Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients

Abstract

Background Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce. Methods We retrospectively analyzed a carefully phenotyped single-center (University Children’s Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant recipients (mean age at transplantation, 8.6 ± 5.0 years) at increased risk of graft function deterioration. Patients had received their transplant between January 1, 1999, and January 31, 2010. We examined at time of late index biopsies (more than 1-year post-transplant, occurring after January 2004) the association of antibodies against the angiotensin II type 1 receptor (AT1R), the endothelin type A receptor (ETAR), the MHC class I chain-like gene A (MICA), and vimentin in conjunction with overall and complement-binding donor-specific HLA antibodies (HLA-DSA) with graft histology and function. Results We observed a high prevalence (62.9%) of non-HLA antibody positivity. Seventy-two percent of HLA-DSA positive patients showed additional positivity for at least one non-HLA antibody. Antibodies against AT1R, ETAR, and MICA were associated with the histological phenotype of ABMR. The cumulative load of HLA-DSA and non-HLA antibodies in circulation was related to the degree of microinflammation in peritubular capillaries. Non-HLA antibody positivity was an independent non-invasive risk factor for graft function deterioration (adjusted hazard ratio 6.38, 95% CI, 2.11–19.3). Conclusions Our data indicate that the combined detection of antibodies to HLA and non-HLA targets may allow a more comprehensive assessment of the patients’ immune responses against the kidney allograft and facilitates immunological risk stratification.

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

“…Assessment of dnDSA was done at least yearly and during each episode of graft function deterioration and before initiation of anti-rejection therapy using LABScreen Luminex kits of One Lambda (Canoga Park, CA, USA), which use single HLA-antigen-coated beads and enable identification of immunoglobulin G (IgG) alloantibody specificities against HLA-A, -B, -C, -Cw, -DR, -DQ, and -DP antigens, as previously described [18][19][20]. A mean fluorescence intensity (MFI) cutoff value of > 500 was considered positive.…”

Anti-glutathione S-transferase theta 1 antibodies correlate with graft loss in non-sensitized pediatric kidney recipients

“…Among non-HLA antigens reported to be involved in Tx damage (11,13,16,23,(25)(26)(27), GSTT1 represents an interesting model, as it may function as both an allo-and autoantigen.…”

The Summarized Assessment of Endothelin A Receptor Expression in Renal Transplant Compartments Associated with Antibody-Mediated Rejection

“…Preformed IgG antibodies targeting non-HLA antigens expressed on glomerular endothelial cells were also described as associated with early acute microvascular rejection [ 29 ]. The need for detecting antibodies to HLA but also non-HLA antibodies were noticed by pediatricians to provide a more comprehensive assessment of the patient immune responses to the renal transplant and improved immunological risk stratification [ 30 ].…”