Kidney Week

Abstract: TH-PO848

The Emergence of Goodpasture’s Disease Following Hematopoietic Stem Cell Transplant: Clues to Disease Etiology?

Session Information

• Glomerular Diseases: Immunology and Inflammation - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Pedchenko, Vadim, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Vadim Pedchenko,

• Gray, Paul E., Sydney Children’s Hospital, Sydney, New South Wales, Australia

Paul E. Gray,

• Mccarthy, Hugh J., Syndey Children''s Hospital Network, Westmead, New South Wales, Australia

Hugh J. Mccarthy,

• Saleem, Moin, University of Bristol, Bristol, United Kingdom

Moin Saleem,

• Kitching, A. Richard, Monash University, Monash Health, Clayton, Victoria, Australia

A. Richard Kitching,

• Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Agnes B. Fogo,

• Hudson, Billy G., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Billy G. Hudson,

Introduction

Goodpasture’s disease is an autoimmune disorder caused by autoantibodies against collagen IV in the glomerular and alveolar basement membranes. It has been postulated that a conformational change of the native autoantigen, the α345NC1 hexamer of collagen IV, is imperative for the development of disease. Perturbation of the quaternary structure causes dissociation of the hexamer, which elicits autoantibodies against subunits, but not the native hexamer. This contrasts with Alport’s post-transplant nephritis, where the pathogenic alloantibody binds directly to native NC1 hexamer.

Case Description

We studied a patient who developed anti-GBM disease following allogeneic haematopoietic stem cell transplant. Autoantibody specificity was analysed by ELISA including binding to individual NC1 monomers of collagen IV (α1-α6), immunodominant epitopes of α3 chain, and native versus dissociated NC1 hexamers from glomerular basement membrane. Binding of autoantibody from patient serum to normal kidney GBM was also assessed. Anti-GBM antibodies were directed against the α3 NC1 domain of collagen IV and developed rapidly reaching peak level in patient serum within 5 weeks. They targeted predominantly the E_A epitope of α3 NC1. Antibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon hexamer dissociation. None of the polymorphic genetic differences between donor and recipient collagen IV genes would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture’s susceptibility HLA-allele DRB1*1501.

Discussion

This is the first report of Goodpasture’s disease occurring post-HSCT where the pathogenesis has been studied from onset to recovery. The specificity and binding properties of the antibodies along with sequencing results indicate that this is a post-transplant autoimmune rather than alloimmune phenomenon. This case also demonstrated the rapidity, in a matter of weeks, of high titres of pathogenic antibody production highlighting the nature of emergent Goodpasture’s disease. Our findings demonstrate the importance for early diagnosis of Goodpasture’s disease and timely treatment for preserving kidney function.