A Comparison of Two Types of Rabbit Antithymocyte Globulin Induction Therapy in Immunological High-Risk Kidney Recipients: A Prospective Randomized Control Study

F Burkhalter, S Schaub, Ch Bucher, L Gürke, A Bachmann, H Hopfer, M Dickenmann, J Steiger, I Binet, F Burkhalter, S Schaub, Ch Bucher, L Gürke, A Bachmann, H Hopfer, M Dickenmann, J Steiger, I Binet

Abstract

Background: Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy.

Methods: Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids.

Results: The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21-128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22-132) (Thymo-group) (p = 0.69).

Conclusion: We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.

Conflict of interest statement

The authors received a financial support from ROCHE for the realisation of this study. This financial support does not alter our adherence to PLOS ONE policies on sharing data and material.

Figures

Fig 1. Patient Flow Chart.
Fig 1. Patient Flow Chart.
Fig 2. Patients survival.
Fig 2. Patients survival.
Fig 3. Hematological values during follow-up (A)…
Fig 3. Hematological values during follow-up (A) Median white blood cells (WBC) count, (B) Median lymphocyte count, (C) Median thrombocyte count, (D) Median haemoglobin, (E) Mediant T- (CD3+) and B- (CD19+) cell count.
Fig 4. Cumulative incidence of biopsy proven…
Fig 4. Cumulative incidence of biopsy proven clinical and subclinical rejection episodes in the ATG- and Thymo-Group.
(A) Days to any allograft rejection, (B) Days to antibody mediated allograft rejection (AMR), (C) Time to any T-cell mediated allograft rejection (TCMR).

References

    1. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, et al. Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant 2011. October;11(10):2132–43. 10.1111/j.1600-6143.2011.03640.x
    1. Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, et al. Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol 2012. December;23(12):2061–71. 10.1681/ASN.2012070664
    1. Akalin E, Dinavahi R, Friedlander R, Ames S, de BG, Sehgal V, et al. Addition of plasmapheresis decreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. Clin J Am Soc Nephrol 2008. July;3(4):1160–7. 10.2215/CJN.05321107
    1. Bachler K, Amico P, Honger G, Bielmann D, Hopfer H, Mihatsch MJ, et al. Efficacy of induction therapy with ATG and intravenous immunoglobulins in patients with low-level donor-specific HLA-antibodies. Am J Transplant 2010. May;10(5):1254–62. 10.1111/j.1600-6143.2010.03093.x
    1. Haririan A, Nogueira J, Kukuruga D, Schweitzer E, Hess J, Gurk-Turner C, et al. Positive cross-match living donor kidney transplantation: longer-term outcomes. Am J Transplant 2009. March;9(3):536–42. 10.1111/j.1600-6143.2008.02524.x
    1. Mai ML, Ahsan N, Wadei HM, Genco PV, Geiger XJ, Willingham DL, et al. Excellent renal allograft survival in donor-specific antibody positive transplant patients-role of intravenous immunoglobulin and rabbit antithymocyte globulin. Transplantation 2009. January 27;87(2):227–32. 10.1097/TP.0b013e31818c962b
    1. Popow I, Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger GJ, Kundi M, et al. A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant 2013. December;13(12):3103–13. 10.1111/ajt.12514
    1. Kyllonen LE, Eklund BH, Pesonen EJ, Salmela KT. Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety. Transplantation 2007. July 15;84(1):75–82. 10.1097/01.tp.0000268084.64888.f3
    1. Kho MM, Bouvy AP, Cadogan M, Kraaijeveld R, Baan CC, Weimar W. The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients. Transpl Immunol 2012. June;26(4):186–90. 10.1016/j.trim.2012.02.003
    1. Kuypers DR, Malaise J, Claes K, Evenepoel P, Maes B, Coosemans W, et al. Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 2005. May;20 Suppl 2:ii33–9, ii62.
    1. Norrby J, Olausson M. A randomized clinical trial using ATG Fresenius or ATG Merieux as induction therapy in kidney transplantation. Transplant Proc 1997. November;29(7):3135–6.
    1. Schnetzler B, Leger P, Volp A, Dorent R, Pavie A, Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Transpl Int 2002. June;15(6):317–25. 10.1007/s00147-002-0418-9
    1. Malaise J, Kuypers DR, Claes K, Evenepoel P, Maes B, Coosemans W, et al. Immunosuppressive drugs after simultaneous pancreas-kidney transplantation. Transplant Proc 2005. July;37(6):2840–2. 10.1016/j.transproceed.2005.05.022
    1. Rostaing L, Lavayssiere L, Kamar N. Hematologic adverse effects of 2 different polyclonal antilymphocyte preparations in de novo kidney transplant patients. Exp Clin Transplant 2010. June;8(2):178–80.
    1. Pihusch M. Bleeding complications after hematopoietic stem cell transplantation. Semin Hematol 2004. January;41(1 Suppl 1):93–100.
    1. Ducloux D, Kazory A, Challier B, Coutet J, Bresson-Vautrin C, Motte G, et al. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation 2004. April 15;77(7):1029–33.
    1. Civati G, Minetti E, Busnach G, Perego A, Brando B, Broggi ML, et al. Low incidence of acute rejection in kidney grafts treated with initial quadruple therapy: a retrospective analysis comparing two ATGs. Transplant Proc 1998. June;30(4):1343–5.
    1. Hocker B, Bohm S, Fickenscher H, Kusters U, Schnitzler P, Pohl M, et al. (Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation. Transpl Int 2012. July;25(7):723–31. 10.1111/j.1432-2277.2012.01485.x
    1. Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, et al. Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 2006. October 15;108(8):2874–80. 10.1182/blood-2006-03-011791
    1. Mensen A, Na IK, Hafer R, Meerbach A, Schlecht M, Pietschmann ML, et al. Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. J Cancer Res Clin Oncol 2014. November;140(11):1971–80. 10.1007/s00432-014-1742-z
    1. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004. February;4(2):222–30.
    1. Abou-Ayache R, Buchler M, Lepogamp P, Westeel PF, Le MY, Etienne I, et al. CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine A. Nephrol Dial Transplant 2008. June;23(6):2024–32. 10.1093/ndt/gfm873
    1. Ejaz NS, Shields AR, Alloway RR, Sadaka B, Girnita AL, Mogilishetty G, et al. Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients. Am J Transplant 2013. December;13(12):3142–54. 10.1111/ajt.12493
    1. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007. July;21(7):1387–94. 10.1038/sj.leu.2404683
    1. Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology. Drugs 2010. April 16;70(6):691–732. 10.2165/11315940-000000000-00000
    1. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol 2006. October;17(10):2844–53. 10.1681/ASN.2006050422
    1. D'Addio F, Boenisch O, Magee CN, Yeung MY, Yuan X, Mfarrej B, et al. Prolonged, low-dose anti-thymocyte globulin, combined with CTLA4-Ig, promotes engraftment in a stringent transplant model. PLoS One 2013;8(1):e53797 10.1371/journal.pone.0053797
    1. Zand MS, Vo T, Huggins J, Felgar R, Liesveld J, Pellegrin T, et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 2005. June 15;79(11):1507–15.
    1. Krepsova E, Tycova I, Sekerkova A, Wohlfahrt P, Hruba P, Striz I, et al. Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance. BMC Nephrol 2015;16:146 10.1186/s12882-015-0141-2
    1. Muller TF, Grebe SO, Neumann MC, Heymanns J, Radsak K, Sprenger H, et al. Persistent long-term changes in lymphocyte subsets induced by polyclonal antibodies. Transplantation 1997. November 27;64(10):1432–7.

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