Research Project: Koç University Transplant Immunology Research Centre of Excellence
Loading...
Contributors
Funders
ID
EC.00134
Authors
Süsal, Caner
Faculty Member
Publications
Targeting IL-6 in antibody-mediated kidney transplant rejection
(Oxford University Press, 2025-05) Süsal, Caner; Kanbay, Mehmet; Mızrak, Berk; Çöpür, Sidar; Akgül, Sebahat Usta; Alper, Ezgi Nur; Ortiz, Alberto; School of Medicine; TIREX (Koç University Transplant Immunology Research Centre of Excellence); Yes; SCHOOL OF MEDICINE; Research Center
Interleukin (IL)-6 is a major pro-inflammatory cytokine and central regulator of innate and adaptive immune responses. Clinical trials testing antibodies against IL-6 or its receptors have demonstrated its involvement in the pathogenesis of several autoimmune and inflammatory disorders and in the systemic inflammation and anemia associated to kidney failure and also in kidney allograft rejection. Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of naïve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development. Following promising results with a clazakizumab in a phase 2 placebo-controlled trial, a large phase 3 trial (IMAGINE) was terminated in 2024 for futility at interim analysis. Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation.
Incidence, risk factors, management strategies, and outcomes of antibody-mediated rejection in pediatric kidney transplant recipients—a multicenter analysis of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN)
(Springer, 2025) Süsal, Caner; Fichtner, Alexander; Gauche, Laura; Tran, Thuong Hien; Waldherr, Ruediger; Krupka, Kai; Guzzo, Isabella; Carraro, Andrea; Oh, Jun; Zirngibl, Matthias; Weitz, Marcus; Koenig, Jens; Buescher, Anja; Berta, Laszlo; Simon, Thomas; Awan, Atif; Rusai, Krisztina; Topaloglu, Rezan; Peruzzi, Licia; Printza, Nikoleta; Kim, Jon Jin; Weber, Lutz T.; Melk, Anette; Pape, Lars; Rieger, Susanne; Patry, Christian; Hoecker, Britta; Toenshoff, Burkhard; TIREX (Koç University Transplant Immunology Research Centre of Excellence); Yes; Research Center
Background This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). Methods We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant. Results The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5
Imlifidase in kidney transplantation
(Oxford Univ Press, 2024) Çöpür, Sidar; Güldan, Mustafa; Hasbal, Nuri Barış; Kanbay, Mehmet; Koçak, Burak; Özbek, Laşin; Süsal, Caner; Topçu, Ahmet Umur; Callemeyn, Jasper; Segelmark, Marten; TIREX (Koç University Transplant Immunology Research Centre of Excellence); KUH (Koç University Hospital); School of Medicine; Yes; KUH (KOÇ UNIVERSITY HOSPITAL); Research Center; SCHOOL OF MEDICINE
Kidney transplantation, the gold-standard therapeutic approach for patients with end-stage kidney disease, offers improvement in patient survival and quality of life. However, broad sensitization against human leukocyte antigens often resulting in a positive crossmatch against the patient's living donor or the majority of potential deceased donors in the allocation system represents a major obstacle due to a high risk for antibody-mediated rejection, delayed graft function and allograft loss. Kidney-paired donation and desensitization protocols have been established to overcome this obstacle, with limited success. Imlifidase, a novel immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes and recombinantly produced in Escherichia coli, is a promising agent for recipients with a positive crossmatch against their organ donor with high specificity towards IgG, rapid action and high efficacy in early pre-clinical and clinical studies. However, the rebound of IgG after a few days can lead to antibody-mediated rejection, making the administration of potent immunosuppressive regimens in the early post-transplant phase necessary. There is currently no comparative study evaluating the efficiency of imlifidase therapy compared with conventional desensitization protocols along with the lack of randomized control trials, indicating the clear need for future large-scale clinical studies in this field. Besides providing a practical framework for the clinical use of the agent, our aim in this article is to evaluate the underlying mechanism of action, efficiency and safety of imlifidase therapy in immunologically high-risk kidney transplant recipients.
Influence of donor sex and age on graft outcome in kidney transplantation
(Oxford University Press, 2023) Süsal, Caner; Melk, A.; Sugianto, R.I.; Zhang X, Dahhou M, Döhler B, Süsal C, Sapir-Pichhadze R, Wong G, Foster BJ.; TIREX (Koç University Transplant Immunology Research Centre of Excellence); KUH (Koç University Hospital); School of Medicine; Yes; KUH (KOÇ UNIVERSITY HOSPITAL); Research Center; SCHOOL OF MEDICINE
Background: There is a known recipient sex–dependent association between donor sex and kidney transplant survival. We hypoth esized that donor age also modifies the association between donor sex and graft survival. Methods: First, deceased donor kidney transplant recipients (1988–2019, n = 461 364) recorded in the Scientific Registry of Transplan Recipients, the Australia and New Zealand Dialysis and Transplant Registry and the Collaborative Transplant Study were analyzed. W used multivariable Cox regression models to estimate the association between donor sex and death censored graft loss, accountin for the modifying effects of recipient sex and donor age; donor age was categorized as 5–19, 20–34, 35–49, 50–59 and ≥60 years. Result from cohort-specific Cox models were combined using individual patient data meta-analysis. Results: Among female recipients of donors aged <60 years, graft loss hazards did not differ by donor sex; recipients of female donor ≥60 years showed significantly lower graft loss hazards than recipients of male donors of the same age [combined adjusted hazar ratio (aHR) 0.90, 95% CI 0.86–0.94]. Among male recipients, female donors aged <50 years were associated with significantly highe graft loss hazards than same-aged male donors (5–19 years: aHR 1.11, 95% CI 1.02–1.21; 20–34 years: aHR 1.08, 95% CI 1.02–1.15; 35 49 years: aHR 1.07, 95% CI 1.04–1.10). There were no significant differences in graft loss by donor sex among male recipients of donor aged ≥50 years. Conclusion: Donor age modifies the association between donor sex and graft survival. Older female donors were associated wit similar or lower hazards of graft failure than older male donors in both male and female recipients, suggesting a better functiona reserve of older female donor kidneys.
Risk stratification before living donor kidney transplantation in patients with preformed donor-specific antibodies by different crossmatch methods
(Lippincott Williams and Wilkins, 2024) Süsal, Caner; Ziemann, Malte; Lindemann, Monika; Hallensleben, Michael; Altermann, Wolfgang; Althaus, Karina; Budde, Klemens; Einecke, Gunilla; Eisenberger, Ute; Ender, Andrea; Feldkamp, Thorsten; Grahammer, Florian; Guthoff, Martina; Holzmann-Littig, Christopher; Hugo, Christian; Kauke, Teresa; Kemmner, Stephan; Koch, Martina; Lachmann, Nils; Marget, Matthias; Morath, Christian; Nitschke, Martin; Renders, Lutz; Scherer, Sabine; Stumpf, Julian; Schwenger, Vedat; Sommer, Florian; Spriewald, Bernd; Suesal, Caner; Zecher, Daniel; Heinemann, Falko M.; Verboom, Murielle; TIREX (Koç University Transplant Immunology Research Centre of Excellence); KUH (Koç University Hospital); Yes; KUH (KOÇ UNIVERSITY HOSPITAL); Research Center
Background.Preformed donor-specific HLA antibodies (DSA) are a well-known risk factor in kidney transplantation. There is still considerable debate, however, about the optimal risk stratification among patients with preformed DSA. Additionally, data on the prognostic value of different crossmatch assays in DSA-positive patients are scarce. Methods.DSA-positive living kidney transplant recipients were selected from a multicenter study examining 4233 consecutive renal transplants. An additional 7 patients from 2 further centers were included. Flow cytometric crossmatches (FXM), Luminex-based crossmatches, and virtual crossmatches based on C1q- and C3d-binding antibodies (C1qXM and C3dXM) were performed retrospectively using pretransplant sera and lymphocytes isolated from fresh samples. These samples were obtained from 44 donor and recipient pairs from 12 centers. Clinical outcome data and the control group without DSA were compiled from the previous study and were supplemented by data on 10-y death-censored graft survival (10yGS). Results.Between 19% (C3dXM) and 46% (FXM) of crossmatches were positive. Crossmatch-positive patients showed high incidences of antibody-mediated rejection (AMR) within 6 mo (up to 60% in B-cell FXM+ patients). The incidence of AMR in crossmatch-negative patients ranged between 5% (FXM-) and 13% (C1qXM-). 10yGS was significantly impaired in patients with positive T-cell FXM and total FXM compared with both patients without DSA and those with DSA with negative FXM. Conclusions.Especially FXM are useful for risk stratification, as the outcome of DSA-positive, FXM-negative patients is similar to that of DSA-negative patients, whereas FXM-positive patients have both more AMR and decreased 10yGS. Because of their lower sensitivity, the significance of Luminex-based crossmatches, C1qXM, and C3dXM would have to be examined in patients with stronger DSA.
