PMID- 36442540
OWN - NLM
STAT- MEDLINE
DCOM- 20230227
LR  - 20230717
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 103
IP  - 3
DP  - 2023 Mar
TI  - Precision nephrology identified tumor necrosis factor activation variability in 
      minimal change disease and focal segmental glomerulosclerosis.
PG  - 565-579
LID - S0085-2538(22)00966-8 [pii]
LID - 10.1016/j.kint.2022.10.023 [doi]
AB  - 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.
CI  - Copyright (c) 2022 International Society of Nephrology. All rights reserved.
FAU - Mariani, Laura H
AU  - Mariani LH
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA. Electronic address: lmariani@med.umich.edu.
FAU - Eddy, Sean
AU  - Eddy S
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - AlAkwaa, Fadhl M
AU  - AlAkwaa FM
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - McCown, Phillip J
AU  - McCown PJ
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Harder, Jennifer L
AU  - Harder JL
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Nair, Viji
AU  - Nair V
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Eichinger, Felix
AU  - Eichinger F
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Martini, Sebastian
AU  - Martini S
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Ademola, Adebowale D
AU  - Ademola AD
AD  - Department of Paediatrics, Faculty of Clinical Sciences, College of Medicine, 
      University of Ibadan, Ibadan, Oyo State, Nigeria.
FAU - Boima, Vincent
AU  - Boima V
AD  - Department of Medicine and Therapeutics, University of Ghana Medical School, 
      College of Health Sciences, University of Ghana, Accra, Ghana.
FAU - Reich, Heather N
AU  - Reich HN
AD  - Division of Nephrology, Department of Medicine, University Health Network and 
      University of Toronto, Toronto, Ontario, Canada.
FAU - El Saghir, Jamal
AU  - El Saghir J
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Godfrey, Bradley
AU  - Godfrey B
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Ju, Wenjun
AU  - Ju W
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Tanner, Emily C
AU  - Tanner EC
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Vega-Warner, Virginia
AU  - Vega-Warner V
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Wys, Noel L
AU  - Wys NL
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Adler, Sharon G
AU  - Adler SG
AD  - Division of Nephrology and Hypertension at Harbor-UCLA Medical Center and The 
      Lundquist Institute for Biomedical Innovation, Torrance, California, USA.
FAU - Appel, Gerald B
AU  - Appel GB
AD  - Division of Nephrology, Department of Medicine, Columbia University Irving 
      Medical Center, New York, New York, USA.
FAU - Athavale, Ambarish
AU  - Athavale A
AD  - Division of Nephrology-Hypertension, University of San Diego, California, San 
      Diego, California, USA.
FAU - Atkinson, Meredith A
AU  - Atkinson MA
AD  - Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Bagnasco, Serena M
AU  - Bagnasco SM
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Barisoni, Laura
AU  - Barisoni L
AD  - Department of Pathology and Medicine, Division of Nephrology, Duke University 
      School of Medicine, Durham, North Carolina, USA.
FAU - Brown, Elizabeth
AU  - Brown E
AD  - Division of Nephrology, Department of Pediatrics, University of Texas 
      Southwestern Medical Center, Dallas, Texas, USA.
FAU - Cattran, Daniel C
AU  - Cattran DC
AD  - Division of Nephrology, Department of Medicine, University Health Network and 
      University of Toronto, Toronto, Ontario, Canada.
FAU - Coppock, Gaia M
AU  - Coppock GM
AD  - Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Dell, Katherine M
AU  - Dell KM
AD  - Center for Pediatric Nephrology, Cleveland Clinic, Case Western Reserve 
      University, Cleveland, Ohio, USA.
FAU - Derebail, Vimal K
AU  - Derebail VK
AD  - University of North Carolina Kidney Center, Division of Nephrology and 
      Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North 
      Carolina, USA.
FAU - Fervenza, Fernando C
AU  - Fervenza FC
AD  - Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo 
      Clinic, Rochester, Minnesota, USA.
FAU - Fornoni, Alessia
AU  - Fornoni A
AD  - Katz Family Division of Nephrology and Hypertension, Department of Medicine, 
      University of Miami Miller School of Medicine, Miami, Florida, USA.
FAU - Gadegbeku, Crystal A
AU  - Gadegbeku CA
AD  - Department of Kidney Medicine, Glickman Urological and Kidney Institute, 
      Cleveland Clinic, Cleveland, Ohio, USA.
FAU - Gibson, Keisha L
AU  - Gibson KL
AD  - Pediatric Nephrology Division, School of Medicine, University of North Carolina, 
      Chapel Hill, North Carolina, USA.
FAU - Greenbaum, Laurence A
AU  - Greenbaum LA
AD  - Division of Nephrology, Department of Pediatrics, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Hingorani, Sangeeta R
AU  - Hingorani SR
AD  - Division of Nephrology, Department of Pediatrics, University of Washington, 
      Seattle, Washington, USA.
FAU - Hladunewich, Michelle A
AU  - Hladunewich MA
AD  - Division of Nephrology, Department of Medicine, University Health Network and 
      University of Toronto, Toronto, Ontario, Canada.
FAU - Hodgin, Jeffrey B
AU  - Hodgin JB
AD  - Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Hogan, Marie C
AU  - Hogan MC
AD  - Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo 
      Clinic, Rochester, Minnesota, USA.
FAU - Holzman, Lawrence B
AU  - Holzman LB
AD  - Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Jefferson, J Ashley
AU  - Jefferson JA
AD  - Division of Nephrology, Department of Medicine, University of Washington, 
      Seattle, Washington, USA.
FAU - Kaskel, Frederick J
AU  - Kaskel FJ
AD  - Division of Pediatric Nephrology, Montefiore Medical Center, Bronx, New York, 
      USA.
FAU - Kopp, Jeffrey B
AU  - Kopp JB
AD  - National Institute of Diabetes and Digestive Diseases, National Institutes of 
      Health, Bethesda, Maryland, USA.
FAU - Lafayette, Richard A
AU  - Lafayette RA
AD  - Department of Medicine, Division of Nephrology, Stanford University, Stanford, 
      California, USA.
FAU - Lemley, Kevin V
AU  - Lemley KV
AD  - Department of Pediatrics, Keck School of Medicine of the University of Southern 
      California, Los Angeles, California, USA.
FAU - Lieske, John C
AU  - Lieske JC
AD  - Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo 
      Clinic, Rochester, Minnesota, USA.
FAU - Lin, Jen-Jar
AU  - Lin JJ
AD  - Department of Pediatrics, Wake Forest University School of Medicine, 
      Winston-Salem, North Carolina, USA.
FAU - Menon, Rajarasee
AU  - Menon R
AD  - Department of Computational Medicine and Bioinformatics, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Meyers, Kevin E
AU  - Meyers KE
AD  - Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, 
      Pennsylvania, USA.
FAU - Nachman, Patrick H
AU  - Nachman PH
AD  - Division of Nephrology and Hypertension, Department of Medicine, University of 
      Minnesota, Minneapolis, Minnesota, USA.
FAU - Nast, Cynthia C
AU  - Nast CC
AD  - Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, 
      USA.
FAU - O'Shaughnessy, Michelle M
AU  - O'Shaughnessy MM
AD  - Department of Medicine, Division of Renal Medicine, Cork University Hospital, 
      Cork, Ireland.
FAU - Otto, Edgar A
AU  - Otto EA
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Reidy, Kimberly J
AU  - Reidy KJ
AD  - Division of Pediatric Nephrology, Montefiore Medical Center, Bronx, New York, 
      USA.
FAU - Sambandam, Kamalanathan K
AU  - Sambandam KK
AD  - Division of Nephrology, Department of Pediatrics, University of Texas 
      Southwestern Medical Center, Dallas, Texas, USA; Division of Nephrology, 
      Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Sedor, John R
AU  - Sedor JR
AD  - Lerner Research Institutes, Cleveland Clinic, Cleveland, Ohio, USA; Department of 
      Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA; 
      Department of Physiology, Case Western Reserve University, Cleveland, Ohio, USA; 
      Department of Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.
FAU - Sethna, Christine B
AU  - Sethna CB
AD  - Division of Pediatric Nephrology, Cohen Children's Medical Center, New Hyde Park, 
      New York, USA.
FAU - Singer, Pamela
AU  - Singer P
AD  - Division of Pediatric Nephrology, Cohen Children's Medical Center, New Hyde Park, 
      New York, USA.
FAU - Srivastava, Tarak
AU  - Srivastava T
AD  - Section of Nephrology, Children's Mercy Hospital, Kansas City, Missouri, USA.
FAU - Tran, Cheryl L
AU  - Tran CL
AD  - Pediatric Nephrology, Mayo Clinic, Rochester, Minnesota, USA.
FAU - Tuttle, Katherine R
AU  - Tuttle KR
AD  - Division of Nephrology, Department of Medicine, University of Washington, 
      Seattle, Washington, USA; Providence Medical Research Center, Providence Health 
      Care, University of Washington, Spokane, Washington, USA.
FAU - Vento, Suzanne M
AU  - Vento SM
AD  - Division of Nephrology, Department of Pediatrics, New York University School of 
      Medicine, New York, New York, USA.
FAU - Wang, Chia-Shi
AU  - Wang CS
AD  - Division of Nephrology, Department of Pediatrics, Emory University School of 
      Medicine, Atlanta, Georgia, USA.
FAU - Ojo, Akinlolu O
AU  - Ojo AO
AD  - Department of Population Health, School of Medicine, University of Kansas Medical 
      Center, Kansas City, Kansas, USA.
FAU - Adu, Dwomoa
AU  - Adu D
AD  - Department of Medicine and Therapeutics, University of Ghana Medical School, 
      College of Health Sciences, University of Ghana, Accra, Ghana.
FAU - Gipson, Debbie S
AU  - Gipson DS
AD  - Division of Nephrology, Department of Pediatrics, University of Michigan, Ann 
      Arbor, Michigan, USA.
FAU - Trachtman, Howard
AU  - Trachtman H
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA.
FAU - Kretzler, Matthias
AU  - Kretzler M
AD  - Division of Nephrology, Department of Internal Medicine, University of Michigan, 
      Ann Arbor, Michigan, USA; Department of Computational Medicine and 
      Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. Electronic 
      address: kretzler@umich.edu.
LA  - eng
GR  - U01 DK107131/DK/NIDDK NIH HHS/United States
GR  - UG3 TR003288/TR/NCATS NIH HHS/United States
GR  - K23 DK118189/DK/NIDDK NIH HHS/United States
GR  - U54 DK083912/DK/NIDDK NIH HHS/United States
GR  - U54 DK116913/DK/NIDDK NIH HHS/United States
GR  - K08 DK115891/DK/NIDDK NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - P30 DK081943/DK/NIDDK NIH HHS/United States
GR  - U54 HG006939/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221125
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 0 (Tumor Necrosis Factors)
SB  - IM
CIN - Kidney Int. 2023 Mar;103(3):464-466. PMID: 36822751
MH  - Humans
MH  - *Glomerulosclerosis, Focal Segmental/pathology
MH  - *Nephrosis, Lipoid/diagnosis
MH  - Tissue Inhibitor of Metalloproteinase-1
MH  - *Nephrology
MH  - *Nephrotic Syndrome/diagnosis
MH  - Tumor Necrosis Factors/therapeutic use
PMC - PMC10347421
MID - NIHMS1899961
OTO - NOTNLM
OT  - TNF
OT  - data integration
OT  - nephrotic syndrome
OT  - transcriptomics
EDAT- 2022/11/29 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/07/14
CRDT- 2022/11/28 19:23
PHST- 2022/02/08 00:00 [received]
PHST- 2022/10/25 00:00 [revised]
PHST- 2022/10/28 00:00 [accepted]
PHST- 2022/11/29 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2022/11/28 19:23 [entrez]
PHST- 2023/07/14 00:00 [pmc-release]
AID - S0085-2538(22)00966-8 [pii]
AID - 10.1016/j.kint.2022.10.023 [doi]
PST - ppublish
SO  - Kidney Int. 2023 Mar;103(3):565-579. doi: 10.1016/j.kint.2022.10.023. Epub 2022 
      Nov 25.