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Background: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries., Methods: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods., Results: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y., Conclusions: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-human leukocyte antigen (non-HLA) antibodies including antibodies targeting Angiotensin II type 1 (AT1R) and Endothelin-1 type A (ETAR) receptors represent a topic of interest in kidney transplantation (KTx). This exploratory substudy evaluated the impact of everolimus (EVR) or mycophenolic acid (MPA) in combination with tacrolimus (TAC) or cyclosporine A (CsA) in patients with preformed non-HLA antibodies, potentially associated rejections and/or their impact on renal function over 1 year., Methods: All eligible patients were randomized (1:1:1) before transplantation to receive either EVR/TAC, EVR/CsA, or MPA/TAC regimen. The effect of these regimens on the formation of non-HLA antibodies within one year post de novo KTx and the association with clinical events was evaluated descriptively in randomized ( n  = 268) population., Results: At Month 12, in EVR/TAC group, higher incidence of patients negative for AT1R- and ETAR-antibodies (82.2% and 76.7%, respectively) was noted, whereas the incidence of AT1R- and ETAR-antibodies positivity (28.1% and 34.7%, respectively) was higher in the MPA/TAC group. Non-HLA antibodies had no influence on clinical outcomes in any treatment group and no graft loss or death was reported., Conclusions: The studied combinations of immunosuppressants were safe with no influence on clinical outcomes and suggested minimal exposure of calcineurin inhibitors for better patient management., Clinical Trial Registration: https://clinicaltrials.gov/ (NCT01843348; EudraCT number: 2011-005238-21)., Competing Interests: WA received consulting honoraria from Novartis. IH was in the advisory board of Novartis and received honoraria for lectures from Takeda, Biotest, MSD, CareDx, Novartis, Astellas, Bayer, and Astra Zeneca. FT has received study honoraria from Novartis, Sanofi, Astellas, Alexion, Hexal, Chiesi, and Pfizer. BS received study honoraria and was in the advisory board of Novartis. JH, CS, and AE are employees of Novartis. BN was in the advisory board and received funding from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Philippe, Arns, Ditt, Hauser, Thaiss, Sommerer, Suwelack, Dragun, Hillen, Schiedel, Elsässer and Nashan.)

Background: Studies prospectively monitoring de novo donor-specific antibodies (dnDSAs) and their clinical impact are sparse. This substudy of ATHENA was initiated to evaluate the effect of everolimus (EVR) or mycophenolic acid (MPA) in combination with reduced calcineurin inhibitor (CNI, tacrolimus [TAC] or cyclosporine [CsA]) on the formation of human leukocyte antibodies (HLA), including dnDSA, and the impact on clinical outcomes in kidney transplant (KTx) recipients., Methods: All eligible patients were randomized 1:1:1 to receive either EVR + TAC, EVR + CsA or MPA + TAC, with basiliximab induction plus steroids after transplantation up to Month 12. The incidence of dnDSA by treatment group and the association with clinical events were evaluated descriptively as an exploratory objective in the intent-to-treat (ITT) and per-protocol (PP) populations with at least one antibody assessment., Results: Overall, none of the patients in the EVR + TAC group had either dnDSA or antibody mediated rejection (PP or ITT population) and only one patient with dnDSA in the TAC + MPA group had antibody mediated rejection., Conclusion: The EVR regimen was comparable to MPA regimen with an extremely low incidence of dnDSA over 1 year of treatment., Competing Interests: WA received consulting honoraria from Novartis. IAH was in the advisory board of Novartis and received honoraria for lectures from Takeda, Biotest, MSD, CareDx, Novartis, Astellas, Bayer, and Astra Zeneca. FT has received study honoraria from Novartis, Sanofi, Astellas, Alexion, Hexal, Chiesi, and Pfizer. BS received study honoraria and was in the advisory board of Novartis. JH, CS, and AE are employees of Novartis. BN was in the advisory board and received funding from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Arns, Philippe, Ditt, Hauser, Thaiss, Sommerer, Suwelack, Dragun, Hillen, Schiedel, Elsässer and Nashan.)

Hemodialysis patients faced an excess morbidity and mortality during the COVID-19 pandemic. We evaluated the effect of second-generation mRNA vaccines against Omicron BA.4 and BA.5 variants of SARS-CoV-2 on humoral immunity. The study population comprised 66 adult hemodialysis patients who have encountered four SARS-CoV-2 antigen contacts through vaccination or infection. We assessed their humoral response using an anti-SARS-CoV-2 spike receptor binding domain IgG antibody assay (S-RBD-ab), measuring neutralizing antibodies against ancestral strain of SARS-CoV-2, Delta, and Omicron in a surrogate virus neutralization test (SVNT), and specifically against BA.5 in a plaque reduction neutralization test (PRNT) before and four weeks after vaccination with Comirnaty Original/Omicron BA.4-5. During the following six months, SARS-CoV-2 infections and symptom severity were documented. The bivalent mRNA vaccine led to a 7.6-fold increase in S-RBD-ab levels and an augmented inhibition of the Omicron variant in SVNT by 35% (median). Seroconversion in the Omicron BA.5-specific PRNT was attained by in 78.4% of previously negative patients (29/37). Levels of S-RBD-ab correlated with inhibition in the Omicron-specific SVNT and neutralization titers in the BA.5-PRNT. Eleven SARS-CoV-2 infections occurred in the six-month follow-up, none of which took a life-threatening course. The bivalent mRNA vaccine improved the SARS-CoV-2 virus variant-specific humoral immunity in chronic hemodialysis patients. Measurement of S-RBD-ab can be used in hemodialysis patients to estimate their humoral immunity status against Omicron BA.5.

Background: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients., Methods: Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients. Follow-up was until year five after surgery., Results: The 10 MIC patients had an excellent clinical course with stable kidney graft function, no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections, and no opportunistic infections. In comparison, a retrospectively matched control group receiving standard immunosuppressive therapy had a higher frequency of DSA (log rank P = 0.046) and more opportunistic infections (log rank P = 0.033). Importantly, MIC patients, and in particular the four patients who had received the highest cell number 7 days before surgery and received low immunosuppression during follow-up, continued to show a lack of anti-donor T lymphocyte reactivity in vitro and high CD19 + CD24 hi CD38 hi transitional and CD19 + CD24 hi CD27 + memory B lymphocytes until year five after surgery., Conclusions: MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no de novo DSA development and no opportunistic infections. In the future, MIC infusions might contribute to graft protection while reducing the side effects of immunosuppressive therapy. However, this approach needs further validation in direct comparison with prospective controls., Trial Registration: https://clinicaltrials.gov/, identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30., Competing Interests: MSa, CMo, CK, GO, MZ, MSm, PT, and ASm together with the University of Heidelberg, are co-founders of TolerogenixX GmbH, Heidelberg, Germany, a biotechnology company that holds licenses for MIC treatment. CK, GO, and PT hold a patent for MIC treatment. MSa, CMo, CK, GO, CSü, MZ, MSm, PT, AS, and VD together with the University of Heidelberg and TolerogenixX GmbH filed a patent application for MIC treatment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schaier, Morath, Wang, Kleist, Opelz, Tran, Scherer, Pham, Ekpoom, Süsal, Ponath, Kälble, Speer, Benning, Nusshag, Mahler, Pego da Silva, Sommerer, Hückelhoven-Krauss, Czock, Mehrabi, Schwab, Waldherr, Schnitzler, Merle, Schwenger, Krautter, Kemmner, Fischereder, Stangl, Hauser, Kälsch, Krämer, Böhmig, Müller-Tidow, Reiser, Zeier, Schmitt, Terness, Schmitt and Daniel.)

Introduction: Donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study)., Methods and Analysis: Sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy., Ethics and Dissemination: Ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings., Trial Registration Number: NCT05365672., Competing Interests: Competing interests: CM, ASchmitt, MS, CK, GO, PT, MZ and MSchaier together with the University of Heidelberg, are cofounders of TolerogenixX GmbH, Heidelberg, Germany, a biotechnology company that holds licenses for MIC treatment. CK, GO, and PT hold a patent for MIC treatment. CM, ASchmitt, MSchmitt, CK, GO, CSüsal, PT, MZ, VD and MSchaier together with the University of Heidelberg and TolerogenixX GmbH filed a patent application for MIC treatment. JR is cofounder and shareholder of Trisaq, a biopharmaceutical company that develops novel therapy for kidney diseases., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83-98). 2-year Kaplan-Meier estimates of time to progression and overall survival were 78% (95% CI 65-90) and 68% (95% CI 55-80) - similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2-17). In the low-risk group, 2-year EFS was 66% (95% CI 45-86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing., (© 2022. The Author(s).)

BACKGROUND Varices of the upper gastrointestinal tract are due to portal hypertension and can result from occlusion of the portal venous system. This report is of a 55-year-old man with recurrent gastrointestinal bleeding due to stricture of the portal vein anastomotic site to inferior vena cava (IVC) 12 years after combined pancreas and kidney transplantation. CASE REPORT A 55-year-old man presented bleeding episodes requiring transfusion of more than 70 units of red blood cells (RBCs), complicated by bacterial and viral infection episodes including cytomegalovirus (CMV) reactivation and hepatitis E and transient impairment of function of the renal allograft. Endoscopy, computed tomography (CT) scan, and angiography revealed jejunal varices due to anastomotic stricture at the portal vein to IVC as the cause of the hemorrhage. Neither conservative therapy nor an anastomosis between the splenic vein of the graft and the internal iliac vein as a bypass could stop the life-threatening bleeding. During the recurrent bleeding, CD4 T lymphocytes were low, indicating immunodeficiency despite paused immunosuppressive therapy. After the hemorrhage resolved and immunosuppression was restarted, CD4 T lymphocyte levels normalized. Finally, to stop the hemorrhage and save the transplanted kidney and the patient's life, graft pancreatectomy was performed. Long-term damage to the renal transplant was not found. CONCLUSIONS This report is of a rare case of portal hypertension as a long-term complication of transplant surgery. Although acute venous thrombosis at the anastomotic site is a recognized postoperative complication of pancreatic transplant surgery, this case highlights the importance of post-transplant follow-up and diagnostic imaging.

The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.