Prediction of HLA-DQ in Deceased Donors and its Clinical Significance in Kidney Transplantation
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Background: HLA-DQ typing in deceased donors is not mandatory in Korea. Therefore, when patients develop DQ antibodies after kidney transplantation (KT) from deceased donor, it is impossible to determine whether they are donor-specific antibodies (DSA). We developed DQ prediction programs for the HLA gene and evaluated their clinical utility. Methods: Two HLA-DQ prediction programs were developed: one based on Lewontin’s linkage disequilibrium (LD) and haplotype frequency and the other on an artificial neural network (ANN). Low-resolution HLA-A, -B, -DR, and -DQ typing data of 5,603 Korean patients were analyzed in terms of haplotype frequency and used to develop an ANN DQ prediction program. Predicted DQ (pDQ) genotype accuracy was analyzed using the typed DQ data of 403 patients. pDQ DSA agreement, sensitivity, specificity, and false-negative rate was evaluated using 1,970 single-antigen bead assays performed on 885 KT recipients. The clinical significance of DQ and pDQ DSA was evaluated in 411 KT recipients. Results: pDQ genotype accuracies were 75.4% (LD algorithm) and 75.7% (ANN). When the second most likely pDQ (LD algorithm) was also considered, the genotype accuracy increased to 92.6%. pDQ DSA (LD algorithm) agreement, sensitivity, specificity, and false-negative rate were 97.5%, 97.3%, 98.6%, and 2.4%, respectively. The antibody-mediated rejection treatment frequency was significantly higher in DQ or pDQ DSA-positive patients than in DQ or pDQ DSA-negative patients (P<0.001). Conclusions: Our DQ prediction programs showed good accuracy and could aid DQ DSA detection in patients who had undergone deceased donor KT without donor HLA-DQ typing.
Abstract
Background: HLA-DQ typing in deceased donors is not mandatory in Korea. Therefore, when patients develop DQ antibodies after kidney transplantation (KT) from deceased donor, it is impossible to determine whether they are donor-specific antibodies (DSA). We developed DQ prediction programs for the HLA gene and evaluated their clinical utility. Methods: Two HLA-DQ prediction programs were developed: one based on Lewontin’s linkage disequilibrium (LD) and haplotype frequency and the other on an artificial neural network (ANN). Low-resolution HLA-A, -B, -DR, and -DQ typing data of 5,603 Korean patients were analyzed in terms of haplotype frequency and used to develop an ANN DQ prediction program. Predicted DQ (pDQ) genotype accuracy was analyzed using the typed DQ data of 403 patients. pDQ DSA agreement, sensitivity, specificity, and false-negative rate was evaluated using 1,970 single-antigen bead assays performed on 885 KT recipients. The clinical significance of DQ and pDQ DSA was evaluated in 411 KT recipients. Results: pDQ genotype accuracies were 75.4% (LD algorithm) and 75.7% (ANN). When the second most likely pDQ (LD algorithm) was also considered, the genotype accuracy increased to 92.6%. pDQ DSA (LD algorithm) agreement, sensitivity, specificity, and false-negative rate were 97.5%, 97.3%, 98.6%, and 2.4%, respectively. The antibody-mediated rejection treatment frequency was significantly higher in DQ or pDQ DSA-positive patients than in DQ or pDQ DSA-negative patients (P<0.001). Conclusions: Our DQ prediction programs showed good accuracy and could aid DQ DSA detection in patients who had undergone deceased donor KT without donor HLA-DQ typing.
참고문헌 (19)
- Ozawa M, "Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience", Clin Transpl, pp.265~290 (2006)
- DeVos JM, "Donor-specific HLA-DQ antibodies may contribute to poor graft outcome after renal transplantation", Kidney Int, 82, pp.598~604 (2012)
- Willicombe M, "De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy", Transplantation, 94, pp.172~177 (2012)
- Everly MJ, "Incidence and impact of de novo donor-specific alloantibody in primary renal allografts", Transplantation, 95, pp.410~417 (2013)
- Lee H, "Clinical significance of HLA-DQ antibodies in the development of chronic antibodymediated rejection and allograft failure in kidney transplant recipients", Medicine (Baltimore), 95, pp.e3094~ (2016)
- Kobayashi T, "Significant association between chronic antibody-mediated rejection and donor-specific antibodies against HLA-DRB rather than DQB in renal transplantation", Hum Immunol, 72, pp.11~17 (2011)
- Shinae Yu, "Pre-Transplant Angiotensin II Type 1 Receptor Antibodies and Anti-Endothelial Cell Antibodies Predict Graft Function and Allograft Rejection in a Low-Risk Kidney Transplantation Setting", Annals of Laboratory Medicine, 40(5), pp.398~408 (2020), 대한진단검사의학회[DOI]
- "OPTN Policies"[URL]
- "Eurotransplant Manual© version 4.6 Chapter 10 Histocompatibility testing in: Eurotransplant"[URL]
- Gabriel SB, "The structure of haplotype blocks in the human genome", Science, 296, pp.2225~2229 (2002)
- Otegbeye F, "Understanding population-wide haplotype frequencies of human leukocyte antigen (HLA) alleles in linkage disequilibrium is important for hematopoietic stem cell transplantation", Rev Bras Hematol Hemoter, 39, pp.187~188 (2017)
- Slatkin M, "Linkage disequilibrium--understanding the evolutionary past and mapping the medical future", Nat Rev Genet, 9, pp.477~485 (2008)
- Haas M, "The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials", Am J Transplant, 18, pp.293~307 (2018)
- Navarrete C, "Genetic and functional relationship of the HLA-DR and HLA-DQ antigens", Immunogenetics, 21, pp.97~101 (1985)
- Bushell A, "HLA-DQ mismatches between donor and recipient in the presence of HLA-DR compatibility do not influence the function or outcome of renal transplants", Hum Immunol, 26, pp.179~189 (1989)
- Lim WH, "HLA-DQ mismatches and rejection in kidney transplant recipients", Clin J Am Soc Nephrol, 11, pp.875~883 (2016)
- Leeaphorn N, "HLA-DQ mismatching and kidney transplant outcomes", Clin J Am Soc Nephrol, 13, pp.763~771 (2018)
- Freitas MCS, "The role of immunoglobulin-G subclasses and C1q in de novo HLADQ donor-specific antibody kidney transplantation outcomes", Transplantation, 95, pp.1113~1119 (2013)
- Haas M, "Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions", Am J Transplant, 14, pp.272~283 (2014)