Ju, Emily C. Tanner, Virginia Vega-Warner, Noel L. Wys, Sharon G. Adler, Gerald B. Appel, Ambarish AthavaleMeredith A. Atkinson, Serena M. Bagnasco, Laura Barisoni, Elizabeth Brown, Daniel C. Cattran, Gaia M. Coppock, Katherine M. Dell, Vimal K. Derebail, Fernando C. Fervenza, Alessia Fornoni, Crystal A. Gadegbeku, Keisha L. Gibson, Laurence A. Greenbaum, Sangeeta R. Hingorani, Michelle A. Hladunewich, Jeffrey B. Hodgin, Marie C. Hogan, Lawrence B. Holzman, J. Ashley Jefferson, Frederick J. Kaskel, Jeffrey B. Kopp, Richard A. Lafayette, Kevin V. Lemley, John C. Lieske, Jen Jar Lin, Rajarasee Menon, Kevin E. Meyers, Patrick H. Nachman, Cynthia C. Nast, Michelle M. O'Shaughnessy, Edgar A. Otto, Kimberly J. Reidy, Kamalanathan K. Sambandam, John R. Sedor, Christine B. Sethna, Pamela Singer, Tarak Srivastava, Cheryl L. Tran, Katherine R. Tuttle, Suzanne M. Vento, Chia shi Wang, Akinlolu O. Ojo, Dwomoa Adu, Debbie S. Gipson, Howard Trachtman, Matthias Kretzler

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Original languageEnglish (US)
Pages (from-to)565-579
Number of pages15
JournalKidney international
Volume103
Issue number3
DOIs
StatePublished - Mar 2023

Bibliographical note

Funding Information:
We thank Dr. Lalita Subramanian for help with writing, editing, and formatting this manuscript. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the Else Kröner-Fresenius Foundation (ERCB), University of Michigan, the NephCure Kidney International and the Halpin Foundation, and the Applied Systems Biology Core at the University of Michigan George M. O’Brien Kidney Translational Core Center (2P30-DK-08194). LHM is supported through funding from NIH/NIDDK, K08 DK115891-01. We acknowledge the role of the H3Africa Consortium in making this research possible through the sharing of data and knowledge. The NIH (USA) and Wellcome Trust (UK) have provided the core funding for the H3Africa Consortium, and more information is available at https://h3africa.org/. This research was supported by the following grants from NIH/National Human Genome Research Institute (NHGRI)/NIDDK: H3Africa Kidney Disease Study (U54 HG006939), H3Africa Kidney Disease Cohort Study (U01 DK107131), H3Africa Kidney Disease Collaborative Centers (9U54 DK116913). The views expressed in this paper do not represent the views of the H3Africa Consortium or their funders. ERCB, NEPTUNE, and H3Africa contributing members are listed in the Supplementary Acknowledgment.

Funding Information:
We thank Dr. Lalita Subramanian for help with writing, editing, and formatting this manuscript. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the Else Kröner-Fresenius Foundation (ERCB), University of Michigan, the NephCure Kidney International and the Halpin Foundation, and the Applied Systems Biology Core at the University of Michigan George M. O'Brien Kidney Translational Core Center (2P30-DK-08194). LHM is supported through funding from NIH/NIDDK, K08 DK115891-01. We acknowledge the role of the H3Africa Consortium in making this research possible through the sharing of data and knowledge. The NIH (USA) and Wellcome Trust (UK) have provided the core funding for the H3Africa Consortium, and more information is available at https://h3africa.org/. This research was supported by the following grants from NIH/National Human Genome Research Institute (NHGRI)/NIDDK: H3Africa Kidney Disease Study (U54 HG006939), H3Africa Kidney Disease Cohort Study (U01 DK107131), H3Africa Kidney Disease Collaborative Centers (9U54 DK116913). The views expressed in this paper do not represent the views of the H3Africa Consortium or their funders. ERCB, NEPTUNE, and H3Africa contributing members are listed in the Supplementary Acknowledgment. All co-authors have contributed to the manuscript. LHM, SE, MK, KRT, PHN, JCL, DCC, DA, KLG, JRS, HNR, SMB, LB, RAL, JBH, DSG, JLH, LBH, HT, and CAG conceptualized this study; LHM, SE, VB, WJ, SMB, JLH, J-JL, FMA, MMO, VN, and PJM contributed to data curation; LHM, SE, FMA, PJM, WJ, and JLH did the formal analysis; LHM, SE, MK, VB, DA, JCL, JRS, AF, LBH, RAL, LB, DSG, and AOO were involved in funding acquisition; LHM, SE, MK, PJM, KRT, VB, KVL, LB, SGA, ADA, TS, C-SW, FCF, CLT, DCC, WJ, DA, KLG, BG, KEM, LBH, SMB, RAL, JBH, MAA, and J-JL investigated the findings; FMA, SM, PJM, BG, JBH, VN, SE, and JLH developed the methodology; LHM, SE, KRT, VB, FE, KKS, TS, FCF, SMV, DA, KLG, and KEM were involved in project administration; KVL, LAG, SGA, ADA, AA, LHM, JCL, FCF, SMV, CLT, DA, KLG, BG, AF, KEM, HNR, LBH, RAL, JBH, MAA, J-JL, and MK provided resources; SE, FMA, and PJM worked on software used in the study; SE, FE, FMA, and PJM performed bioinformatic processing and analyses in the study; LHM, SE, KRT, VB, ADA, AA, JCL, VKD, KLG, AF, KEM, HNR, LBH, RAL, MK, and JLH supervised the study; VB, ADA and WJ worked on study validation; NLW, VV-W, ECT, and JES performed kidney organoid experiments; BG, RM, PJM, and EAO coordinated processing and analysis of single nuclear RNA-seq samples; LHM, SE, VB, CBS, FMA, ADA, PJM, KEM, and LBH helped with visualization; LHM, SE, VB, PJM, and JLH wrote the original draft; all authors reviewed and provided valuable feedback on the manuscript.

Publisher Copyright:
© 2022 International Society of Nephrology

Keywords

  • TNF
  • data integration
  • nephrotic syndrome
  • transcriptomics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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