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T-cell receptor diversity in minimal change disease in the NEPTUNE study

  • Original Article
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Abstract

Background

Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses.

Methods

To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples.

Results

Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients.

Conclusions

While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information.

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Data availability

The underlying data are available through the NEPTUNE Study by ancillary study application.

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Acknowledgements

We thank the participants and their families without whom this study would not be possible. The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the US Government. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Members of the Nephrotic Syndrome Study Network (NEPTUNE)

NEPTUNE Enrolling Centers

Cleveland Clinic, Cleveland, OH: K Dell*, J Sedor**, M Schachere#, J Negrey#

Children’s Hospital, Los Angeles, CA: K Lemley*, S Tang#

Children’s Mercy Hospital, Kansas City, MO: T Srivastava*, S Morrison#

Cohen Children’s Hospital, New Hyde Park, NY: C Sethna*, M Pfaiff #

Columbia University, New York, NY: P Canetta*, A Pradhan#

Emory University, Atlanta, GA: L Greenbaum*, C Wang**, E Yun#

Harbor-University of California Los Angeles Medical Center: S Adler*, J LaPage#

John H. Stroger Jr. Hospital of Cook County, Chicago, IL: A Athavale*, M Itteera

Johns Hopkins Medicine, Baltimore, MD: M Atkinson*, T Dell#

Mayo Clinic, Rochester, MN: F Fervenza*, M Hogan**, J Lieske*, V Chernitskiy#

Montefiore Medical Center, Bronx, NY: F Kaskel*, M Ross*, P Flynn#

NIDDK Intramural, Bethesda MD: J Kopp*, J Blake#

New York University Medical Center, New York, NY: L Malaga-Dieguez*, O Zhdanova**, F Modersitzki#, S Vento#

Stanford University, Stanford, CA: R Lafayette*, B Yeung#

Temple University, Philadelphia, PA: I Lee*, S Quinn-Boyle#

University Health Network Toronto: H Reich *, M Hladunewich**, P Ling#, M Romano#

University of Miami, Miami, FL: A Fornoni*, C Bidot#

University of Michigan, Ann Arbor, MI: M Kretzler*, D Gipson*, A Williams#, C Klida#

University of North Carolina, Chapel Hill, NC: V Derebail*, K Gibson*, A Froment#, J Ormond-Foster#

University of Pennsylvania, Philadelphia, PA: L Holzman*, K Meyers**, K Kallem#, A Swenson#

University of Texas Southwestern, Dallas, TX: K Sambandam*, Z Wang#, M Rogers#

University of Washington, Seattle, WA: A Jefferson*, S Hingorani**, K Tuttle**§, M Bray #, E Pao#, A Cooper#§

Wake Forest University Baptist Health, Winston-Salem, NC: JJ Lin*, Stefanie Baker#

Data Analysis and Coordinating Center: M Kretzler*, L Barisoni**, G Alter, H Desmond, S Eddy, D Fermin, C Gadegbeku**, B Gillespie**, D Gipson**, L Holzman**, V Kurtz, M Larkina, S Li, S Li, CC Lienczewski, J Liu, T Mainieri, L Mariani**, M Sampson**, J Sedor**, A Smith, A Williams, J Zee.

Digital Pathology Committee: Carmen Avila-Casado (University Health Network, Toronto), Serena Bagnasco (Johns Hopkins University), Joseph Gaut (Washington University in St Louis), Stephen Hewitt (National Cancer Institute), Jeff Hodgin (University of Michigan), Kevin Lemley (Children’s Hospital of Los Angeles), Laura Mariani (University of Michigan), Matthew Palmer (University of Pennsylvania), Avi Rosenberg (Johns Hopkins University), Virginie Royal (University of Montreal), David Thomas (University of Miami), Jarcy Zee (University of Pennsylvania) Co-Chairs: Laura Barisoni (Duke University) and Cynthia Nast (Cedar Sinai).

*Principal investigator; **Co-investigator; #Study coordinator

§Providence Medical Research Center, Spokane, WA

Funding

The Nephrotic Syndrome Rare Disease Clinical Research Network III (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). NEPTUNE (U54DK083912) is funded under a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. All RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. This publication was made possible by R01 DK108329, R01 DK097836, and the Clinical and Translational Science Collaborative of Cleveland, UL1TR0002548 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research.

Author information

Authors and Affiliations

  1. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Shiying Liu, William S. Bush, Kristy Miskimen, Jessica N. Cooke Bailey & Dana C. Crawford

  2. Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA

    Shiying Liu, William S. Bush, Kristy Miskimen, Jessica N. Cooke Bailey & Dana C. Crawford

  3. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    William S. Bush, Kristy Miskimen & Dana C. Crawford

  4. Glickman Urological and Kidney Disease and Lerner Research Institutes, Cleveland Clinic, Cleveland, OH, USA

    Agustin Gonzalez-Vicente, John R. Sedor & John F. O’Toole

  5. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA

    Ioanna Konidari & Jacob L. McCauley

Authors
  1. Shiying Liu
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  2. William S. Bush
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  3. Kristy Miskimen
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  4. Agustin Gonzalez-Vicente
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  5. Jessica N. Cooke Bailey
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  6. Ioanna Konidari
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  7. Jacob L. McCauley
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  8. John R. Sedor
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  9. John F. O’Toole
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  10. Dana C. Crawford
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Contributions

DCC, JFO, and JRS conceived the study. JFO, JRS, KM, JLM, IK, and DCC collected the data. SL and DCC analyzed the data and JFO, JRS, WSB, J.N.C.B., and A.G.V. provided critical interpretation. S.L. and D.C.C. wrote the manuscript with input from all authors. All authors provided critical feedback and helped shape the research, analysis, and manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Dana C. Crawford.

Ethics declarations

Statement of ethics

This ancillary study was approved by the NEPTUNE Ancillary Study Committee and Steering Committee as well as local Institutional Review Boards. Written informed consent was obtained for adult participants. For pediatric patients, parents provided written consent and, when appropriate, assent was obtained.

Conflict of interest

JRS has received research funding for randomized clinical trials in nephrotic syndrome from Goldfinch, Novartis, and Calliditas. He has also consulted for Maze, Goldfinch, Boehringer Ingelheim, in the last three years and receives royalties from Sanofi for transgenic mice. The other authors have no conflicts of interest to declare.

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Liu, S., Bush, W.S., Miskimen, K. et al. T-cell receptor diversity in minimal change disease in the NEPTUNE study. Pediatr Nephrol 38, 1115–1126 (2023). https://doi.org/10.1007/s00467-022-05696-x

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