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<p>The molecular pathophysiology of nephrotic syndrome remains largely elusive in pediatric patients. While most children with minimal change disease (MCD) show favorable responses to immunosuppressive therapy, those with focal segmental glomerulosclerosis (FSGS) often exhibit poorer treatment responses, with many experiencing either partial remission or no remission of proteinuria. The need for reliable glomerular disease biomarkers to predict treatment response and understand molecular pathways governing responsiveness and resistance is a critical unmet need in pediatric nephrology. In this study, we sought to characterize urine proteomes in children with MCD and FSGS to identify biomarkers distinguishing disease activity and associated molecular pathways. Using quantitative proteomics, urine proteins from children with MCD and FSGS in the CureGN Study were identified and correlated with disease onset and activity. Unbiased cluster analyses of nephrotic urine proteomes demonstrated a cluster with relatively increased immune response and complement proteins, suggesting important distinctions in disease characteristics within the nephrotic subgroups. These analyses yielded patient subpopulations with proteinuria and distinct urine proteome differences associated with 116 proteins exerting cluster separation in the multivariate analyses. These findings highlight the potential of unsupervised clustering to identify disease subgroups and provide insights into the underlying molecular heterogeneity within nephrotic syndrome, paving the way for more tailored therapeutic strategies and improved patient management.</p>

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Defining subgroups of pediatric nephrotic patients with urine proteomics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月11日

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  • Timothy D. Cummins,
  • Laura H. Mariani,
  • Daniel W. Wilkey,
  • Saeed A. Jortani,
  • Margaret Helmuth,
  • Madhavi J. Rane,
  • Michael L. Merchant,
  • Yu Kamigaki,
  • Chandra Theesfeld,
  • Phillip J. McCown,
  • Wenjun Ju,
  • Julie A. Dougherty,
  • Susan McRitchie,
  • Wimal Pathmasiri,
  • Matthias Kretzler,
  • Susan J. Sumner,
  • William E. Smoyer,
  • Jon B. Klein,
  • Wooin Ahn,
  • Gerald Appel,
  • Paul Appelbaum,
  • Revekka Babayev,
  • Andrew Bomback,
  • Pietro Canetta,
  • Brenda Chan,
  • Vivette Denise D’Agati,
  • Samitri Dogra,
  • Hilda Fernandez,
  • Ali Gharavi,
  • William Hines,
  • Syed Ali Husain,
  • Namrata Jain,
  • Krzysztof Kiryluk,
  • Fangming Lin,
  • Maddalena Marasa,
  • Glen Markowitz,
  • Hila Milo Rasouly,
  • Sumit Mohan,
  • Nicola Mongera,
  • Jordan Nestor,
  • Thomas Nickolas,
  • Jai Radhakrishnan,
  • Maya Rao,
  • Simone Sanna-Cherchi,
  • Shayan Shirazian,
  • Michael Barry Stokes,
  • Natalie Uy,
  • Anthony Valeri,
  • Natalie Vena,
  • Bartosz Foroncewicz,
  • Barbara Moszczuk,
  • Krzysztof Mucha,
  • Agnieszka Perkowska-Ptasińska,
  • Gian Marco Ghiggeri,
  • Francesca Lugani,
  • Josephine Ambruzs,
  • Helen Liapis,
  • Rossana Baracco,
  • Amrish Jain,
  • Isa Ashoor,
  • Diego Aviles,
  • Tarak Srivastava,
  • Sun-Young Ahn,
  • Prasad Devarajan,
  • Elif Erkan,
  • Donna Claes,
  • Hillarey Stone,
  • Sherene Mason,
  • Rasheed Gbadegesin,
  • Liliana Gomez-Mendez,
  • Larry Greenbaum,
  • Chia-shi Wang,
  • Hong Julie Yin,
  • Yi Cai,
  • Goebel Jens,
  • Julia Steinke,
  • Donald Weaver,
  • Jerome Lane,
  • Carl Cramer,
  • Cindy Pan,
  • Neil Paloian,
  • Rajasree Sreedharan,
  • David Selewski,
  • Katherine Twombley,
  • Corinna Bowers,
  • Mary Dreher,
  • Mahmoud Kallash,
  • John Mahan,
  • Samantha Sharpe,
  • William Smoyer,
  • Amira Al-Uzri,
  • Sandra Iragorri,
  • Myda Khalid,
  • Craig Belsha,
  • Joseph Alge,
  • Michael Braun,
  • A. C. Gomez,
  • Scott Wenderfer,
  • Tetyana Vasylyeva,
  • Daniel Feig,
  • Gabriel Cara Fuentes,
  • Melisha Hannah,
  • Carla Nester,
  • Aftab Chishti,
  • Jon Klein,
  • Chryso Katsoufis,
  • Wacharee Seeherunvong,
  • Michelle Rheault,
  • Craig Wong,
  • Nisha Mathews,
  • John Barcia,
  • Agnes Swiatecka-Urban,
  • Sharon Bartosh,
  • Tracy Hunley,
  • Vikas Dharnidharka,
  • Joseph Gaut,
  • Louis-Philippe Laurin,
  • Virginie Royal,
  • Anand Achanti,
  • Milos Budisavljevic,
  • Sally Self,
  • Cybele Ghossein,
  • Yonatan Peleg,
  • Shikha Wadhwani,
  • Salem Almaani,
  • Isabelle Ayoub,
  • Tibor Nadasdy,
  • Samir Parikh,
  • Brad Rovin,
  • Anthony Chang,
  • Huma Fatima,
  • Bruce Julian,
  • Jan Novak,
  • Matthew Renfrow,
  • Dana Rizk,
  • Dhruti Chen,
  • Vimal Derebail,
  • Ronald Falk,
  • Keisha Gibson,
  • Dorey Glenn,
  • Susan Hogan,
  • Koyal Jain,
  • J. Charles Jennette,
  • Amy Mottl,
  • Caroline Poulton,
  • Manish Kanti Saha,
  • Agnes Fogo,
  • Neil Sanghani,
  • Jason Kidd,
  • Selvaraj Muthusamy,
  • Jeffrey Schelling,
  • Jean Hou,
  • Kevin Lemley,
  • Warren Mika,
  • Pierre Russo,
  • Michelle Denburg,
  • Amy Kogon,
  • Kevin Meyers,
  • Madhura Pradhan,
  • Raed Bou Matar,
  • John O’Toole,
  • John Sedor,
  • Christine Sethna,
  • Suzanne Vento,
  • Mohamed Atta,
  • Serena Bagnasco,
  • Alicia Neu,
  • John Sperati,
  • Sharon Adler,
  • Tiane Dai,
  • Ram Dukkipati,
  • Fernando Fervenza,
  • Sanjeev Sethi,
  • Frederick Kaskel,
  • Kaye Brathwaite,
  • Kimberly Reidy,
  • Joseph Weisstuch,
  • Ming Wu,
  • Olga Zhdanova,
  • Jurgen Heymann,
  • Jeffrey Kopp,
  • Meryl Waldman,
  • Cheryl Winkler,
  • Katherine Tuttle,
  • Jill Krissberg,
  • Richard Lafayette,
  • Kamal Fahmeedah,
  • Elizabeth Talley,
  • Michelle Hladunewich,
  • Rulan Parekh,
  • Carmen Avila-Casado,
  • Daniel Cattran,
  • Reich Heather,
  • Philip Boll,
  • Yelena Drexler,
  • Alessia Fornoni,
  • Patrick Gipson,
  • Jeffrey Hodgin,
  • Andrea Oliverio,
  • Jon Hogan,
  • Lawrence Holzman,
  • Matthew Palmer,
  • Gaia Coppock,
  • Blaise Abromovitz,
  • Michael Mortiz,
  • Charles Alpers,
  • J. Ashley Jefferson,
  • Elizabeth Brown,
  • Kamal Sambandam,
  • Bethany Roehm,
  • Bruce Robinson,
  • Abigail Smith,
  • Cynthia Nast,
  • Laura Barisoni,
  • Brenda Gillespie,
  • Debbie Gipson,
  • Matthias Kretzler,
  • Laura Mariani,
  • Lisa M. Guay-Woodford

摘要

The molecular pathophysiology of nephrotic syndrome remains largely elusive in pediatric patients. While most children with minimal change disease (MCD) show favorable responses to immunosuppressive therapy, those with focal segmental glomerulosclerosis (FSGS) often exhibit poorer treatment responses, with many experiencing either partial remission or no remission of proteinuria. The need for reliable glomerular disease biomarkers to predict treatment response and understand molecular pathways governing responsiveness and resistance is a critical unmet need in pediatric nephrology. In this study, we sought to characterize urine proteomes in children with MCD and FSGS to identify biomarkers distinguishing disease activity and associated molecular pathways. Using quantitative proteomics, urine proteins from children with MCD and FSGS in the CureGN Study were identified and correlated with disease onset and activity. Unbiased cluster analyses of nephrotic urine proteomes demonstrated a cluster with relatively increased immune response and complement proteins, suggesting important distinctions in disease characteristics within the nephrotic subgroups. These analyses yielded patient subpopulations with proteinuria and distinct urine proteome differences associated with 116 proteins exerting cluster separation in the multivariate analyses. These findings highlight the potential of unsupervised clustering to identify disease subgroups and provide insights into the underlying molecular heterogeneity within nephrotic syndrome, paving the way for more tailored therapeutic strategies and improved patient management.