Johannes Holle1, Lena Berenberg-Goßler2, Kaiyin Wu3, Ortraud Beringer4, Florian Kropp4, Dominik Müller2, Julia Thumfart2. 1. Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. johannes-benjamin.holle@charite.de. 2. Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany. 3. Department of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 4. Department of Pediatrics and Adolescent Medicine, Pediatric Nephrology, Ulm University Medical Center, Ulm, Germany.
Abstract
BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G). METHODS: The method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers. RESULTS: Mean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset. CONCLUSIONS: IC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.
BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is a rare cause of glomerulopathy in children. Recently, a new classification based on immunohistological features has been established. Infections and anomalies in complement-regulating genes, leading to alternative complement pathway activation, are suspected to trigger the disease. Nevertheless, little is known about optimal treatment and outcome in children with immune-complex-MPGN (IC-MPGN) and C3-glomerulopathy (C3G). METHODS: The method used is retrospective analysis of clinical, histological, and genetic characteristics of 14 pediatric patients with MPGN in two medical centers. RESULTS: Mean age of the patients was 10.6 ± 4.5 years. Patients were grouped into C3G (n = 6) and IC-MPGN (n = 8). One patient showed a likely pathogenic variant in the CFHR5 gene. All 10 patients had risk polymorphisms in complement-regulating genes. Most patients were treated with ACE inhibition, steroids, and mycophenolate mofetil. Three patients with C3G received eculizumab. Median follow-up was 2.3 years. After 1 year of disease, three patients (two C3G, one IC-MPGN) reached complete, five patients partial (three IC-MPGN, two C3G), and five patients no remission (four IC-MPGN, one C3G). One patient progressed to end-stage renal disease (ESRD) 6 years after disease onset. CONCLUSIONS:IC-MPGN and C3G are rare disorders in children. Most patients have signs of complement activation associated with risk polymorphisms or likely pathogenic variants in complement-regulating genes. Steroids and mycophenolate mofetil seem to be effective and for some patients, eculizumab might be a treatment option. Outcome is heterogeneous and precise differentiation between IC-MPGN and C3G is still pending.
Authors: Andrew S Bomback; Richard J Smith; Gaetano R Barile; Yuzhou Zhang; Eliot C Heher; Leal Herlitz; M Barry Stokes; Glen S Markowitz; Vivette D D'Agati; Pietro A Canetta; Jai Radhakrishnan; Gerald B Appel Journal: Clin J Am Soc Nephrol Date: 2012-03-08 Impact factor: 8.237
Authors: Nicholas R Medjeral-Thomas; Michelle M O'Shaughnessy; John A O'Regan; Carol Traynor; Michael Flanagan; Limy Wong; Chia Wei Teoh; Atif Awan; Mary Waldron; Tom Cairns; Patrick O'Kelly; Anthony M Dorman; Matthew C Pickering; Peter J Conlon; H Terence Cook Journal: Clin J Am Soc Nephrol Date: 2013-10-31 Impact factor: 8.237
Authors: Rubén Martínez-Barricarte; Meike Heurich; Francisco Valdes-Cañedo; Eduardo Vazquez-Martul; Eva Torreira; Tamara Montes; Agustín Tortajada; Sheila Pinto; Margarita Lopez-Trascasa; B Paul Morgan; Oscar Llorca; Claire L Harris; Santiago Rodríguez de Córdoba Journal: J Clin Invest Date: 2010-09-13 Impact factor: 14.808
Authors: Fengxiao Bu; Nicolo Ghiringhelli Borsa; Michael B Jones; Erika Takanami; Carla Nishimura; Jill J Hauer; Hela Azaiez; Elizabeth A Black-Ziegelbein; Nicole C Meyer; Diana L Kolbe; Yingyue Li; Kathy Frees; Michael J Schnieders; Christie Thomas; Carla Nester; Richard J H Smith Journal: J Am Soc Nephrol Date: 2015-08-17 Impact factor: 10.121
Authors: H P H Neumann; M Salzmann; B Bohnert-Iwan; T Mannuelian; C Skerka; D Lenk; B U Bender; M Cybulla; P Riegler; A Königsrainer; U Neyer; A Bock; U Widmer; D A Male; G Franke; P F Zipfel Journal: J Med Genet Date: 2003-09 Impact factor: 6.318
Authors: Edwin K S Wong; Kevin J Marchbank; Hannah Lomax-Browne; Isabel Y Pappworth; Harriet Denton; Katie Cooke; Sophie Ward; Amy-Claire McLoughlin; Grant Richardson; Valerie Wilson; Claire L Harris; B Paul Morgan; Svetlana Hakobyan; Paul McAlinden; Daniel P Gale; Heather Maxwell; Martin Christian; Roger Malcomson; Timothy H J Goodship; Stephen D Marks; Matthew C Pickering; David Kavanagh; H Terence Cook; Sally A Johnson Journal: Clin J Am Soc Nephrol Date: 2021-09-22 Impact factor: 8.237
Authors: Hannah J Lomax-Browne; Nicholas R Medjeral-Thomas; Sean J Barbour; Jack Gisby; Heedeok Han; Andrew S Bomback; Fernando C Fervenza; Thomas H Cairns; Richard Szydlo; Sven-Jean Tan; Stephen D Marks; Aoife M Waters; Gerald B Appel; Vivette D D'Agati; Sanjeev Sethi; Cynthia C Nast; Ingeborg Bajema; Charles E Alpers; Agnes B Fogo; Christoph Licht; Fadi Fakhouri; Daniel C Cattran; James E Peters; H Terence Cook; Matthew C Pickering Journal: Clin J Am Soc Nephrol Date: 2022-07 Impact factor: 10.614
Authors: Andrew S Bomback; David Kavanagh; Marina Vivarelli; Matthias Meier; Yaqin Wang; Nicholas J A Webb; Angelo J Trapani; Richard J H Smith Journal: Kidney Int Rep Date: 2022-08-02
Authors: Marloes A H M Michels; Kioa L Wijnsma; Roel A J Kurvers; Dineke Westra; Michiel F Schreuder; Joanna A E van Wijk; Antonia H M Bouts; Valentina Gracchi; Flore A P T Engels; Mandy G Keijzer-Veen; Eiske M Dorresteijn; Elena B Volokhina; Lambertus P W J van den Heuvel; Nicole C A J van de Kar Journal: Pediatr Nephrol Date: 2021-09-02 Impact factor: 3.714