Human Neutrophil Antibodies are Associated with Severe Early Rejection in Kidney Transplant Recipients
Timothy Key1, Vaughan Carter2, Paula Goodwin1, John Goodwin1, Andrea Harmer1, Amanda Knight4, Faye Mather1, William McKane5, Anthony Poles3, Keith Rigg4.
1Histocompatibility and Immunogenetics Laboratory, NHS Blood and Transplant, Sheffield, United Kingdom; 2Histocompatibility and Immunogenetics Laboratory, NHS Blood and Transplant, Newcastle, United Kingdom; 3Histocompatibility and Immunogenetics Laboratory, NHS Blood and Transplant, Bristol, United Kingdom; 4Kidney Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; 5Sheffield Kidney Institute, Northern General Hopsital, Sheffield, United Kingdom
Introduction: In kidney transplantation most positive donor crossmatches and antibody mediated rejection are caused by Human Leucocyte Antigen specific antibodies (HLA Ab). A range of non-HLA antibodies, directed against other polymorphic antigen systems have been implicated where no HLA donor specific antibodies (HLA-DSA) are detected. Non-HLA antibodies are reported to have a range of effects on transplant outcome. The effect of Human Neutrophil Antigen donor specific antibody (HNA-DSA) has not been documented. The HNA system consists of five groups (HNA1-5) present on a diverse range of extracellular structures. Antibodies to HNA (HNA Ab) are known to cause severe and sometimes fatal consequences in transfusion associated lung injury (TRALI) and neonatal alloimmune neutropaenia (NAIN). HNA-3 is a bi-alleic system comprising HNA-3a (SLC44A2*01) and 3b (SLC44A2*02) and is expressed on many cell types including in the kidney. Around 5% of Caucasian’s are homozygous HNA-3b and therefore at risk of allosensitisation to HNA-3a. We report experience in four patients undergoing kidney transplant with pre-formed HNA-3a DSA.
Materials and Methods: All recipients were Caucasoid females, parous and undergoing first kidney transplant in 3 UK centres. Recipients and donors were HNA genotyped by Sequence Based Typing. Recipients were tested for HNA Ab by indirect granulocyte immunofluorescence test (GIFT), lymphocyte immunofluorescence test (LIFT) and Luminex®. Recipients were tested for HLA Ab by Luminex®. Pre-transplant crossmatch was by 3 colour flow cytometry.
Results and Discussion:
Patient 1 Deceased donor (DD) transplant 2006, ATG induction therapy, severe vascular rejection in first 2 weeks, currently stable graft function
Patient 2 Living donor transplant 2013, ATG induction therapy, good initial function, rise in proteinuria over 3 years, eGFR now 28, biopsy pending.
Patient 3 DD transplant 2016 received basiliximab, tacrolimus/MMF/prednisolone immunosuppression, acute antibody mediated rejection day 5 post-transplant treated with ATG, graft failed after 10 months.
Patient 4 DD transplant September 2017, basiliximab, tacrolimus/MMF/prednisolone immunosuppression. eGFR currently 34, biopsy considered.
HNA-3a IgG Ab was detected in all recipients. HNA genotyping identified that all recipients were HNA-3b3b. All donors expressed HNA-3a. No recipients had HLA-DSA at the time of transplant. All cases had a positive pre-transplant donor T and B cell flow cytometric crossmatch (FCXM). The autologous FCXM was negative in all cases
Conclusion: Antibodies to HNA-3a cause a positive FCXM in allosensitised HNA-3b homozygous individuals. A positive FCXM will occur with the majority of donors as 95% of individuals express HNA-3a. The pathological significance of HNA-3a antibodies should be carefully considered prior to kidney transplantation. Despite ATG induction, two patients had severe early rejection and one has probable chronic transplant glomerulopathy.
