Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

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

doi:10.2215/CJN.16801221

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

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 LichtFadi Fakhouri, Daniel C. Cattran, James E. Peters, H. Terence Cook, Matthew C. Pickering

Research output: Contribution to journal › Article › peer-review

Abstract

Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN.We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

Original language	English (US)
Pages (from-to)	994-1007
Number of pages	14
Journal	Clinical Journal of the American Society of Nephrology
Volume	17
Issue number	7
DOIs	https://doi.org/10.2215/CJN.16801221
State	Published - Jul 2022

ASJC Scopus subject areas

Epidemiology
Critical Care and Intensive Care Medicine
Nephrology
Transplantation

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10.2215/CJN.16801221

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Lomax-Browne, H. J., Medjeral-Thomas, N. R., Barbour, S. J., Gisby, J., Han, H., Bomback, A. S., Fervenza, F. C., Cairns, T. H., Szydlo, R., Tan, S. J., Marks, S. D., Waters, A. M., Appel, G. B., D’agati, V. D., Sethi, S., Nast, C. C., Bajema, I., Alpers, C. E., Fogo, A. B., ... Pickering, M. C. (2022). Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis. Clinical Journal of the American Society of Nephrology, 17(7), 994-1007. https://doi.org/10.2215/CJN.16801221

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis. / Lomax-Browne, Hannah J.; Medjeral-Thomas, Nicholas R.; Barbour, Sean J. et al.
In: Clinical Journal of the American Society of Nephrology, Vol. 17, No. 7, 07.2022, p. 994-1007.

Research output: Contribution to journal › Article › peer-review

Lomax-Browne, HJ, Medjeral-Thomas, NR, Barbour, SJ, Gisby, J, Han, H, Bomback, AS, Fervenza, FC, Cairns, TH, Szydlo, R, Tan, SJ, Marks, SD, Waters, AM, Appel, GB, D’agati, VD, Sethi, S, Nast, CC, Bajema, I, Alpers, CE, Fogo, AB, Licht, C, Fakhouri, F, Cattran, DC, Peters, JE, Cook, HT & Pickering, MC 2022, 'Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis', Clinical Journal of the American Society of Nephrology, vol. 17, no. 7, pp. 994-1007. https://doi.org/10.2215/CJN.16801221

@article{8f21477024be4e98804e71756ef1146a,

title = "Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis",

abstract = "Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN.We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.",

author = "Lomax-Browne, {Hannah J.} and Medjeral-Thomas, {Nicholas R.} and Barbour, {Sean J.} and Jack Gisby and Heedeok Han and Bomback, {Andrew S.} and Fervenza, {Fernando C.} and Cairns, {Thomas H.} and Richard Szydlo and Tan, {Sven Jean} and Marks, {Stephen D.} and Waters, {Aoife M.} and Appel, {Gerald B.} and D{\textquoteright}agati, {Vivette D.} and Sanjeev Sethi and Nast, {Cynthia C.} and Ingeborg Bajema and Alpers, {Charles E.} and Fogo, {Agnes B.} and Christoph Licht and Fadi Fakhouri and Cattran, {Daniel C.} and Peters, {James E.} and Cook, {H. Terence} and Pickering, {Matthew C.}",

note = "Funding Information: Achillion, Alexion, Catalyst, ChemoCentryx, Novartis, Silence, and Visterra. D.C. Cattran reports consultancy agreements with Alny-lam, Calliditis, Forsee, Horizon, Principia, and Reistone; research funding from Alnylam; honoraria from Alexion, Calliditis, Kyowa Hakko Kirin Co., and Principia; serving in an advisory or leadership role for Alnylam, NephCure, Standardised Outcomes in Nephrology-Glomerular Disease (SONG-GD), and UpToDate; and other interests or relationships with Aurinea, Dimerix, Novartis, and Vera Therapeutics. H.T. Cook reports consultancy agreements with Alexion Pharmaceuticals, Apellis Pharmaceuticals, Aurinia, and Novartis and research funding from Alexion Pharmaceuticals. V.D. D{\textquoteright}Agati reports serving on the editorial board of Kidney International. F. Fakhouri reports consultancy agreements with Alexion, Alnylam, Apellis, Novartis, and Roche; honoraria from Alexion, Alnylam, Apellis, Novartis, and Roche; and serving in an advisory or leadership role for Alexion, Alnylam, Apellis, Novartis, and Roche. F.C. Fervenza reports consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; honoraria from UpToDate; and serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate. A.B. Fogo reports consultancy agreements with Novartis; research funding from Bayer, Gilead, and Novartis; honoraria from Amgen, GlaxoSmithKline, and Novartis; serving in an advisory or leadership role for an advisory committee for Bayer; serving on the editorial boards for American Journal of Pathology, American Journal of Physiology Renal Physiology, Human Pathology, and JASN; serving as an associate editor of Kidney International and Laboratory Investigation; serving as a subject editor for Current Opinion Nephrology and Hypertension (guest editor for the yearly pathology focus) and Nephrology Dialysis and Transplantation; and serving as a speaker at various national nephrology meetings and as President of the International Society of Nephrology (president as of April 19, 2021). C. Licht reports consultancy agreements with Alexion, Apellis Pharmaceuticals, Inc., AstraZeneca Rare Disease, Genentech, Inc.–Hoffmann La Roche, and Novartis; research funding from Aurin Biotech, Inc. and Pfizer Inc.; honoraria from Alexion, Apellis Pharmaceuticals, Inc., AstraZeneca Rare Disease, and Novartis; consulting honoraria and unrestricted research funding from Alexion, Aurinia, Eleva, and Novartis; patents or royalties for Factor H for the treatment of chronic nephropathies and production thereof (international patent WO 2007/038995 A1, US patent 11/992,194, CSL Behring patent 2005_M006_A105, Finnegan patent 06478.1518-00000); serving on the editorial boards of Kidney International, Nephrology Dialysis Transplantation, and Pediatric Nephrology; serving in an advisory or leadership role for Alexion, the steering committee of the Alport Syndrome Treatments and Outcomes Registry, AstraZeneca Rare Disease International atypical hemolytic uremic syndrome (aHUS) Registry scientific advisory board, the safety board of the European Treatment Trial for Alport Syndrome, and the safety advisory board of OPKO Health, Inc.; and speakers bureau for Alexion and AstraZeneca Rare Disease. S.D. Marks reports employment with Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust; the hospital receives funding for immunosuppressive drug studies by Astellas and Novartis. S.D. Marks reports serving as an associate editor for pediatric transplantation for the following journals: British Journal for Renal Medicine, Pediatric Nephrology, Pediatric Transplantation, and Transplantation. C.C. Nast reports serving in an advisory or leadership role for BioCryst. M.C. Pickering reports consultancy agreements with Achillion, Alexion Pharmaceuticals, Apelllis Pharmaceuticals, and Gyroscope Pharmaceuticals; scientific advisory board fees from Gyroscope; consultancy fees from Alexion Pharma Consultancy and Apellis Pharma; and serving on the Gyroscope Pharmaceuticals scientific advisory board. S. Sethi reports consultancy agreements with Novartis and honorarium for teaching, grand rounds, lectures, UpToDate, and reviewing slides for a study for Novartis. S.-J. Tan reports honoraria from AstraZeneca Australia. A.M. Waters reports working as a consultant medical director for Purespring Therapeutics Ltd. All remaining authors have nothing to disclose. Funding Information: C.E. Alpers reports consultancy agreements with AstraZeneca, Mantra Bio, and Travere; research funding from Boehringer-Ingelheim and Sana; and serving on the editorial boards of American Journal of Kidney Diseases, American Journal of Pathology, CJASN, Journal of Nephrology, Kidney360, and Laboratory Investigation. G.B. Appel reports consultancy agreements with Achillion, Alexion, Apellis, Aurinia, Bristol Myers Squibb, Chemocentryx, E. Lilly, EMD Serono, Genentech, Genzyme-Sanofi, GlaxoSmithKline, Mallinkrodt, Merck, Novartis, Omeros, Pfizer, Reata, Travere Therapeutics, and Vera Therapeutics; research funding from Achillion-Alexion, Apellis, Bristol Myers Squibb, Chemocentryx, EMD Serono, Genentech-Roche, Mallinkrodt, Reata, and Sanofi-Genzyme; honoraria from Aurinia and GlaxoSmithKline; royalties from UpToDate; serving in an advisory or leadership role for the UpToDate Editorial Board; serving in an advisory or leadership role on the medical advisory boards for Alexion, Alexion-Achillion, Apellis, Aurinia, BM Squib, Genentech, GlaxoSmith-Kline Lilly, Reata, Roche, and Sanofi; and speakers bureau for Auri-nia (lectures on lupus nephritis) and GlaxoSmithKline (lectures on lupus nephritis). I. Bajema reports consultancy agreements with Aurinia, Boehringer Ingelheim, CatBio, GlaxoSmithKline, Novartis, and Toleranzia and serving as Director of the Bajema Institute of Pathology, as Vice President of the European Vasculitis Society, and as President of the Renal Pathology Society. S.J. Barbour reports consultancy agreements with Achillion, Alexion, Inception Sciences, Novartis, and Visterra; research funding from Alexion and Roche; and honoraria from Alexion and Roche. A.S. Bomback reports consultancy agreements with Catalyst, Chemocentryx, Novartis, Otsuka, Q32, Silence Therapeutics, and Visterra; honoraria from Alexion, Aurinia, Calliditas, GlaxoSmithKline, Novartis, Principio, Travere, and UpToDate; and consulting honoraria from Funding Information: This study was funded by an Achillion Pharmaceuticals unrestricted grant WIII_P63681. N.R. Medjeral-Thomas is supported by an Imperial College London and Wellcome Trust post-doctoral Research Fellowship WIII_P80067. M.C. Pickering is supported by Wellcome Trust Senior Fellow in Clinical Science grant 212252/Z/ 18/Z. Funding Information: We thank and acknowledge David Apelian and Hetal Kocinsky for support and general advice with the study inception. We acknowledge the invaluable support for this study by Dr. Thomas Barbour. We thank all of the C3 Glomerulopathy Natural History Study patients, local site research personnel, and our site lead investigators: Dr. Kay Tan, The Royal Wolverhampton National Health Service (NHS) Trust; Dr. Mark Lambie, University Hospitals of North Midlands NHS Trust; Dr. Santhanakrishnan Balasubrama-nian, York Teaching Hospital NHS Foundation Trust; Dr. Arvind Ponnusamy, Lancashire Teaching Hospitals NHS Foundation Trust; Dr. Matthew Hall, Nottingham University Hospitals NHS Trust; Dr. Lucy Smyth, Royal Devon and Exeter NHS Foundation Trust; Dr. David Milford, Birmingham Women{\textquoteright}s and Children{\textquoteright}s NHS Foundation Trust; Dr. Bisher Kawar, Sheffield Teaching Hospitals NHS Foundation Trust; Dr. Kay Tyerman, Leeds Teaching Hospitals NHS Trust; Dr. Durga Kanigicherla, Manchester University NHS Foundation Trust; Dr. John Booth, Barts Health NHS Trust; Dr. Jo Taylor, Dorset County Hospital NHS Foundation Trust; Dr. Martin Christian, Nottingham University Hospitals NHS Trust; Dr. Jennifer Pinney, University Hospitals Birmingham NHS Foundation Trust; Dr. Nick Webb, Manchester University NHS Foundation Trust; Dr. Edwin Wong, Newcastle upon Tyne Hospitals NHS Foundation Trust; Dr. Daniel Gale, Royal Free London NHS Foundation Trust; Dr. Tarun Bansal, Bradford Teaching Hospitals NHS Foundation Trust; Dr. Colin Geddes, NHS Greater Glasgow and Clyde; Dr. Jonathan Barratt, University Hospitals of Leicester NHS Trust; Dr. Waqar Ayub, University Hospitals of Coventry and Warwickshire; and Dr. Rachel Jones, Cambridge University Hospitals NHS Foundation Trust. We acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare National Health Service Trust and Imperial College London and from the NIHR Clinical Research Network. Publisher Copyright: {\textcopyright} 2022 by the American Society of Nephrology.",

year = "2022",

month = jul,

doi = "10.2215/CJN.16801221",

language = "English (US)",

volume = "17",

pages = "994--1007",

journal = "Clinical Journal of the American Society of Nephrology",

issn = "1555-9041",

publisher = "American Society of Nephrology",

number = "7",

}

TY - JOUR

T1 - Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

AU - Lomax-Browne, Hannah J.

AU - Medjeral-Thomas, Nicholas R.

AU - Barbour, Sean J.

AU - Gisby, Jack

AU - Han, Heedeok

AU - Bomback, Andrew S.

AU - Fervenza, Fernando C.

AU - Cairns, Thomas H.

AU - Szydlo, Richard

AU - Tan, Sven Jean

AU - Marks, Stephen D.

AU - Waters, Aoife M.

AU - Appel, Gerald B.

AU - D’agati, Vivette D.

AU - Sethi, Sanjeev

AU - Nast, Cynthia C.

AU - Bajema, Ingeborg

AU - Alpers, Charles E.

AU - Fogo, Agnes B.

AU - Licht, Christoph

AU - Fakhouri, Fadi

AU - Cattran, Daniel C.

AU - Peters, James E.

AU - Cook, H. Terence

AU - Pickering, Matthew C.

N1 - Funding Information: Achillion, Alexion, Catalyst, ChemoCentryx, Novartis, Silence, and Visterra. D.C. Cattran reports consultancy agreements with Alny-lam, Calliditis, Forsee, Horizon, Principia, and Reistone; research funding from Alnylam; honoraria from Alexion, Calliditis, Kyowa Hakko Kirin Co., and Principia; serving in an advisory or leadership role for Alnylam, NephCure, Standardised Outcomes in Nephrology-Glomerular Disease (SONG-GD), and UpToDate; and other interests or relationships with Aurinea, Dimerix, Novartis, and Vera Therapeutics. H.T. Cook reports consultancy agreements with Alexion Pharmaceuticals, Apellis Pharmaceuticals, Aurinia, and Novartis and research funding from Alexion Pharmaceuticals. V.D. D’Agati reports serving on the editorial board of Kidney International. F. Fakhouri reports consultancy agreements with Alexion, Alnylam, Apellis, Novartis, and Roche; honoraria from Alexion, Alnylam, Apellis, Novartis, and Roche; and serving in an advisory or leadership role for Alexion, Alnylam, Apellis, Novartis, and Roche. F.C. Fervenza reports consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; honoraria from UpToDate; and serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate. A.B. Fogo reports consultancy agreements with Novartis; research funding from Bayer, Gilead, and Novartis; honoraria from Amgen, GlaxoSmithKline, and Novartis; serving in an advisory or leadership role for an advisory committee for Bayer; serving on the editorial boards for American Journal of Pathology, American Journal of Physiology Renal Physiology, Human Pathology, and JASN; serving as an associate editor of Kidney International and Laboratory Investigation; serving as a subject editor for Current Opinion Nephrology and Hypertension (guest editor for the yearly pathology focus) and Nephrology Dialysis and Transplantation; and serving as a speaker at various national nephrology meetings and as President of the International Society of Nephrology (president as of April 19, 2021). C. Licht reports consultancy agreements with Alexion, Apellis Pharmaceuticals, Inc., AstraZeneca Rare Disease, Genentech, Inc.–Hoffmann La Roche, and Novartis; research funding from Aurin Biotech, Inc. and Pfizer Inc.; honoraria from Alexion, Apellis Pharmaceuticals, Inc., AstraZeneca Rare Disease, and Novartis; consulting honoraria and unrestricted research funding from Alexion, Aurinia, Eleva, and Novartis; patents or royalties for Factor H for the treatment of chronic nephropathies and production thereof (international patent WO 2007/038995 A1, US patent 11/992,194, CSL Behring patent 2005_M006_A105, Finnegan patent 06478.1518-00000); serving on the editorial boards of Kidney International, Nephrology Dialysis Transplantation, and Pediatric Nephrology; serving in an advisory or leadership role for Alexion, the steering committee of the Alport Syndrome Treatments and Outcomes Registry, AstraZeneca Rare Disease International atypical hemolytic uremic syndrome (aHUS) Registry scientific advisory board, the safety board of the European Treatment Trial for Alport Syndrome, and the safety advisory board of OPKO Health, Inc.; and speakers bureau for Alexion and AstraZeneca Rare Disease. S.D. Marks reports employment with Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust; the hospital receives funding for immunosuppressive drug studies by Astellas and Novartis. S.D. Marks reports serving as an associate editor for pediatric transplantation for the following journals: British Journal for Renal Medicine, Pediatric Nephrology, Pediatric Transplantation, and Transplantation. C.C. Nast reports serving in an advisory or leadership role for BioCryst. M.C. Pickering reports consultancy agreements with Achillion, Alexion Pharmaceuticals, Apelllis Pharmaceuticals, and Gyroscope Pharmaceuticals; scientific advisory board fees from Gyroscope; consultancy fees from Alexion Pharma Consultancy and Apellis Pharma; and serving on the Gyroscope Pharmaceuticals scientific advisory board. S. Sethi reports consultancy agreements with Novartis and honorarium for teaching, grand rounds, lectures, UpToDate, and reviewing slides for a study for Novartis. S.-J. Tan reports honoraria from AstraZeneca Australia. A.M. Waters reports working as a consultant medical director for Purespring Therapeutics Ltd. All remaining authors have nothing to disclose. Funding Information: C.E. Alpers reports consultancy agreements with AstraZeneca, Mantra Bio, and Travere; research funding from Boehringer-Ingelheim and Sana; and serving on the editorial boards of American Journal of Kidney Diseases, American Journal of Pathology, CJASN, Journal of Nephrology, Kidney360, and Laboratory Investigation. G.B. Appel reports consultancy agreements with Achillion, Alexion, Apellis, Aurinia, Bristol Myers Squibb, Chemocentryx, E. Lilly, EMD Serono, Genentech, Genzyme-Sanofi, GlaxoSmithKline, Mallinkrodt, Merck, Novartis, Omeros, Pfizer, Reata, Travere Therapeutics, and Vera Therapeutics; research funding from Achillion-Alexion, Apellis, Bristol Myers Squibb, Chemocentryx, EMD Serono, Genentech-Roche, Mallinkrodt, Reata, and Sanofi-Genzyme; honoraria from Aurinia and GlaxoSmithKline; royalties from UpToDate; serving in an advisory or leadership role for the UpToDate Editorial Board; serving in an advisory or leadership role on the medical advisory boards for Alexion, Alexion-Achillion, Apellis, Aurinia, BM Squib, Genentech, GlaxoSmith-Kline Lilly, Reata, Roche, and Sanofi; and speakers bureau for Auri-nia (lectures on lupus nephritis) and GlaxoSmithKline (lectures on lupus nephritis). I. Bajema reports consultancy agreements with Aurinia, Boehringer Ingelheim, CatBio, GlaxoSmithKline, Novartis, and Toleranzia and serving as Director of the Bajema Institute of Pathology, as Vice President of the European Vasculitis Society, and as President of the Renal Pathology Society. S.J. Barbour reports consultancy agreements with Achillion, Alexion, Inception Sciences, Novartis, and Visterra; research funding from Alexion and Roche; and honoraria from Alexion and Roche. A.S. Bomback reports consultancy agreements with Catalyst, Chemocentryx, Novartis, Otsuka, Q32, Silence Therapeutics, and Visterra; honoraria from Alexion, Aurinia, Calliditas, GlaxoSmithKline, Novartis, Principio, Travere, and UpToDate; and consulting honoraria from Funding Information: This study was funded by an Achillion Pharmaceuticals unrestricted grant WIII_P63681. N.R. Medjeral-Thomas is supported by an Imperial College London and Wellcome Trust post-doctoral Research Fellowship WIII_P80067. M.C. Pickering is supported by Wellcome Trust Senior Fellow in Clinical Science grant 212252/Z/ 18/Z. Funding Information: We thank and acknowledge David Apelian and Hetal Kocinsky for support and general advice with the study inception. We acknowledge the invaluable support for this study by Dr. Thomas Barbour. We thank all of the C3 Glomerulopathy Natural History Study patients, local site research personnel, and our site lead investigators: Dr. Kay Tan, The Royal Wolverhampton National Health Service (NHS) Trust; Dr. Mark Lambie, University Hospitals of North Midlands NHS Trust; Dr. Santhanakrishnan Balasubrama-nian, York Teaching Hospital NHS Foundation Trust; Dr. Arvind Ponnusamy, Lancashire Teaching Hospitals NHS Foundation Trust; Dr. Matthew Hall, Nottingham University Hospitals NHS Trust; Dr. Lucy Smyth, Royal Devon and Exeter NHS Foundation Trust; Dr. David Milford, Birmingham Women’s and Children’s NHS Foundation Trust; Dr. Bisher Kawar, Sheffield Teaching Hospitals NHS Foundation Trust; Dr. Kay Tyerman, Leeds Teaching Hospitals NHS Trust; Dr. Durga Kanigicherla, Manchester University NHS Foundation Trust; Dr. John Booth, Barts Health NHS Trust; Dr. Jo Taylor, Dorset County Hospital NHS Foundation Trust; Dr. Martin Christian, Nottingham University Hospitals NHS Trust; Dr. Jennifer Pinney, University Hospitals Birmingham NHS Foundation Trust; Dr. Nick Webb, Manchester University NHS Foundation Trust; Dr. Edwin Wong, Newcastle upon Tyne Hospitals NHS Foundation Trust; Dr. Daniel Gale, Royal Free London NHS Foundation Trust; Dr. Tarun Bansal, Bradford Teaching Hospitals NHS Foundation Trust; Dr. Colin Geddes, NHS Greater Glasgow and Clyde; Dr. Jonathan Barratt, University Hospitals of Leicester NHS Trust; Dr. Waqar Ayub, University Hospitals of Coventry and Warwickshire; and Dr. Rachel Jones, Cambridge University Hospitals NHS Foundation Trust. We acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare National Health Service Trust and Imperial College London and from the NIHR Clinical Research Network. Publisher Copyright: © 2022 by the American Society of Nephrology.

PY - 2022/7

Y1 - 2022/7

N2 - Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN.We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

AB - Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN.We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

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JO - Clinical Journal of the American Society of Nephrology

JF - Clinical Journal of the American Society of Nephrology

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Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

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