Biomarker Studies

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

Pre-Transplant Findings

With the collaboration of 29 centers, it was possible to show in a first study of 3,900 kidney transplants that pre-transplant determination of sCD30, especially in combination with HLA antibodies, is a good indicator for estimating the risk of graft rejection (1). In a multi-center study we could extend this finding to donor-specific HLA antibodies (DSA) detected by single antigen bead technology (SAB). In pre-sensitized patients with cytotoxic or ELISA-reactive HLA antibodies, pre-transplant DSA influenced graft survival; however, only if the patients were, in addition, positive also for sCD30 (2). Graft survival was not impaired in DSA-positive pre-sensitized patients with low sCD30 indicating that an activated immune system and T cell help is a prerequisite for pre-transplant DSA to exert their harmful effects. In our local cohort of immunologically high-risk patients we could demonstrate that, in the absence of sCD30, pre-transplant DSA disappear after transplantation in many patients, and high-risk patients with pre-transplant positivity of the activation marker sCD30 are at a seven times higher risk of graft loss than sCD30-negative recipients (2). Our data suggest that patients positive for both pre-transplant DSA and sCD30 require special measures, whereas exclusion of DSA-positive patients from transplantation in the absence of high sCD30 may not be justified in all cases, even if the pre-transplant DSA are strong and complement activating (2,3).
In a recent study, we found that, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increases the risk of delayed graft function (DGF) (4). DGF alone doubled the risk for graft loss and the risk increased further if HLA antibodies or DSA were present pre-transplant, indicating that measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for pre-sensitized patients.
In a survey of more than 160,000 patients transplanted between 1982 and 2002 we made the surprising observation that high pre-transplant 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 (5). In the CTS Serum Study pre-transplant presence of non-HLA MICA antibodies were associated with poor outcome (6). Currently we are investigating the role of donor-specific MICA antibodies in kidney transplantation.

Post-Transplant Findings

In a previous pilot study of 56 kidney recipients we found that measuring sCD30 in the first week post-transplant was useful for identifying recipients at risk of impending graft rejection. On post-transplant 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 (7). An additional study showed that increased sCD30 and neopterin at 1 year post-transplant are predictive of chronic allograft nephropathy at 2 years (8).
In further course we extended our studies to a prospective multicenter study in which sCD30 was determined in 2,322 adult deceased-donor kidney recipients at several time intervals post-transplantation. Patients with a high sCD30 on day 30 showed a two-fold higher risk of graft loss after 3 years than recipients with a low sCD30 (9). Although an association was found between pre- and post-transplant sCD30 levels, patients with high sCD30 on post-transplant day 30 demonstrated significantly lower 3-year graft survival irrespective of the pretransplant level. In Cox regression analysis in which serum creatinine was considered a confounder high sCD30 and high creatinine on post-transplant day 30 were found to be independent risk factors for subsequent graft loss. As in pretransplant studies, patients with high sCD30 and HLA antibodies post-transplant showed a strikingly impaired graft survival. Our studies indicate that a serum level between 80 and 100 ng/mL can be used as a clinically meaningful cut-off for tests before and 40 ng/mL as a cut-off for tests after transplantation.
In another multicenter effort de novo and especially C1q-positive DSA proved to be indicators of subsequent graft loss (10). In line with these findings, 6 of 80 desensitized patients from our local immunologically high-risk cohort lost their graft within the first 4 years after transplantation due to antibody-mediated rejection (3). All 6 were C1q-DSA-positive prior to failure. Five were sCD30-positive before and all were sCD30-positive after transplantation.
Experimental studies underline the key role of CD30 in the generation of alloimmune responses (11-13), and clinical studies in kidney, heart, lung and stem cell transplant recipients support the relevance of sCD30 and HLA antibody monitoring in organ and stem cell transplantation (14-31).

Study Design

I. Serum collection for "Pre-Transplant Serum Study"

II. Serum collection for "Post-Transplant Serum Study"

Serum Collection Scheme
Pre-Tx First Post-Tx Week One Month Additional Sera
Day 0 Days 2, 6 Day 30 approx. Days 90, 180, 365, 730, yearly thereafter

Serum samples

1-2 ml serum without additives (minimum 0.5 ml). Two hours after blood donation, the serum should be separated from cell material by centrifugation and frozen and stored at -20°C.

DNA samples

EDTA blood, buffy coat and in the case of donor also spleen tissue can be frozen and stored at -20°C
Shipment of frozen samples to Heidelberg, Germany, at dates to be announced (twice a year).



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  2. Süsal C, Döhler B, Ruhenstroth A, Morath C, Slavcev A, Fehr T, Wagner E, Krüger B, Rees M, Balen S, Živcic-Cosic S, Norman DJ, Kuypers D, Emonds MP, Pisarski P, Bösmüller C, Weimer R, Mytilineos J, Scherer S, Tran TH, Gombos P, Schemmer P, Zeier M, Opelz G. A Collaborative Transplant Study Report. Donor-specific antibodies require preactivated immune system to harm renal transplant. EBioMedicine 9: 366-371, 2016.
  3. Schaefer SM, Süsal C, Opelz G, Döhler B, Becker LE, Klein K, Sickmüller S, Waldherr R, Macher-Goeppinger S, Schemmer P, Beimler J, Zeier M, Morath C. Pre-transplant soluble CD30 in combination with total DSA but not pre-transplant C1q-DSA predicts antibody-mediated graft loss in presensitized high-risk kidney transplant recipients. HLA 87: 89-99, 2016.
  4. Morath C, Döhler B, Kälble F, Pego da Silva L, Echterdiek F, Schwenger V, Živcic-Cosic S, Katalinic N, Kuypers D, Benöhr P, Haubitz M, Ziemann M, Nitschke M, Emmerich F, Pisarski P, Karakizlis H, Weimer R, Ruhenstroth A, Scherer S, Tran TH, Mehrabi A, Zeier M, Süsal C . Pre-transplant HLA antibodies and delayed graft function in the current era of kidney transplantation. Front Immunol 11: 1886-1895, 2020.
  5. Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 365: 1570-1576, 2005.
  6. Zou Y, Stastny P, Süsal C, Döhler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 357: 1293-1300, 2007.
  7. 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.
  8. 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.
  9. Süsal C, Döhler B, Sadeghi M, Salmela KT, Weimer R, Zeier M, Opelz G. Posttransplant sCD30 as a predictor of kidney graft outcome. Transplantation 91: 1364-1369, 2011.
  10. Süsal C, Wettstein D, Döhler B, Morath C, Ruhenstroth A, Scherer S, Tran TH, Gombos P, Schemmer P, Wagner E, Fehr T, Živcic-Cosic S, Balen S, Weimer R, Slavcev A, Bösmüller C, Norman DJ, Zeier M, Opelz G; Collaborative Transplant Study Report. Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing. Transplantation 99: 1976-1980, 2015.
  11. 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.
  12. Velásquez SY, Süsal C, Opelz G, García LF, Alvarez CM. Alloantigen-stimulated induction and release of CD30 in patients with end-stage renal failure. Hum Immunol 73: 1102-1108, 2012.
  13. Velásquez SY, García LF, Opelz G, Alvarez CM, Süsal C. Release of soluble CD30 after allogeneic stimulation is mediated by memory T cells and regulated by IFN-? and IL-2. Transplantation 96: 154-161, 2013.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  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. 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.
  26. 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.
  27. 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.
  28. 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.
  29. Grenzi PC, Campos ÉF, Silva HT Jr, Felipe CR, Franco MF, Soares MF, Medina-Pestana JO, Gerbase-DeLima M. Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation. Transpl Immunol 32: 61-65, 2015.
  30. de Holanda MI, Matuck T, de Carvalho DDBM, Domingues EMFL, Curvo R, Glasberg DS, Santos AMG, Borela ÁM, Pôrto LC. Soluble CD30, Acute Rejection, and Graft Survival: Pre- and 6-Month Post-Transplant Determinations-When Is the Best Time to Measure? Transplant Proc 50: 728-736, 2018.
  31. Chen YB, McDonough S, Hasserjian R, Chen H, Coughlin E, Illiano C, Park IS, Jagasia M, Spitzer TR, Cutler CS, Soiffer RJ, Ritz J. Expression of CD30 in patients with acute graft-versus-host disease. Blood 120: 691-696, 2012.