Diagnostics and treatment of a severe humoral rejection after liver transplantation: donor-specific antibodies as a still underestimated cause of graft failure

 

 Buy Article Permissions and Reprints

Abstract

Background: Donor-specific antibodies (DSAs) are increasingly being considered a cause of complications after liver transplant (LT). However, neither monitoring of DSAs nor the appropriate therapeutic procedures for humoral graft damage are yet standardized. Here we report a case of DSA-positive humoral rejection after LT that was successfully treated with plasmapheresis and immunoglobulins.

Methods: Human leukocyte antigen (HLA)-specific DSAs were detected by Luminex bead assay. Patient characteristics, laboratory values, and data about the patient’s general condition were documented from April 2013 to June 2015.

Case report: Eighteen months after LT, a 54-year-old man experienced severe hepatopathy with rapidly increasing transaminase activity and total bilirubin levels. Histologic findings were inconclusive, demonstrating chronic cholestasis and minimal positive staining for C4 d. However, an analysis for anti-HLA antibodies detected DSAs against HLA class II molecules with high mean fluorescence intensity. The patient underwent 8 courses of plasmapheresis, resulting in sustained amelioration of his condition and decreases in bilirubin levels and transaminase activity.

Conclusion: De novo DSAs can be responsible for graft failure after LT. Thus, procedures aimed at detecting DSAs are recommended, and regular monitoring of DSAs after LT is important for individualized risk management. Plasmapheresis is an efficient therapeutic procedure for DSA-associated graft failure.

Zusammenfassung

Hintergrund: Es existieren vermehrt Hinweise, dass donorspezifische Antikörper (DSAs) eine wichtige Ursache für Komplikationen nach Lebertransplantation (LT) darstellen. Trotzdem wurde bisher weder ein standardisiertes Monitoring nach LT etabliert, noch gibt es Vorgaben bez. des therapeutischen Vorgehens im Falle eines humoralen Transplantatschadens. Hier präsentieren wir den Fall einer erfolgreichen Behandlung eines Patienten mit humoraler Rejektion nach LT.

Methoden: HLA-spezifische DSAs wurden mittels eines Luminex-basierten Verfahrens nachgewiesen. Patientendaten und Laborparameter wurden in der Zeit von April 2013 bis Juni 2015 dokumentiert.

Fallbericht: Ein 54-jähriger Patient entwickelte 18 Monate nach LT eine schwere Hepatopathie mit raschem Anstieg der Transaminasen sowie des Gesamt-Bilirubins. Die histologischen Ergebnisse waren unspezifisch und zeigten u. a. eine chronische Cholestase sowie eine minimale C4d-Reaktivität. Bei der Untersuchung auf DSAs wurden Antikörper gegen HLA-Klasse-II-Antigene nachgewiesen. Es wurden 8 Zyklen Plasmapherese durchgeführt, was zu einer Besserung des Allgemeinzustands sowie zu einer deutlichen Regredienz der Leberparameter führte.

Diskussion: De novo DSAs können eine humorale Rejektion nach LT verursachen. Aus diesem Grund ist ein regelmäßiges Monitoring der DSAs eine wichtige Maßnahme hinsichtlich eines individualisierten Risikomanagements. Plasmapherese stellt eine effiziente Methode zur Behandlung einer humoralen Rejektion dar.

• References

• 1 Tait BD, Susal 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: 19-47
  CrossrefPubMedGoogle Scholar
• 2 Benseler V, McCaughan GW, Schlitt HJ et al. The liver: a special case in transplantation tolerance. Semin Liver Dis 2007; 27: 194-213
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol 2003; 3: 51-62
  CrossrefPubMedGoogle Scholar
• 4 Donaldson PT, Thomson LJ, Heads A et al. IgG donor-specific crossmatches are not associated with graft rejection or poor graft survival after liver transplantation. An assessment by cytotoxicity and flow cytometry. Transplantation 1995; 60: 1016-1023
  CrossrefPubMedGoogle Scholar
• 5 Lobo PI, Spencer C, Douglas MT et al. The lack of long-term detrimental effects on liver allografts caused by donor-specific anti-HLA antibodies. Transplantation 1993; 55: 1063-1066
  CrossrefPubMedGoogle Scholar
• 6 Ruiz R, Tomiyama K, Campsen J et al. Implications of a positive crossmatch in liver transplantation: a 20-year review. Liver Transpl 2012; 18: 455-460
  CrossrefPubMedGoogle Scholar
• 7 Castillo-Rama M, Castro MJ, Bernardo I et al. Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: role of human leukocyte antigen compatibility. Liver Transpl 2008; 14: 554-562
  CrossrefPubMedGoogle Scholar
• 8 Kheradmand T, Anthony TL, Harland RC et al. Antibody-mediated rejection in ABO compatible husband to wife living donor liver transplant and review of the literature. Hum Immunol 2014; 75: 578-583
  CrossrefPubMedGoogle Scholar
• 9 Lan X, Zhang MM, Pu CL et al. Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: a meta-analysis. World J Gastroenterol 2010; 16: 3457-3464
  CrossrefPubMedGoogle Scholar
• 10 Muro M, Lopez-Alvarez MR, Campillo JA et al. Influence of human leukocyte antigen mismatching on rejection development and allograft survival in liver transplantation: is the relevance of HLA-A locus matching being underestimated?. Transpl Immunol 2012; 26: 88-93
  CrossrefPubMedGoogle Scholar
• 11 Musat AI, Agni RM, Wai PY et al. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011; 11: 500-510
  CrossrefPubMedGoogle Scholar
• 12 Taner T, Stegall MD, Heimbach JK. Antibody-mediated rejection in liver transplantation: current controversies and future directions. Liver Transpl 2014; 20: 514-527
  CrossrefPubMedGoogle Scholar
• 13 Abu-Elmagd KM, Wu G, Costa G et al. Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver. Am J Transplant 2012; 12: 3047-3060
  CrossrefPubMedGoogle Scholar
• 14 Campbell P. Clinical relevance of human leukocyte antigen antibodies in liver, heart, lung and intestine transplantation. Curr Opin Organ Transplant 2013; 18: 463-469
  CrossrefPubMedGoogle Scholar
• 15 Kaneku H, O'Leary JG, Banuelos N et al. De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant 2013; 13: 1541-1548
  CrossrefPubMedGoogle Scholar
• 16 Terasaki PI, McClelland JD. Microdroplet Assay of Human Serum Cytotoxins. Nature 1964; 204: 998-1000
  PubMedGoogle Scholar
• 17 Heinemann FM. HLA genotyping and antibody characterization using the Luminex Multiplex technology. Transfusion medicine and hemotherapy: offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 2009; 36: 273-278
  PubMedGoogle Scholar
• 18 Reinsmoen NL, Lai CH, Heidecke H et al. Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients. Transplantation 2010; 90: 1473-1477
  Google Scholar
• 19 Hiemann NE, Meyer R, Wellnhofer E et al. Non-HLA antibodies targeting vascular receptors enhance alloimmune response and microvasculopathy after heart transplantation. Transplantation 2012; 94: 919-924
  PubMedGoogle Scholar
• 20 Neumann UP, Lang M, Moldenhauer A et al. Significance of a T-lymphocytotoxic crossmatch in liver and combined liver-kidney transplantation. Transplantation 2001; 71: 1163-1168
  CrossrefPubMedGoogle Scholar
• 21 Rasmussen A, Davies HF, Jamieson NV et al. Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation 1995; 59: 919-921
  CrossrefPubMedGoogle Scholar
• 22 Grabhorn E, Binder TM, Obrecht D et al. Long-term clinical relevance of de novo donor-specific antibodies after pediatric liver transplantation. Transplantation 2015; DOI: 10.1097/TP.0000000000000638.
  PubMedGoogle Scholar
• 23 Miyagawa-Hayashino A, Yoshizawa A, Uchida Y et al. Progressive graft fibrosis and donor-specific human leukocyte antigen antibodies in pediatric late liver allografts. Liver Transpl 2012; 18: 1333-1342
  CrossrefPubMedGoogle Scholar
• 24 Del Bello A, Congy-Jolivet N, Danjoux M et al. De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients. Transplant Int 2015; 28: 1371-1382
  CrossrefPubMedGoogle Scholar
• 25 Abdou AG, Asaad NY, Ehsan N et al. The diagnostic impact of C4d, CD68, and NF-kappaB expression in the differentiation between recurrent Hepatitis C and acute cellular rejection after liver transplantation. Appl Immunohistochem Mol Morphol 2015; DOI: 10.1097/PAI.0000000000000245.
  PubMedGoogle Scholar
• 26 Hubscher SG. Antibody-mediated rejection in the liver allograft. Curr Opin Organ Transplant 2012; 17: 280-286
  PubMedGoogle Scholar
• 27 Bellamy CO, Herriot MM, Harrison DJ et al. C4d immunopositivity is uncommon in ABO-compatible liver allografts, but correlates partially with lymphocytotoxic antibody status. Histopathology 2007; 50: 739-749
  CrossrefPubMedGoogle Scholar
• 28 Coppell JA, Richardson PG, Soiffer R et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2010; 16: 157-168
  CrossrefPubMedGoogle Scholar
• 29 Faioni EM, Mannucci PM. Venocclusive disease of the liver after bone marrow transplantation: the role of hemostasis. Leuk Lymphoma 1997; 25: 233-245
  CrossrefPubMedGoogle Scholar
• 30 Sebagh M, Azoulay D, Roche B et al. Significance of isolated hepatic veno-occlusive disease/sinusoidal obstruction syndrome after liver transplantation. Liver Transpl 2011; 17: 798-808
  CrossrefPubMedGoogle Scholar
• 31 Shen T, Feng XW, Geng L et al. Reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation. World J Gastroenterol 2015; 21: 6422-6426
  CrossrefPubMedGoogle Scholar
• 32 Yamada N, Urahashi T, Ihara Y et al. Veno-occlusive disease/sinusoidal obstruction syndrome associated with potential antibody-mediated rejection after pediatric living donor liver transplantation: a case report. Transplant Proc 2012; 44: 810-813
  CrossrefPubMedGoogle Scholar
• 33 Zimmerman MA, Schiller J, Kim J et al. Pathologic sequelae of allosensitization in liver transplantation. J Surg Res 2016; 200: 195-199
  CrossrefPubMedGoogle Scholar
• 34 Muro M, Moya-Quiles MR, Mrowiec A. Humoral response in liver allograft transplantation: a review of the role of anti-human leukocyte antigen (HLA) antibodies. Curr Protein Pept Sci 2016; Feb 26. [Epub ahead of print]
  PubMedGoogle Scholar
• 35 Del Bello A, Congy-Jolivet N, Danjoux M et al. Donor-specific antibodies and liver transplantation. Hum Immunol 2016; DOI: 10.1016/j.humimm.2016.02.006.
  PubMedGoogle Scholar
• 36 Ho MH, Wu SY, Ou KW et al. Retransplant as rescue treatment for ABO-compatible living-donor liver transplant related antibody-mediated rejection: a case report. Exp Clin Transplant DOI: 10.6002/ect.2015.0308.
  PubMedGoogle Scholar
• 37 Galian JA, Mrowiec A, Muro M. Molecular targets on B-cells to prevent and treat antibody-mediated rejection in organ transplantation. Present and future. Expert Opin Ther Targets 2016; 1-9 DOI: 10.1517/14728222.2016.1135904.
  PubMedGoogle Scholar
• 38 Wilson CH, Agarwal K, Carter V et al. Late humoral rejection in a compliant ABO-compatible liver transplant recipient. Transplantation 2006; 82: 988-989
  PubMedGoogle Scholar
• 39 Watson R, Kozlowski T, Nickeleit V et al. Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation. Am J Transplant 2006; 6: 3022-3029
  CrossrefPubMedGoogle Scholar
• 40 Kamar N, Lavayssiere L, Muscari F et al. Early plasmapheresis and rituximab for acute humoral rejection after ABO-compatible liver transplantation. World J Gastroenterol 2009; 15: 3426-3430
  CrossrefPubMedGoogle Scholar
• 41 Paterno F, Shiller M, Tillery G et al. Bortezomib for acute antibody-mediated rejection in liver transplantation. Am J Transplant 2012; 12: 2526-2531
  CrossrefPubMedGoogle Scholar