HLA matching and graft survival in kidney transplantation
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Washington University School of Medicine
The evidence that antigens of the human leukocyte antigen (HLA) system provide the major barrier to acceptance of renal transplants was first obtained with living-related-donor transplants. Graft survival was superior in sibling pairs having both the same serologically defined HLA antigens and a nonreactive in vitro mixed lymphocyte proliferative response when compared with randomly matched, deceased donors treated with the same immunosuppressive drugs, principally azathioprine and prednisone. (The mixed lymphocyte response [MLR] is an in vitro estimate of incompatibility in which the degree of proliferation of the recipient lymphocytes to donor lymphocytes is measured.) There was an intermediate level of graft survival in haploidentical parent-to-child or sibling-to-sibling transplants in which one but not both of the haplotypes matched.
The most valuable databases now in existence are those representing pooling of information from a large number of collaborating centers. Although such pooled data may suffer from variations in protocols and undocumented selection factors, the power of univariate analyses becomes compelling when thousands of patients are included. These large databases include the United Network for Organ Sharing (UNOS), the Collaborative Transplant Study (CTS), the Scientific Registry of Transplant Recipients (SRTR), the American Southeast Organ Procurement Foundation (SEOPF), the United Kingdom Transplant Service, Eurotransplant, the Australian New Zealand Data (ANZDATA), and others.
The methods used to test for HLA antigens and antibodies have changed over time and become more sophisticated. Historically, serology and cellular-based assays such as the complement-dependent cellular lymphocytotoxicity (CDC) assay were used to determine HLA antigens and anti-HLA antibodies. Antigens are now molecularly defined through DNA analysis, providing allelic-level definition of the antigens, and anti-HLA antibodies can now be detected using flow cytometry, solid-phase immunoassays, and single-antigen bead assays such as Luminex [1,2]. These assays can also be used to detect non-HLA antibodies .
RELATIVE IMPORTANCE OF HLA-A,-B, AND -DR
The simple assumption that each mismatch for HLA antigens has equal weight has not been borne out. The initial Collaborative Transplant Study (CTS) analysis showed that the major impact comes from the DR and B antigens, with little additional effect from the A antigens [4,5]. The UK Transplant and Eurotransplant data are somewhat similar, with DR matching having a much greater effect than that of B or A [6,7]. Another study found that HLA-DR mismatches (and the number of rejection episodes) correlated with poor long-term survival . Each antigen also appears to exert its effect at different times posttransplant, with the maximal effect of DR and B mismatching occurring within the first six months and two years posttransplant, respectively .
An analysis of the United Network for Organ Sharing (UNOS) registry of patients transplanted between January 1, 1987 and December 31, 2013 confirms the importance of minimizing mismatches and maximizing matches . In this study of 189,141 first adult kidney-alone transplants, there was a 13 percent higher risk with one HLA mismatch (hazard ratio [HR] 1.13, 95% CI 1.06-1.21) and a 64 percent higher risk with six HLA mismatches (HR 1.64, 95% CI 1.56-1.73), with increasing risk for each level of mismatch. In contradistinction to previous studies, these results were independent of locus.
- Fuggle SV, Martin S. Tools for human leukocyte antigen antibody detection and their application to transplanting sensitized patients. Transplantation 2008; 86:384.
- Gebel HM, Bray RA. HLA antibody detection with solid phase assays: great expectations or expectations too great? Am J Transplant 2014; 14:1964.
- Tait BD, Süsal C, Gebel HM, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013; 95:19.
- Opelz G. Correlation of HLA matching with kidney graft survival in patients with or without cyclosporine treatment. Transplantation 1985; 40:240.
- Opelz, G. Collaborative Transplant Study Newsletter 1988; number 3.
- Gilks WR, Bradley BA, Gore SM, Klouda PT. Substantial benefits of tissue matching in renal transplantation. Transplantation 1987; 43:669.
- Doxiadis II, de Fijter JW, Mallat MJ, et al. Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility. Transplantation 2007; 83:1207.
- Coupel S, Giral-Classe M, Karam G, et al. Ten-year survival of second kidney transplants: impact of immunologic factors and renal function at 12 months. Kidney Int 2003; 64:674.
- Dialysis and Transplantation, Owen WF, Pereira BJ, Sayegh MH (Eds), WB Saunders, Philadelphia 2000. p.504.
- Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
- Doxiadis II, Smits JM, Schreuder GM, et al. Association between specific HLA combinations and probability of kidney allograft loss: the taboo concept. Lancet 1996; 348:850.
- Reisaeter AV, Leivestad T, Vartdal F, et al. A strong impact of matching for a limited number of HLA-DR antigens on graft survival and rejection episodes: a single-center study of first cadaveric kidneys to nonsensitized recipients. Transplantation 1998; 66:523.
- Pfeiffer K, Vögeler U, Albrecht KH, et al. HLA-DP antibodies in patients awaiting renal transplantation. Transpl Int 1995; 8:180.
- Qiu J, Cai J, Terasaki PI, et al. Detection of antibodies to HLA-DP in renal transplant recipients using single antigen beads. Transplantation 2005; 80:1511.
- Youngs D. HLA-DP alloantibodies. ASHI Quarterly 2004; 28:60.
- Muczynski KA, Ekle DM, Coder DM, Anderson SK. Normal human kidney HLA-DR-expressing renal microvascular endothelial cells: characterization, isolation, and regulation of MHC class II expression. J Am Soc Nephrol 2003; 14:1336.
- Laux G, Mansmann U, Deufel A, et al. A new epitope-based HLA-DPB matching approach for cadaver kidney retransplants. Transplantation 2003; 75:1527.
- Nelson KA, Youngs D, Marks MH. Acute humoral rejection is associated with antibodies to HLA-DP. Am J Transplant 2005; 5:245.
- Samaniego M, Mezrich J, Torrealba J, et al. C4d-positive acute antibody-mediated rejection due to anti-HLA-DP antibody: a tale of one patient and a review of the University of Wisconsin experience. Clin Transpl 2006; :503.
- Goral S, Prak EL, Kearns J, et al. Preformed donor-directed anti-HLA-DP antibodies may be an impediment to successful kidney transplantation. Nephrol Dial Transplant 2008; 23:390.
- Singh P, Colombe BW, Francos GC, et al. Acute humoral rejection in a zero mismatch deceased donor renal transplant due to an antibody to an HLA-DP alpha. Transplantation 2010; 90:220.
- Jolly EC, Key T, Rasheed H, et al. Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation. Am J Transplant 2012; 12:2845.
- Morales-Buenrostro LE, Terasaki PI, Marino-Vázquez LA, et al. "Natural" human leukocyte antigen antibodies found in nonalloimmunized healthy males. Transplantation 2008; 86:1111.
- Freitas MC, Rebellato LM, Ozawa M, et al. The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes. Transplantation 2013; 95:1113.
- Devos JM, Gaber AO, Teeter LD, et al. Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation 2014; 97:534.
- Lim WH, Chapman JR, Coates PT, et al. HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients. Clin J Am Soc Nephrol 2016; 11:875.
- The Organ Procurement Transplant Network. OPTN/UNOS Histocompatibility Committee AMENDED Report to the Board of Directors. November 8-9, 2010, St. Louis, MO. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf (Accessed on August 31, 2014).
- Ling M, Marfo K, Masiakos P, et al. Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients. Hum Immunol 2012; 73:879.
- Bryan CF, Luger AM, Smith JL, et al. Sharing kidneys across donor-service area boundaries with sensitized candidates can be influenced by HLA C. Clin Transplant 2010; 24:56.
- Gilbert M, Paul S, Perrat G, et al. Impact of pretransplant human leukocyte antigen-C and -DP antibodies on kidney graft outcome. Transplant Proc 2011; 43:3412.
- Chapman JR, Taylor C, Ting A, Morris PJ. Hyperacute rejection of a renal allograft in the presence of anti-HLA-Cw5 antibody. Transplantation 1986; 42:91.
- Bachelet T, Couzi L, Guidicelli G, et al. Anti-Cw donor-specific alloantibodies can lead to positive flow cytometry crossmatch and irreversible acute antibody-mediated rejection. Am J Transplant 2011; 11:1543.
- Aubert O, Bories MC, Suberbielle C, et al. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies. Am J Transplant 2014; 14:1439.
- Cecka JM, Terasaki PI. The UNOS Renal Transplant Registry. In: Clinical Transplants 1993, Terasaki PI, Cecka JM (Eds), UCLA Tissue Typing Laboratory, Los Angeles 1994. p.1.
- Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med 2000; 343:1078.
- The Scientific Registry of Transplant Recipients http://www.ustransplant.org (Accessed on February 02, 2010).
- Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342:605.
- Meier-Kriesche HU, Ojo AO, Leichtman AB, et al. Interaction of mycophenolate mofetil and HLA matching on renal allograft survival. Transplantation 2001; 71:398.
- Andresdottir MB, Hoitsma AJ, Assmann KJ, et al. The impact of recurrent glomerulonephritis on graft survival in recipients of human histocompatibility leucocyte antigen-identical living related donor grafts. Transplantation 1999; 68:623.
- Lee CM, Carter JT, Alfrey EJ, et al. Prolonged cold ischemia time obviates the benefits of 0 HLA mismatches in renal transplantation. Arch Surg 2000; 135:1016.
- Schnitzler MA, Hollenbeak CS, Cohen DS, et al. The economic implications of HLA matching in cadaveric renal transplantation. N Engl J Med 1999; 341:1440.
- OPTN. Kidney Allocation System (KAS) "Out-of-the-gate" Monitoring Report. January 15, 2015. http://optn.transplant.hrsa.gov/media/1142/kas_monitoring_report.pdf (Accessed on February 18, 2015).
- Su X, Zenios SA, Chakkera H, et al. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant 2004; 4:1501.
- Opelz G, Döhler B. Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades. Transplantation 2007; 84:137.
- http://www.ustransplant.org (Accessed on February 02, 2010).
- Orandi BJ, Luo X, Massie AB, et al. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med 2016; 374:940.
- Meier-Kriesche HU, Scornik JC, Susskind B, et al. A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients. Transplantation 2009; 88:23.
- Young CJ, Gaston RS. Renal transplantation in black Americans. N Engl J Med 2000; 343:1545.
- Roberts JP, Wolfe RA, Bragg-Gresham JL, et al. Effect of changing the priority for HLA matching on the rates and outcomes of kidney transplantation in minority groups. N Engl J Med 2004; 350:545.
- Mutinga N, Brennan DC, Schnitzler MA. Consequences of eliminating HLA-B in deceased donor kidney allocation to increase minority transplantation. Am J Transplant 2005; 5:1090.
- Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci U S A 1994; 91:6259.
- Zwirner NW, Marcos CY, Mirbaha F, et al. Identification of MICA as a new polymorphic alloantigen recognized by antibodies in sera of organ transplant recipients. Hum Immunol 2000; 61:917.
- Zou Y, Heinemann FM, Grosse-Wilde H, et al. Detection of anti-MICA antibodies in patients awaiting kidney transplantation, during the post-transplant course, and in eluates from rejected kidney allografts by Luminex flow cytometry. Hum Immunol 2006; 67:230.
- Sumitran-Karuppan S, Tyden G, Reinholt F, et al. Hyperacute rejections of two consecutive renal allografts and early loss of the third transplant caused by non-HLA antibodies specific for endothelial cells. Transpl Immunol 1997; 5:321.
- Mizutani K, Terasaki P, Rosen A, et al. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant 2005; 5:2265.
- Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant 2007; 7:408.
- Zou Y, Stastny P, Süsal C, et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 2007; 357:1293.
- Gratwohl A, Döhler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008; 372:49.
- Burlingham WJ, Grailer AP, Heisey DM, et al. The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors. N Engl J Med 1998; 339:1657.
- Sanfilippo F. Transplantation tolerance--the search continues. N Engl J Med 1998; 339:1700.
- RELATIVE IMPORTANCE OF HLA-A,-B, AND -DR
- RELATIVE IMPORTANCE OF HLA-DP AND -DQ
- RELATIVE IMPORTANCE OF HLA-C
- IMPORTANCE OF EARLY REJECTION EPISODES
- LONG-TERM GRAFT SURVIVAL
- Survival compared with waiting list
- IMPACT OF DE-EMPHASIS OF HLA MATCHING
- HLA AND ORGAN ALLOCATION IN BLACKS
- LESS SPECIFIC HLA MATCHING
- OTHER HISTOCOMPATIBILITY ANTIGENS
- H-Y antigen
- EXPOSURE TO NONINHERITED HLA ALLELES