ASSAYS TO PREDICT ALLOGRAFT REJECTION

V. Kosmoliaptsis¹, L. Sharples², A.N. Chaudhry³, R.J. Johnson⁴, S.V. Fuggle⁵, T.R. Dafforn⁶, D.J. Halsall⁷, J.A. Bradley⁸, C.J. Taylor^9
1Department Of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge/UNITED KINGDOM, ²Mrc Biostatistics Unit, University of Cambridge, Cambridge/UNITED KINGDOM, ³Department Of Renal Medicine, University of Cambridge, Cambridge/UNITED KINGDOM, ⁴Statistics And Clinical Audit, NHS Blood and Transplant (UK), Bristol/UNITED KINGDOM, ⁵Scientific Advisor, NHS Blood and Transplant (UK), Bristol/UNITED KINGDOM, ⁶School Of Biosciences, University of Birmingham, Birmingham/UNITED KINGDOM, ⁷Department Of Clinical Biochemistry, University of Cambridge, Cambridge/UNITED KINGDOM, ⁸Department Of Surgery, University of Cambridge, Cambridge/UNITED KINGDOM, ⁹Tissue Typing Laboratory, University of Cambridge, Cambridge/UNITED KINGDOM

Body: Introduction: Conventional approaches to HLA matching for deceased donor (DD) kidney allocation regard all HLA mismatches within a given locus as having equal weighting. We hypothesised that HLA alloantigen immunogenicity for a given patient’s HLA type can be predicted by differences in structural and physiochemical properties and examined whether this approach provides a better assessment of transplant compatibility. Methods: A computer program was developed to compare each potential mismatched HLA class I (n=1,964) and class II (n=1,604) specificity with the HLA type of a cohort of highly sensitised patients (n=62) and calculate the number of amino acid mismatches (AAM, after inter-locus subtraction) and the overall hydrophobicity and electrostatic mismatch score (HMS and EMS). The ability of these immunogenicity indices to predict the likelihood and magnitude of an alloantibody response (determined using single antigen HLA class I and II antibody detection beads) against mismatched HLA was assessed. We next examined the influence of AAM, EMS and HMS on the outcome of adult DD kidney transplants, undertaken in the UK from 1990 to 2005. To enable direct comparison of the effect of each variable, independent of their confounding inter-relationships when there are multiple HLA mismatches present, we considered only transplants that were HLA-DR matched and had a zero or one HLA-A or -B mismatch (n=5,247). Univariate and multivariate analyses were performed using log-rank tests and Cox-regression. Results: There was a strong correlation between increasing number of AAM for both HLA class I and class II and the occurrence (p<0.0001, odds ratio for each AAM increase 3.85) and magnitude (p<0.0001) of alloantibody responses. Mismatched HLA class I and II specificities with 0-1 AAM led to weak alloantibody responses (median MFI 2,276 and 32 respectively) in contrast to those with ≥8 AAM (median MFI 11,822 and 5,128 respectively). Similarly, HMS and EMS correlated strongly with both alloantibody production and the strength of the alloantibody response (p<0.0001 for class I and II). Kidney transplants with a single HLA-A or -B mismatch had lower graft survival compared to fully HLA matched transplants (81.9% v 84.2% at 5 years, HR 1.2, p=0.004). However, of the single HLA-A or -B mismatched transplants those with zero or 1 AAM had significantly higher survival compared to transplants with 2 or more AAM (89.3% v 81.8% at 5 years, HR 1.5, p=0.03). The number of AAM was an independent predictor of transplant survival after adjusting for the underlying HLA matching effect (p=0.02). Physiochemical disparity scores correlated closely with the number of AAM such that no additional predictive value for transplant survival was observed in this dataset. Conclusion: Information derived from the structural and physiochemical properties of HLA class I and class II allows prediction of HLA alloantigen immunogenicity for a given recipient HLA type and may be of greater clinical relevance than conventional HLA matching.

Disclosure: All authors have declared no conflicts of interest.