Special Studies

Participation in these studies must be in compliance with your local ethical and patient consent guidelines.

CTS Pre- and Posttransplant Serum Study

Introduction

Pretransplant determination of a recipient’s risk of graft rejection is a prerequisite for the application of recipient-tailored immunosuppression. Currently, lymphocytotoxic panel reactivity (PRA) is the gold standard for estimating the immunological responder state of kidney recipients. For recipients without PRA, who make up the majority, a categorization into high or low immunological risk is not possible.

With the collaboration of 29 centers, it was possible to show in a study of 3900 kidney transplants that pretransplant determination of the T cell activation marker sCD30 (1) is a good indicator for estimating the risk of graft rejection (2,3). Patients possessing both PRA and high sCD30 in their pretransplant serum had a particularly poor graft outcome (3). Recipients with high pretransplant soluble CD30 were shown to benefit greatly from HLA matching (4). PRA-positive recipients with high pretransplant IgA-anti-Fab activity demonstrated an excellent graft outcome (5).

Using solid phase ELISA, we observed that the pretransplant presence of anti-HLA class II antibodies in the absence of anti-HLA class I antibodies was of no clinical consequence, even if HLA class II DR mismatches were present (6,7). Another important finding was that there are patients who show reactivity in the lymphocytotoxic PRA test but are completely negative when tested for IgG-anti-HLA antibodies by ELISA. These antibodies, which are either directed against non-HLA alloantigens or belong to an isotype other than IgG, were found to be clinically relevant (6). In a survey of more than 160.000 patients transplanted between 1982 and 2002 we made the surprising observation that high pretransplant lymphocytotoxic PRA influences graft outcome also in transplants from HLA-identical siblings, indicating that non-HLA alloimmunity must play an important role in kidney transplantation (8). In agreement with these findings are studies in which the posttransplant presence of non-HLA anti-MICA was associated with poor outcome (9).

In a pilot study of 56 kidney recipients we found that measuring sCD30 in the first week posttransplant was useful for identifying recipients at risk of impending graft rejection. On posttransplant days 3-5 we were able to differentiate recipients who subsequently developed acute rejection from recipients with an uncomplicated course and, importantly, from recipients with acute tubular necrosis (ATN) in the absence of rejection (10). An additional study showed that increased sCD30 and neopterin at 1 year posttransplant are predictive of chronic allograft nephropathy at 2 years (11). Initiation of anti-rejection therapy at an early stage and risk-adapted adjustment of immunosuppression may prevent graft damage and improve longterm graft outcome.

Experimental studies underline the key role of CD30 in the generation of an alloimmune response (12), and clinical studies in kidney, heart, and lung transplant recipients support the relevance of serum sCD30 and anti-HLA for pre- and posttransplant monitoring of graft rejection (9,13-23).

High molecular weight proteins, such as antibodies or sCD30, are not overly sensitive to degradation. Serum samples can therefore be utilized for research studies even after prolonged frozen storage. The impact of confounders, such as infection, type of immunosuppression, race and age, year of transplantation, etc., has not been clarified so far due to complex interactions.

Goal of the study

Because of the multifactorial nature of clinical transplantation, it is necessary to study large series of patients. The goal of the present multi-center study is to elucidate the complex interactions at play. The extension of posttransplant immunological testing adds an important new dimension to the project.

References:

  1. Del Prete G, De Carli M, Almerigogna F, Daniel CK, D’Elios MM, Zancuoghi G, Vinante F, Pizzolo G, Romagnani S. Preferential expression of CD30 by human CD4+ T cells producing Th2-type cytokines. FASEB J 9: 81-86, 1995.
  2. Pelzl S, Opelz G, Wiesel M, Schnülle P, Schönemann C, Süsal C. Soluble CD30 as a predictor of kidney graft outcome. Transplantation 73: 3-6, 2002.
  3. Süsal C, Pelzl S, Opelz G. Identification of highly responsive kidney transplant recipients using pretransplant soluble CD30. J Am Soc Nephrol 13: 1650-1656, 2002.
  4. Süsal C, Pelzl S, Opelz G. Strong human leukocyte antigen matching effect in nonsensitized kidney recipients with high pretransplant soluble CD30. Transplantation 76: 1231-1232, 2003.
  5. Süsal C, Döhler B, Opelz G. Graft-protective role of high pretransplantation IgA-anti-Fab autoantibodies: confirmatory evidence obtained in more than 4000 kidney transplants. Transplantation 69: 1337-1340, 2000.
  6. Süsal C, Opelz G. Kidney graft failure and presensitization against HLA class I and class II antigens. Transplantation 73: 1269-1273, 2002.
  7. Süsal C, Opelz G. Good kidney transplant outcome in recipients with presensitization against HLA class II but not HLA class I. Hum Immunol 65: 810-816, 2004.
  8. Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 365: 1570-1576, 2005.
  9. Mizutani K, Terasaki P, Rosen A, Esquenazi V, Miller J, Shih RN, Pei R, Ozawa M, Lee J. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. Am J Transplant 5: 2265-2272, 2005.
  10. Pelzl S, Opelz G, Daniel V, Wiesel M, Süsal C. Evaluation of postransplant soluble CD30 for diagnosis of acute renal allograft rejection. Transplantation 75: 421-423, 2003.
  11. Weimer R, Süsal C, Yildiz S, Staak A, Pelzl S, Renner F, Dietrich H, Daniel V, Kamali-Ernst S, Ernst W, Padberg W, Opelz G. Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of different immunosuppressive regimens. Am J Transplant 6: 1865-1874, 2006.
  12. Martinez OM, Villanueva J, Abtahi S, Beatty PR, Esquivel CO, Krams SM. CD30 expression identifies a functional alloreactive human T-lymphocyte subset. Transplantation 65: 1240-1247, 1998.
  13. Slavcev A, Lacha J, Honsova E, Sajdlova H, Lodererova A, Vitko S, Skibova J, Striz I. Soluble CD30 and HLA antibodies as potential risk factors for kidney transplant rejection. Transpl Immunol 14: 117-121, 2005.
  14. Cinti P, Pretagostini R, Arpino A, Tamburro ML, Mengasini S, Lattanzi R, De Simone P, Berloco P, Molajoni ER. Evaluation of pretransplant immunologic status in kidney-transplant recipients by panel reactive antibody and soluble CD30 determinations. Transplantation 79: 599-601, 2005.
  15. Matinlauri IH, Kyllonen LE, Salmela KT, Helin H, Pelzl S, Süsal C. Serum sCD30 in monitoring of alloresponse in well HLA-matched cadaveric kidney transplantations. Transplantation 80: 1809-1812, 2005.
  16. Yang JL, Hao HJ, Qin B, Bang LQ, Zhang ZH, Xin DQ, Guo YL, Na YQ. The relationship between acute rejection and expression of sCD30 for the patients after kidney transplantation. Zhonghua Yi Xue Za Zhi 85: 651-653, 2005.
  17. Chen JH, Lu R, Chen Y, Wu JY, He Q, Huang HF, Qu LH. Influence of pre-transplant serum level of soluble CD30 on the long-term survival rates of kidney transplant recipients and grafts. Zhonghua Yi Xue Za Zhi 85: 1560-1563, 2005.
  18. Rajakariar R, Jivanji N, Varagunam M, Rafiq M, Gupta A, Sheaff M, Sinnott P, Yaqoob MM. High pre-transplant soluble CD30 levels are predictive of the grade of rejection. Am J Transplant 5: 1922-1925, 2005.
  19. Terasaki PI, Ozawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial. Transplantation 80: 1194-1197, 2005.
  20. Sengül S, Keven K, Görmez U, Kutlay S, Ertürk S, Erbay B. Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation. Transplantation. 81: 1216-1219, 2006.
  21. Frisaldi E, Conca R, Magistroni P, Fasano ME, Mazzola G, Patane F, Zingarelli E, Dall'omo AM, Brusco A, Amoroso A. Prognostic values of soluble CD30 and CD30 gene polymorphisms in heart transplantation. Transplantation 81: 1153-1156, 2006.
  22. Bauwens AM, van de Graaf EA, van Ginkel WG, van Kessel DA, Otten HG. Pre-transplant soluble CD30 is associated with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 25: 416-419, 2006.
  23. Kim KH, Oh EJ, Jung ES, Park YJ, Choi JY, Kim DG, Lee KY, Kang CS. Evaluation of pre- and posttransplantation serum interferon-gamma and soluble CD30 for predicting liver allograft rejection. Transplant Proc 38: 1429-1431, 2006.
  24. Dong W, Shunliang Y, Weizhen W, Qinghua W, Zhangxin Z, Jianming T, He W. Prediction of acute renal allograft rejection in early post-transplantation period by soluble CD30. Transpl Immunol 16: 41-45, 2006.
  25. 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 67: 230-237, 2006.
  26. Rodríguez LM, París SC, Arbeláez M, Cotes JM, Süsal C, Torres Y, García LF. Kidney graft recipients with pretransplantation HLA CLASS I antibodies and high soluble CD30 are at high risk for graft loss. Hum Immunol 68: 652-660, 2007.
  27. Heinemann FM, Rebmann V, Witzke O, Philipp T, Broelsch CE, Grosse-Wilde H. Association of elevated pretransplant sCD30 levels with graft loss in 206 patients treated with modern immunosuppressive therapies after renal transplantation. Transplantation 27: 83: 706-711, 2007.
  28. Langan LL, Park LP, Hughes TL, Irish A, Luxton G, Witt CS, Christiansen FT. Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival. Am J Transplant 7: 847-856, 2007.
  29. Wang D, Wu GJ, Wu WZ, Yang SL, Chen JH, Wang H, Lin WH, Wang QH, Zeng ZX, Tan JM. Pre- and post-transplant monitoring of soluble CD30 levels as predictor of acute renal allograft rejection. Transpl Immunol 17: 278-282, 2007.
  30. 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 7: 408-415, 2007.
  31. Ozawa M, Terasaki PI, Lee JH, Castro R, Alberu J, et al.. 14th international HLA and immunogenetics workshop: report on the prospective chronic rejection project. Tissue Antigens 69 Suppl 1: 174-179, 2007.

see also: Study Design