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

• Type of Material: Article
• Authors: Laura H Mariani, Michigan Medicine, Ann Arbor; Sean Eddy, Michigan Medicine, Ann Arbor; Fadhl M AlAkwaa, Michigan Medicine, Ann Arbor; Phillip J McCown, Michigan Medicine, Ann Arbor; Jennifer L Harder, Michigan Medicine, Ann Arbor; Viji Nair, Michigan Medicine, Ann Arbor; Felix Eichinger, Michigan Medicine, Ann Arbor; Sebastian Martini, Michigan Medicine, Ann Arbor; Adebowale D Ademola, University of Ibadan; Vincent Boima, University of Ghana; Heather N Reich, University Health Network Toronto; Jamal El Saghir, Michigan Medicine, Ann Arbor; Bradley Godfrey, Michigan Medicine, Ann Arbor; Wenjun Ju, Michigan Medicine, Ann Arbor; Emily C Tanner, Michigan Medicine, Ann Arbor; Virginia Vega-Warner, Michigan Medicine, Ann Arbor; Noel L Wys, Michigan Medicine, Ann Arbor; Sharon G Adler, Harbor-UCLA Medical Center, Torrance; Gerald B Appel, Columbia University, New York; Ambarish Athavale, John H Stroger Jr. Hospital of Cook County, Chicago; Meredith A Atkinson, Johns Hopkins School of Medicine; Serena M Bagnasco, Johns Hopkins University; Laura Barisoni, Duke University; Elizabeth Brown, UT Southwestern Medical Center, Dallas; Daniel C Cattran, University Health Network Toronto; Gaia M Coppock, University of Pennsylvania; Katherine M Dell, Case Western Reserve University; Vimal K Derebail, University of North Carolina at Chapel Hill; Fernando C Fervenza, Mayo Clinic, Rochester; Alessia Fornoni, University of Miami Health System; Crystal A Gadegbeku, Cleveland Clinic Health System; Keisha L Gibson, University of North Carolina at Chapel Hill; Larry A Greenbaum, Emory University; Sangeeta R Hingorani, Seattle Children’s Hospital; Michelle A Hladunewich, University of Toronto; Jeffrey B Hodgin, Michigan Medicine, Ann Arbor; Marie Hogan, University of North Carolina at Chapel Hill; Lawrence B Holzman, University of Pennsylvania; J. Ashley Jefferson, University of Washington; Frederick J Kaskel, Montefiore Medical Center, Bronx; Jeffrey B Kopp, National Institutes of Health, Bethesda; Richard A Lafayette, Stanford University; Kevin V Lemley, Childrens’s Hospital Los Angeles; John C Lieske, University of North Carolina at Chapel Hill; Jen-Jar Lin, Wake Forest University; Rajarasee Menon, Michigan Medicine, Ann Arbor; Kevin E Meyers, Children’s Hospital of Philadelphia; Patrick H Nachman, University of Minnesota; Cynthia C Nast, Cedars-Sinai Medical Center; Michelle M O'Shaughnessy, Cork University; Edgar A Otto, Michigan Medicine, Ann Arbor; Kimberly J Reidy, Albert Einstein College of Medicine, Bronx; Kamalanathan K Sambandam, UT Southwestern Medical School; John R Sedor, ase Western Reserve University; Christine B Sethna, Cohen Children’s Medical Center, New Hyde Park; Pamela Singer, Cohen Children’s Medical Center, New Hyde Park; Tarak Srivastava, Children’s Mercy Hospital, Kansas City; Cheryl L Tran, Mayo Clinic, Rochester; Katherine R Tuttle, University of Washington; Suzanne Vento, Cohen Children’s Medical Center, New Hyde Park; Chia-shi Wang, Emory University; Akinlolu O Ojo, University of Kansas; Dwomoa Adu, University of Ghana; Debbie S Gipson, Michigan Medicine, Ann Arbor; Howard Trachtman, Michigan Medicine, Ann Arbor; Matthias Kretzler, Michigan Medicine, Ann Arbor
• Language: English
• Date: 2023-03-01
• Publisher: Elsevier, Inc
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Published by Elsevier, Inc
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.kint.2022.10.023
• Title of Journal or Parent Work: Kidney International
• Volume: 103
• Issue: 3
• Start Page: 565
• End Page: 579
• Grant/Funding Information: National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN) grant U54-DK-083912; additional funding and/or programmatic support by the Else Kröner-Fresenius Foundation (ERCB), University of Michigan, the NephCure Kidney International and the Halpin Foundation; NIH grant 2P30-DK-08194; grants from NIH/NHGRI/NIDDK: H3Africa Kidney Disease Study (U54 HG006939), H3Africa Kidney Disease Cohort Study (U01 DK107131), H3Africa Kidney Disease Collaborative Centers (9U54 DK116913). Dr. Mariani is supported through funding from NIH/NIDDK, K08 DK115891-01.
• Keywords: data integration; TNF; Nephrosis, Lipoid; Glomerulosclerosis, Focal Segmental; Humans; transcriptomics; Nephrotic Syndrome; nephrotic syndrome; Nephrology; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factors
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Rehabilitation and Therapy; Health Sciences, Immunology

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.