Researcher: Süsal, Caner
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Süsal, Caner
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Publication Metadata only Humoral response to SARS-COV-2 MRNA vaccination in previous non-responder kidney transplant recipients after short-term withdrawal of mycophenolic acid(Frontiers, 2022) Benning, Louise; Morath, Christian; Kühn, Tessa; Bartenschlager, Marie; Kim, Heeyoung; Beimler, Joerg; Buylaert, Mirabel; Nusshag, Christian; Kälble, Florian; Reineke, Marvin; Töllner, Maximilian; Schaier, Matthias; Klein, Katrin; Blank, Antje; Schnitzler, Paul; Zeier, Martin; Bartenschlager, Ralf; Thuong Hien Tran; Speer, Claudius; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 351800Seroconversion rates after COVID-19 vaccination are significantly lower in kidney transplant recipients compared to healthy cohorts. Adaptive immunization strategies are needed to protect these patients from COVID-19. In this prospective observational cohort study, we enrolled 76 kidney transplant recipients with no seroresponse after at least three COVID-19 vaccinations to receive an additional mRNA-1273 vaccination (full dose, 100 mu g). Mycophenolic acid was withdrawn in 43 selected patients 5-7 days prior to vaccination and remained paused for 4 additional weeks after vaccination. SARS-CoV-2-specific antibodies and neutralization of the delta and omicron variants were determined using a live-virus assay 4 weeks after vaccination. In patients with temporary mycophenolic acid withdrawal, donor-specific anti-HLA antibodies and donor-derived cell-free DNA were monitored before withdrawal and at follow-up. SARS-CoV-2 specific antibodies significantly increased in kidney transplant recipients after additional COVID-19 vaccination. The effect was most pronounced in individuals in whom mycophenolic acid was withdrawn during vaccination. Higher SARS-CoV-2 specific antibody titers were associated with better neutralization of SARS-CoV-2 delta and omicron variants. In patients with short-term withdrawal of mycophenolic acid, graft function and donor-derived cell-free DNA remained stable. No acute rejection episode occurred during short-term follow-up. However, resurgence of prior anti-HLA donor-specific antibodies was detected in 7 patients.Publication Metadata only Influence of calcineurin inhibitor choice on outcomes in kidney transplant recipients aged >= 60 y: a collaborative transplant study report(Lippincott Williams and Wilkins (LWW), 2022) Echterdiek, Fabian; Döhler, Bernd; Latus, Joerg; Schwenger, Vedat; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800Background: Patients aged >= 60 y represent the fastest growing population among kidney transplant recipients and waitlist patients. They show an elevated infection risk and are frequently transplanted with multiple human leukocyte antigen mismatches. Whether the choice of calcineurin inhibitor influences graft survival, mortality, or key secondary outcomes such as infections in this vulnerable recipient population is unknown. Methods: A total of 31 177 kidney transplants from deceased donors performed between 2000 and 2019 at European centers and reported to the Collaborative Transplant Study were analyzed using multivariable Cox and logistic regression analyses. All recipients were >= 60 y old and received tacrolimus (Tac) or cyclosporine A on an intention-to-treat basis, combined with mycophenolic acid or azathioprine plus/minus steroids. Results: The risk of 3-y death-censored graft loss and patient mortality did not differ significantly between Tac- and cyclosporine A-treated patients (hazard ratio 0.98 and 0.95, P = 0.74 and 0.20, respectively). No difference was found in the overall risk of hospitalization for infection (hazard ratio = 0.95, P = 0.19); however, a lower incidence of rejection treatment (hazard ratio = 0.81, P < 0.001) was observed in Tac-treated patients. Assessment of pathogen-specific hospitalizations revealed no difference in the risk of hospitalization due to bacterial infection (odds ratio = 1.00, P = 0.96), but a significantly higher risk of hospitalization due to human polyomavirus infection was found among Tac-treated patients (odds ratio = 2.45, P = 0.002). The incidence of de novo diabetes was higher for Tac-based immunosuppression (odds ratio = 1.79, P < 0.001). Conclusions: Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in >= 60-y-old kidney transplant recipients.Publication Metadata only Prospective evaluation of donor-derived cell-free DNA (dd-cfDNA) in monitoring response to anti-rejection treatment in kidney transplant recipients with indication biopsy(Wiley, 2022) Benning, L.; Fink, A.; Kälble, F.; Speer, C.; Nusshag, C.; Zeier, M.; Morath, C.; Tran, T.; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 351800Purpose: Donor-derived cell-free DNA (dd-cfDNA) is a marker of allograft injury in kidney transplant recipients (KTR). Little is known about the possible use of dd-cfDNA in evaluating response to anti-rejection treatment in KTR showing histopathological signs of rejection. Methods: We are currently prospectively evaluating the diagnostic benefit of dd-cfDNA in 100 KTR undergoing indication biopsy. dd-cfDNA is quantified in the AlloSeq cfDNA assay (CareDx) at time of biopsy to estimate the association of dd-cfDNA levels with histopathological reporting. To assess the utility of dd-cfDNA in monitoring response to therapy, dd-cfDNA levels are quantified after initiation of treatment on days 7, 30, and 90 following biopsy. Results: Since December 2020, 56 KTR have been enrolled and 21/56 (38%) biopsies were graded as different types of rejection. Patients showing signs of active rejection had significantly higher levels of dd-cfDNA at time of biopsy than patients without any signs for rejection, whereas estimated glomerular filtration rate (eGFR) did not differ significantly between the two groups (P<0.01 and P=0.55, respectively, Figure 1A). In patients with antibody-mediated rejection (ABMR) or T-cell mediated rejection (TCMR), median (IQR) dd-cfDNA levels were highest with 3.4% (1.6-11.3) compared to the 0.4% (0.2-1.2) measured in patients with borderline changes and 0.2% (0.1-0.5) in patients with no signs of rejection. When considering only patients with ABMR or TCMR, we observe decreasing levels of dd-cfDNA following initiation of therapy (pooled slope -0.02; Figure 1B). In patients with borderline changes and low levels of dd-cfDNA (<1%) at time of biopsy we see an increase in eGFR after initiation of corticosteroid pulse therapy, whereas patients with high levels of dd-cfDNA (≥1%) show subsequent eGFR decline (Figure 1C). Conclusions: dd-cfDNA significantly discriminates active rejection at time of biopsy in KTR. Decreasing levels of dd-cfDNA may indicate treatment response in patients with ABMR and TCMR. dd-cfDNA may further help to identify borderline changes with favorable outcome from changes where additional therapy and closer monitoring is needed.Publication Metadata only Kidney transplants from elderly donors: the experience of a reference center in Croatia(Baskent Univ, 2022) Zivcic-Cosic, Stela; Dohler, Bernd; Katalini, Natasa; Marki, Dean; Orli, Lidija; Racki, Sanjin; Spanjol, Josip; Trobonjaca, Zlatko; Süsal, Caner; Faculty Member; School of Medicine; Koç University Hospital; 351800Objectives: Our country Croatia is among the global leaders regarding deceased donation rates, yet we are facing organ shortage and concurrently a sharp decline in our acceptance rates for kidney offers. To reevaluate our organ acceptance policy, we retrospectively analyzed the factors that influenced the posttransplant outcomes of kidneys from elderly deceased donors at our center during a 20-year period and the changes to our organ acceptance criteria during Eurotransplant membership. Materials and Methods: We studied all kidney transplants from donors >= 60 years old during the two 5-year episodes of Eurotransplant membership from 2007 to 2017 (period II and period III) and compared those data to data from the decade before Eurotransplant membership (period I, 1997-2007). Differences in acceptance rates and reasons for the decline of kidney offers between the two 5-year periods of Eurotransplant membership were analyzed. Results: In period I, 14.1% of all kidney allografts were obtained from donors >= 60 years old; in period II and period III the rates were nearly 2-fold higher (27.0% and 25.7%, respectively; P= .007 and P= .008). During the first 5-year period of Eurotransplant membership (period II), we accepted significantly more grafts from marginal donors with a higher number of human leukocyte antigen mismatches compared with period I. Consequently, the 3-month survival rate of kidneys from donors >= 60 years old dropped from 91.1% to as low as 74.2% (P = .034). After application of morestringent human leukocyte antigen matching, especially in human leukocyte antigen DR, and morestringent donor acceptance criteria in period III, graft survival improved to 91.1%. Conclusions: Our experience indicates that careful selection of kidneys from elderly deceased donors and allocation to human leukocyte antigen-matched recipients is important to improve transplant outcomes.Publication Metadata only Induction of long-lasting regulatory B lymphocytes by modified immune cells in kidney transplant recipients(Wolters Kluwer Health, 2023) Morath, Christian; Schaier, Matthias; Ibrahim, Eman; Wang, Lei; Kleist, Christian; Opelz, Gerhard; Ponath, Gerald; Aly, Mostafa; Alvarez, Cristiam M.; Kälble, Florian; Speer, Claudius; Benning, Louise; Nusshag, Christian; Pego Da Silva, Luiza; Sommerer, Claudia; Hückelhoven-Krauss, Angela; Czock, David; Mehrabi, Arianeb; Schwab, Constantin; Waldherr, Rüdiger; Schnitzler, Paul; Merle, Uta; Tran, Thuong Hien; Scherer, Sabine; Böhmig, Georg A.; Müller-Tidow, Carsten; Reiser, Jochen; Zeier, Martin; Schmitt, Michael; Terness, Peter; Schmitt, Anita; Daniel, Volker; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800Background: We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. Methods: Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. Results: Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. Conclusions: These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants.Publication Metadata only Immune response to COVID-19 mRNA vaccination in previous nonresponder kidney transplant recipients after short-term withdrawal of mycophenolic acid 1 and 3 months after an additional vaccine dose(Lippincott Williams and Wilkins (LWW), 2023) Kühn, Tessa; Speer, Claudius; Morath, Christian; Bartenschlager, Marie; Kim, Heeyoung; Beimler, Jörg; Buylaert, Mirabel; Nusshag, Christian; Kälble, Florian; Reineke, Marvin; Töllner, Maximilian; Klein, Katrin; Blank, Antje; Parthé, Sylvia; Schnitzler, Paul; Zeier, Martin; Bartenschlager, Ralf; Tran, Thuong Hien; Schaier, Matthias; Benning, Louise; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800Background: The impaired immune response to coronavirus disease 2019 (COVID-19) vaccination in kidney transplant recipients (KTRs) leads to an urgent need for adapted immunization strategies. Methods: Sixty-nine KTRs without seroconversion after =3 COVID-19 vaccinations were enrolled, and humoral response was determined after an additional full-dose mRNA-1273 vaccination by measuring severe acute respiratory syndrome coronavirus 2-specific antibodies and neutralizing antibody activity against the Delta and Omicron variants 1 and 3 mo postvaccination. T-cell response was analyzed 3 mo postvaccination by assessing interferon-? release. Mycophenolic acid (MPA) was withdrawn in 41 KTRs 1 wk before until 4 wk after vaccination to evaluate effects on immunogenicity. Graft function, changes in donor-specific anti-HLA antibodies, and donor-derived cell-free DNA were monitored in KTRs undergoing MPA withdrawal. Results: humoral response to vaccination was significantly stronger in KTRs undergoing MPA withdrawal 1 mo postvaccination; however, overall waning humoral immunity was noted in all KTRs 3 mo after vaccination. Higher anti-S1 immunoglobulin G levels correlated with better neutralizing antibody activity against the Delta and Omicron variants, whereas no significant association was detected between T-cell response and neutralizing antibody activity. No rejection occurred during study, and graft function remained stable in KTRs undergoing MPA withdrawal. In 22 KTRs with Omicron variant breakthrough infections, neutralizing antibody activity was better against severe acute respiratory syndrome coronavirus 2 wild-type and the Delta variants than against the Omicron variant. Conclusions: MPA withdrawal to improve vaccine responsiveness should be critically evaluated because withdrawing MPA may be associated with enhanced alloimmune response, and the initial effect of enhanced seroconversion rates in KTRs with MPA withdrawal disappears 3 mo after vaccination.Publication Metadata only A multinational cohort study uncovered sex differences in excess mortality after kidney transplant(Elsevier B.V., 2023) Vinson, Amanda J.; Zhang, Xun; Dahhou, Mourad; Döhler, Bernd; Melk, Anette; Sapir-Pichhadze, Ruth; Cardinal, Heloise; Wong, Germaine; Francis, Anna; Pilmore, Helen; Foster, Bethany J.; Süsal, Caner; Other; School of Medicine; 351800Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988–2019). When the donor was male, female recipients 0–12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20–1.99), 13–24 years (1.17, 1.01–1.34), 25–44 years (1.11, 1.05–1.18) and 60 years and older (1.05, 1.02–1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females.Publication Metadata only 423.11: Long-term compromised immune regulation after rituximab induction in blood group incompatible living-donor renal transplantation-5 year results of a prospective pilot study(Lippincott Williams & Wilkins, 2022) Weimer, Rolf; Karakizlis, Hristos; Renner, Fabrice; Dietrich, Hartmut; Daniel, Volker; Schüttler, Christian; Kämper, Daniel; Leicht, Dominik; Wörlen, Michael; Renner, Lene; Milchsack, Katrin; Padberg, Winfried; Opelz, Gerhard; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800Background: An increased frequency of severe infectious diseases and BK viremia has been described after ABOi renal transplantation. As rituximab induction may alter immunoregulation in these patients, we analyzed clinically relevant immune parameters in a prospective renal transplant study up to 5 years posttransplant. Materials and Methods: Mononuclear cell subsets (peripheral blood; lymph nodes taken during transplant surgery), intracellular cytokine responses, CD4 helper function and in-vitro B cell responses were assessed pretransplant and up to 5 years posttransplant in 85 renal transplant recipients (living donation: n=25 ABO incompatible (ABOi) and n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible). Results: Severe infectious diseases occurred more often in ABOi than ABOc recipients within 2 years posttransplant (11/24 (46%) versus 6/30 (20%), P=0.042) but not beyond. The incidence of BK viremia was significantly enhanced in rituximab versus non-rituximab treated patients (1 year: 9/29 (31%) versus 4/54 (7%), P=0.009; 5 years: 10/30 (33%) versus 7/53 (13%), P=0.029). After rituximab induction in ABOi recipients, counts of peripheral blood B cell subsets were profoundly downregulated even 3 years posttransplant and reached the level of non-ABOi recipients after 4 years (memory B cells after 5 years). T-dependent and T-independent B cell responses were significantly impaired in ABOi patients up to 2 years posttransplant (P=0.010 and P=0.053, respectively) whereas CD4 helper activity was not compromised. CD4+ T cell counts were significantly lower in ABOi compared to ABOc recipients at 3 and 6 months (P=0.025 and P=0.046, respectively), but showed no differences in the percentage of Tregs. In regional lymph nodes of ABOi patients, we found a significant downregulation of CD20+ but not CD19+ B cells (P<0.0005), of naive B cells (P=0.031) and short lived plasma cells (P<0.0005) at the time of transplantation. Conclusion: An increased frequency of severe infectious diseases and BK viremia in rituximab treated ABOi renal transplant recipients may be explained by significantly downregulated CD4+ T cell counts up to 6 months and a profoundly delayed B cell repopulation, most pronounced with regard to memory B cells, together with compromised B cell responses up to 2 years posttransplant. IL-10, as a key player in chronic BK virus infection, was not upregulated in rituximab-treated ABOi transplant recipients.Publication Metadata only Bias by censoring for competing events in survival analysis(BMJ Publishing Group, 2022) Coemans, Maarten; Verbeke, Geert; Döhler, Bernd; Naesens, Maarten; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800In survival analysis, competing events preclude the occurrence of the event of interest. The censoring of competing events is common in medical studies but leads to biased cumulative incidence estimators. Competing risks methods, such as the non-parametric Aalen-Johansen method or the semi -parametric Fine and Gray model, alleviate this bias and should be preferred above the Kaplan-Meier method and the Cox model, respectively. As an illustrative example, in a large European cohort, we report on the differences in the cumulative incidence estimates of graft failure after kidney transplantation, caused by censoring for recipient death.Publication Metadata only Natural SARS-CoV-2 infection results in higher neutralization response against variants of concern compared with 2-dose BNT162b2 vaccination in kidney transplant recipients(Elsevier, 2022) Benning, Louise; Morath, Christian; Bartenschlager, Marie; Reineke, Marvin; Toellner, Maximilian; Nusshag, Christian; Kaelble, Florian; Reichel, Paula; Schaier, Matthias; Schnitzler, Paul; Zeier, Martin; Bartenschlager, Ralf; Speer, Claudius; Süsal, Caner; Faculty Member; Koç University Transplant Immunology Research Centre of Excellence (TIREX); School of Medicine; Koç University Hospital; 351800N/A
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