Search

Donor-reactive memory cells represent a barrier to long-term kidney graft survival. A better understanding of regulatory mechanisms that counterbalance alloreactive memory responses may help to identify patients with operational tolerance. This prospective study investigated the equilibrium between memory T cell subsets and regulatory T or B cells (Tregs, Bregs) in peripheral blood of kidney transplant recipients with operational tolerance (N=8), chronic rejection (N=8), and different immunosuppressive treatment regimens (N=81). Patients on hemodialysis and healthy individuals served as controls (N=50). In addition, the expression of Treg- and Breg-associated molecule genes was analyzed. Patients with chronic rejection showed a disrupted memory T cell composition with a significantly higher frequency of circulating CD8(+) terminally differentiated effector memory (TEMRA) T cells than patients with operational tolerance, patients on hemodialysis, or healthy controls (P<0.001). Low frequency of CD8(+) TEMRA and high frequency of Tregs and transitional Bregs were found in operationally tolerant patients. Consequently, operationally tolerant patients showed, as compared to all other transplant recipients with different immunosuppressive regiments, the lowest ratios between CD8(+) TEMRA T cells and Tregs or Bregs (for both P<0.001). Moreover, a specific peripheral blood transcription pattern was found in operationally tolerant patients with an increased expression of Breg- and Treg-associated genes CD22 and FoxP3 and a decreased Fc gamma RIIA/Fc gamma RIIB transcript ratio (for all P<0.001). In conclusion, monitoring the balance between circulating CD8(+) TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with operational tolerance from recipients at risk of graft loss., European Union (EU); Horizon 2020; Research and Innovation Programme; Physician Scientist Program of the Heidelberg Faculty of Medicine; Olympia-Morata Program of the Heidelberg Faculty of Medicine

Background: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients. Methods: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988–2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age. Results: We analyzed 108,918 patients. When the donor was male, female recipients 0–12 years (Relative excess risk (RER) 1.13, 95% CI 1.00–1.26), 13–44 years (RER 1.17, 95% CI 1.10–1.25), and ≥45 years (RER 1.14, 95% CI 1.02–1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13–44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00–1.20), though not significantly (p = 0.05). Conclusions: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences., European Union (EU); Horizon 2020; Research and Innovation Programme; AV has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. AM is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. GW is supported by NHMRC Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). The authors declare no conflict of interest. RSP is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant no. 254386), CIHR (grant FRN-156730) and fellowship grant funding from Paladin Labs Inc.

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., European Union (EU); Horizon 2020; Research and Innovation Programme

HLA-B*39:199 differs from HLA-B*39:10:01 by a G -> A substitution in exon 5 in codon 282., European Union (EU); Horizon 2020; Research and Innovation Programme

Background: Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown. Methods: In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age. Results: Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity. Conclusions: Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss., European Union (EU); Horizon 2020; Research and Innovation Programme; A.J.V. has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. A.M. is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. G.W. is supported by National Health and Medical Research Council Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). R.S.-P. is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant 254386) and Canadian Institutes of Health Research (grant FRN-156730). This study was supported by an operating grant from the Canadian Institutes of Health Research (PJT165832).

We report a case of antibody-mediated rejection treated with the human CD38 monoclonal antibody daratumumab in a 58-year-old female patient with end-stage kidney disease due to autosomal dominant polycystic kidney disease who received an ABO- and human leukocyte antigen antibody-incompatible living donor kidney transplant. The patient experienced an episode of severe antibody-mediated rejection within the first week of transplantation. Blood-group-antibody selective immunoadsorption in combination with administration of four doses of daratumumab (each 1800 mg s.c.) led to a persistent decrease of ABO- and more interestingly donor-specific human leukocyte antigen antibody reactivity and resulted in clinical and histopathological remission with full recovery of graft function, which has remained stable until post-transplant day 212. This case illustrates the potential of targeting CD38 in antibody-mediated rejection., European Union (EU); European Commission (EC); Horizon 2020; Research and Innovation Programme

We report a case of antibody-mediated rejection treated with the human CD38 monoclonal antibody daratumumab in a 58-year-old female patient with end-stage kidney disease due to autosomal dominant polycystic kidney disease who received an ABO- and human leukocyte antigen antibody-incompatible living donor kidney transplant. The patient experienced an episode of severe antibody-mediated rejection within the first week of transplantation. Blood-group-antibody selective immunoadsorption in combination with administration of four doses of daratumumab (each 1800 mg s.c.) led to a persistent decrease of ABO- and more interestingly donor-specific human leukocyte antigen antibody reactivity and resulted in clinical and histopathological remission with full recovery of graft function, which has remained stable until post-transplant day 212. This case illustrates the potential of targeting CD38 in antibody-mediated rejection., European Union (EU); European Commission (EC); Horizon 2020; Research and Innovation Programme

Introduction: Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. Methods: We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity <= 1000 nM; netMHC: binding affinity <= 500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Results: Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Conclusion: Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft functio, European Union (EU); Horizon 2020; Research and Innovation Programme; The CERTAIN registry received funding from Astellas and Novartis. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. All authors declare no other competing interests. The authors gratefully acknowledge the funding of the CERTAIN Registry by a grant from the Dietmar Hopp Stiftung, the European Society for Paediatric Nephrology (ESPN) and The German Society for Paediatric Nephrology (GPN). JKi acknowledges funding from a MRC NIHR fellowship (MR/V037900/1). VK acknowledges funding from an NIHR Fellowship (PDF-2016-09-065) and as a Paul I. Terasaki Scholar. VK acknowledges funding from the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU, Grant number: NIHR203332) in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, the Department of Health or National Health Service Blood and Transplant.

Donor-derived cell-free DNA (dd-cfDNA) identifies allograft injury and discriminates active rejection from no rejection. In this prospective study, 106 kidney transplant recipients with 108 clinically indicated biopsies were enrolled at Heidelberg University Hospital between November 2020 and December 2022 to validate the clinical value of dd-cfDNA in a cohort of German patients. dd-cfDNA was quantified at biopsy and correlated to histopathology. Additionally, dd-cfDNA was determined on days 7, 30, and 90 post-biopsy and analyzed for potential use to monitor response to anti-rejection treatment. dd-cfDNA levels were with a median (IQR) % of 2.00 (0.48-3.20) highest in patients with ABMR, followed by 0.92 (0.19-11.25) in patients with TCMR, 0.44 (0.20-1.10) in patients with borderline changes and 0.20 (0.11-0.53) in patients with no signs of rejection. The AUC for dd-cfDNA to discriminate any type of rejection including borderline changes from no rejection was at 0.72 (95% CI 0.62-0.83). In patients receiving anti-rejection treatment, dd-cfDNA levels significantly decreased during the 7, 30, and 90 days follow-up compared to levels at the time of biopsy (p = 0.006, p = 0.002, and p < 0.001, respectively). In conclusion, dd-cfDNA significantly discriminates active rejection from no rejection. Decreasing dd-cfDNA following anti-rejection treatment may indicate response to therapy., European Union (EU); Horizon 2020; Research and Innovation Programme; LB is funded by the Olympia Morata Program of Heidelberg University. CSp is funded by the Physician Scientist Program of the Heidelberg Faculty of Medicine. For the publication fee we acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding program “Open Access Publikationskosten” as well as by Heidelberg University.

Worldwide 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., European Union (EU); Horizon 2020; Research and Innovation Programme; This study was supported by an operating grant from the Canadian Institutes of Health Research (PJT165832) . Some data reported here were supplied by the Hennepin Healthcare Research Institute (HHRI) as the contractor for the Scientific Registry of Transplant Recipients (SRTR) . The interpretation and reporting of these data are the responsibility of the author (s) and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government. Some data were supplied by the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) . The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the Australia and New Zealand Dialysis and Transplant Registry. We thank the transplant registries Eurotransplant, Italian Centro Nazionale Trapianti, Organitzacio Catalana de Trasplantaments, Nederlandse Transplantatie Stichting, and UK Transplant for collaboration and data exchange with the Collaborative Transplant Study (CTS) and gratefully acknowledge the generous support of the transplantation centers or hospitals that provided data for this study to CTS. AJV has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. AM is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. GW is supported by NHMRC Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). RS-P is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant no. 254386) and CIHR (grant FRN-156730). All the other authors declared no competing interests.

Background: There is a known recipient sex–dependent association between donor sex and kidney transplant survival. We hypothesized 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 Transplant Recipients, the Australia and New Zealand Dialysis and Transplant Registry and the Collaborative Transplant Study were analyzed. We used multivariable Cox regression models to estimate the association between donor sex and death censored graft loss, accounting 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. Results 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 donors ≥60 years showed significantly lower graft loss hazards than recipients of male donors of the same age [combined adjusted hazard ratio (aHR) 0.90, 95% CI 0.86–0.94]. Among male recipients, female donors aged <50 years were associated with significantly higher 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 donors aged ≥50 years. Conclusion: Donor age modifies the association between donor sex and graft survival. Older female donors were associated with similar or lower hazards of graft failure than older male donors in both male and female recipients, suggesting a better functional reserve of older female donor kidneys., European Union (EU); Horizon 2020; Research and Innovation Programme; This study was supported by an operating grant from the Canadian Institutes of Health Research (PJT165832). R.S.-P. is supported by Fonds de recherche du Quebec—Santé chercheur boursier clinicien award (grant no. 311 583). R.I.S. is partially supported by the Women in Transplantation Fellowship Award 2021–2023 (One Lambda Inc.)

Introduction: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. Methods and patients: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. Results: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naive. While the percentage of naive regulatory T cells (Tregs) (CD4(+)FOXP3(low)CD45RA(+)) and regulatory B cells (Bregs, CD20(+)CD24(+)CD38(+)) was similar, AIH patients had fewer activated Tregs (CD4(+)FOXP3(high)CD45RA(-)) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS, This project was funded by the Turkish Association for the Study of the Liver (TASL) charity, and seed funded by Koc University.