The immune response against alloantigens involves the production of antibodies and development of T-cell immunity. Recipients sensitized to HLA antigens may have antibodies to almost all donors and may not be able to find a suitable kidney transplant donor. Strategies available to enable these patients to obtain a transplant are to give priority to highly sensitized patients, to perform therapy for antibody reduction or to transplant with existing antibodies and to intervene as needed with post-transplant treatment. While sensitization against HLA antigens is the most important cause of immunological transplant failure, other types of alloantigens, many of them expressed selectively in endothelial cells, and autoantigens may also be involved. Molecular typing and solid-phase antibody testing have markedly changed this field in the last few years. Methods for the analysis of HLA antibodies and for the study of T-cell reactivity and sensitization will also be discussed. Virtual cross-matching can now be performed for many patients, resulting in considerable savings in time and effort. Successful application of this approach requires the intervention of highly trained personnel with a good understanding of the limitations of the procedure and with intimate knowledge of the antibody profiles of the patients on the waiting list.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Sanfilippo F, Vaughn WK, Bollinger RR, Spees EK (1982) Comparative effects of pregnancy, transfusion, and prior graft rejection on sensitization and renal transplant results. Transplantation 34:360–366
Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O (1966) Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet 2:662–665
Patel R, Terasaki PI (1969) Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 280:735–739
Moraes JR, Stastny P (1977) A new antigen system expressed in human endothelial cells. J Clin Invest 60:449–454
Win TS, Pettigrew GJ (2010) Humoral autoimmunity and transplant vasculopathy: when allo is not enough. Transplantation 90:113–120
Pei R, Lee JH, Shih NJ, Chen M, Terasaki PI (2003) Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities. Transplantation 75:43–49
Waanders MM, Heidt S, Koekkoek KM, Zoet YM, Doxiadis II, Amir A, Heemskerk MH, Mulder A, Brand A, Roelen DL, Claas FH, Ward FE, MacQueen JM, Amos DB, Delmas-Marsalet Y, Johnson A (2008) Monitoring of indirect allorecognition: wishful thinking or solid data? The antiglobulin microcytotoxicity assay in HL-A genotyped families. Tissue Antigens 71:1–15
Ward FE, MacQueen JM, Amos DB, Delmas-Marsalet Y, Johnson A (1975) The antiglobulin microcytotoxicity assay in HL-A genotyped families. Transplantation 19:286–290
Karpinski M, Rush D, Jeffery J, Exner M, Regele H, Dancea S, Pochinco D, Birk P, Nickerson P (2001) Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch. J Am Soc Nephrol 12:2807–2814
El-Awar N, Lee J, Terasaki PI (2005) HLA antibody identification with single antigen beads compared to conventional methods. Hum Immunol 66:989–997
SEOPF (1993) Southeastern organ procurement foundation tissue typing manual. Section B-20:12-13
Rebibou JM, Chabod J, Bittencourt MC, Thevenin C, Chalopin JM, Herve P, Tiberghien P (2000) Flow-PRA evaluation for antibody screening in patients awaiting kidney transplantation. Transplant Proc 32:2745–2746
Cecka JM (2009) Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am J Transplant 10:26–29
Amos DB, Bach FH (1968) Phenotypic expressions of the major histocompatibility locus in man (HL-A): leukocyte antigens and mixed leukocyte culture reactivity. J Exp Med 128:623–637
Grunnet N, Kristensen T, Kornerup HJ, Kissmeyer-Nielsen F (1975) Direct cell mediated lympholysis. A test of allograft-rejection in human kidney recipients. Tissue Antigens 5:280–285
Poggio ED, Heeger PS (2004) Use of cytokine enzyme-linked immunosorbent spot (ELISPOT) assay as an immune monitoring tool in solid organ transplantation. Transplant Rev 18:183–191
Gupta S, Mitchell JD, Markham DW, Mammen PP, Patel PC, Kaiser PA, Stastny P, Ring WS, Dimaio JM, Drazner MH (2008) Utility of the cylex assay in cardiac transplant recipients. J Heart Lung Transplant 27:817–822
Stastny P, Lavingia B, Fixler DE, Yancy CW, Ring WS (2007) Antibodies against donor human leukocyte antigens and the outcome of cardiac allografts in adults and children. Transplantation 84:738–745
Everly MJ, Rebellato LM, Ozawa M, Briley KP, Catrou PG, Haisch CE, Terasaki PI (2010) Beyond histology: lowering human leukocyte antigen antibody to improve renal allograft survival in acute rejection. Transplantation 89:962–967
Lobo PI, Isaacs RB, Spencer CE, Pruett TL, Sanfey HA, Sawyer RG, McCullough C (2002) Improved specificity and sensitivity when using pronase-digested lymphocytes to perform flow-cytometric crossmatch prior to renal transplantation. Transpl Int 15:563–569
Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, Gautreau C, Charron D, Glotz D (2009) Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Contrib Nephrol 162:1–12
Hidalgo LG, Campbell PM, Sis B, Einecke G, Mengel M, Chang J, Sellares J, Reeve J, Halloran PF (2009) De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant 9:2532–2541
Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, Gautreau C, Charron D, Glotz D, Suberbielle-Boissel C (1398) Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 21:1398–1406
Muczynski KA, Ekle DM, Coder DM, Anderson SK (2003) Normal human kidney HLA-DR-expressing renal microvascular endothelial cells: characterization, isolation, and regulation of MHC class II expression. J Am Soc Nephrol 14:1336–1348
Opelz G (2005) Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 365:1570–1576
Lavingia B, Qin Z, Comeaux A, Stastny P (2008) Correlation of antibodies against endothelial cell antigens with outcome of kidney regrafts. Hum Immunol 69:S108–S109
Lavingia B, Comeaux A, Qin Z, Stastny P (2009) Anti-endothelial cell antibodies correlate with the development of TCAD in heart transplant recipients. Hum Immunol 70:S85
Bell SA, Faust H, Mittermuller J, Kolb HJ, Meurer M (1996) Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association. Br J Dermatol 134:848–854
Hirata D, Iwamoto M, Yoshio T, Okazaki H, Masuyama J, Mimori A, Minota S (2000) Nucleolin as the earliest target molecule of autoantibodies produced in MRL/lpr lupus-prone mice. Clin Immunol 97:50–58
Fogal V, Sugahara KN, Ruoslahti E, Christian S (2009) Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature. Angiogenesis 12:91–100
Mizutani K, Terasaki P, Rosen A, Esquenazi V, Miller J, Shih RN, Pei R, Ozawa M, Lee J (2005) Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant 5:2265–2272
Lee PC, Zhu L, Terasaki PI, Everly MJ (2009) HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation 88:568–574
About this article
Cite this article
Stastny, P., Salvador, IM. & Lavingia, B. Evaluation of the highly sensitized transplant recipient. Pediatr Nephrol 26, 1927–1935 (2011). https://doi.org/10.1007/s00467-010-1732-6
- HLA antigens
- Panel reactive antibodies
- Single HLA antigen Luminex beads
- Endothelial cell antigens