Risk Stratification Before Living Donor Kidney Transplantation in Patients With Preformed Donor-specific Antibodies by Different Crossmatch Methods.

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.

Long-Term Outcome after Early Mammalian Target of Rapamycin Inhibitor-Based Immunosuppression in Kidney Transplant Recipients.

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar.

Homozygosity in any HLA locus is a risk factor for specific antibody production: the taboo concept 2.0.

Objective: In a cooperative study of the University Hospital Leipzig, University of Leipzig, and the Charité Berlin on kidney transplant patients, we analysed the occurrence of HLA-specific antibodies with respect to the HLA setup of the patients. We aimed at the definition of specific HLA antigens towards which the patients produced these antibodies. Methods: Patients were typed for the relevant HLA determinants using mainly the next-generation technology. Antibody screening was performed by the state-of-the-art multiplex-based technology using microspheres coupled with the respective HLA alleles of HLA class I and II determinants. Results: Patients homozygous for HLA-A*02, HLA-A*03, HLA-A*24, HLA-B*07, HLA-B*18, HLA-B*35, HLA-B*44, HLA-C*03, HLA-C*04, and HLA-C*07 in the class I group and HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*07, HLA-DRB1*15, HLA-DQA1*01, HLA-DQA1*05, HLA-DQB1*02, HLA-DQB1*03(7), HLA-DQB1*06, HLA-DPA1*01, and HLA-DPB1*04 in the class II group were found to have a significant higher antibody production compared to the heterozygous ones. In general, all HLA determinants are affected. Remarkably, HLA-A*24 homozygous patients can produce antibodies towards all HLA-A determinants, while HLA-B*18 homozygous ones make antibodies towards all HLA-B and selected HLA-A and C antigens, and are associated with an elevation of HLA-DRB1, parts of DQB1 and DPB1 alleles. Homozygosity for the HLA class II HLA-DRB1*01, and HLA-DRB1*15 seems to increase the risk for antibody responses against most of the HLA class I antigens (HLA-A, HLA-B, and HLA-C) in contrast to HLA-DQB1*03(7) where a lower risk towards few HLA-A and HLA-B alleles is found. The widely observed differential antibody response is therefore to be accounted to the patient's HLA type. Conclusion: Homozygous patients are at risk of producing HLA-specific antibodies hampering the outcome of transplantation. Including this information on the allocation procedure might reduce antibody-mediated immune reactivity and prevent graft loss in a patient at risk, increasing the life span of the transplanted organ.

Successful Desensitization with Imlifidase and Daratumumab in a Highly Immunized, Crossmatch Positive, Blood Group-Incompatible Living-Donor Re-Transplant Recipient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients.

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

A Short History of B-Cell HLA Epitopes.

Background: HLA epitopes are currently in the focus of transplantation immunogenetics. The main reason is the complexity of the HLA system with >38,000 alleles, the number of which increases steadily. These alleles are determined by the current state-of-the art typing methods like second- and third-generation sequencing. Screening for HLA antibodies is hampered by the lack of specific target beads with all possible alleles described. Summary: A way to circumvent the problem is to define HLA epitopes. The number of antibody-confirmed epitopes, on the other hand, was found to be 72 for HLA class I and 74 for HLA class II. Here, we elaborate on the current knowledge on these HLA epitopes. Absolute definitions of these structures are not yet available. Key Messages: Making use of eplets is a comparable way allowing statistical analyses. However, one should keep in mind that the results obtained are approximative or perhaps better associative. Continuous collaboration is needed for the full understanding of the HLA epitopes. The reactivity toward epitopes remains patient-specific.

SARS-CoV-2 mRNA vaccination-induced immunological memory in human nonlymphoid and lymphoid tissues.

Tissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination have not been comprehensively analyzed in humans. We therefore studied SARS-CoV-2 mRNA vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow, and spleen compared with paired blood samples from largely virus-naive individuals. As opposed to lymphoid tissues, nonlymphoid organs harbored significantly elevated frequencies of spike-specific CD4+ T cells compared with blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived CD4+ T cells further exhibited increased polyfunctionality over those detected in blood. Single-cell RNA-Seq together with T cell receptor repertoire analysis indicated that the clonotype rather than organ origin is a major determinant of transcriptomic state in vaccine-specific CD4+ T cells. In summary, our data demonstrate that SARS-CoV-2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.

Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients.

BACKGROUND: De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. METHODS: All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000-31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. RESULTS: During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5-5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4-2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6-4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8-3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. CONCLUSIONS: Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints.

Pregnancy after Kidney Transplantation-Impact of Functional Renal Reserve, Slope of eGFR before Pregnancy, and Intensity of Immunosuppression on Kidney Function and Maternal Health.

Women of childbearing age show increased fertility after kidney transplantation. Of concern, preeclampsia, preterm delivery, and allograft dysfunction contribute to maternal and perinatal morbidity and mortality. We performed a retrospective single-center study, including 40 women with post-transplant pregnancies after single or combined pancreas-kidney transplantation between 2003 and 2019. Outcomes of kidney function up to 24 months after the end of pregnancy were compared with a matched-pair cohort of 40 transplanted patients without pregnancies. With a maternal survival rate of 100%, 39 out of 46 pregnancies ended up with a live-born baby. The eGFR slopes to the end of 24 months follow-up showed mean eGFR declines in both groups (-5.4 ± 14.3 mL/min in pregnant versus -7.6 ± 14.1 mL/min in controls). We identified 18 women with adverse pregnancy events, defined as preeclampsia with severe end-organ dysfunction. An impaired hyperfiltration during pregnancy was a significant risk contributor for both adverse pregnancy events (p < 0.05) and deterioration of kidney function (p < 0.01). In addition, a declining renal allograft function in the year before pregnancy was a negative predictor of worsening allograft function after 24 months of follow-up. No increased frequency of de novo donor-specific antibodies after delivery could be detected. Overall, pregnancies in women after kidney transplantation showed good allograft and maternal outcomes.

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation.

Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor's HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood. Based on our recently implemented computational deep learning pipeline to define HLA Class I protein-specific surface residues, we hypothesized a correlation between the number of HLA protein-specific solvent-accessible interlocus amino acid mismatches (arbitrarily called Snowflake) and the incidence of DSA. To validate our hypothesis, we considered two cohorts simultaneously. The kidney transplant cohort (KTC) considers 305 kidney-transplanted patients without DSA prior to transplantation. During the follow-up, HLA antibody screening was performed regularly to identify DSA. The pregnancy cohort (PC) considers 231 women without major sensitization events prior to pregnancy who gave live birth. Post-delivery serum was screened for HLA antibodies directed against the child's inherited paternal haplotype (CSA). Based on the involved individuals' HLA typings, the numbers of interlocus-mismatched antibody-verified eplets (AbvEPS), the T cell epitope PIRCHE-II model and Snowflake were calculated locus-specific (HLA-A, -B and -C), normalized and pooled. In both cohorts, Snowflake numbers were significantly elevated in recipients/mothers that developed DSA/CSA. Univariable regression revealed significant positive correlation between DSA/CSA and AbvEPS, PIRCHE-II and Snowflake. Snowflake numbers showed stronger correlation with numbers of AbvEPS compared to Snowflake numbers with PIRCHE-II. Our data shows correlation between Snowflake scores and the incidence of DSA after allo-immunization. Given both AbvEPS and Snowflake are B cell epitope models, their stronger correlation compared to PIRCHE-II and Snowflake appears plausible. Our data confirms that exploring solvent accessibility is a valuable approach for refining B cell epitope definitions.

The natural history of de novo donor-specific HLA antibodies after kidney transplantation.

Background: De novo donor-specific HLA antibodies (dnDSA) are key factors in the diagnosis of antibody-mediated rejection (ABMR) and related to graft loss. Methods: This retrospective study was designed to evaluate the natural course of dnDSA in graft function and kidney allograft survival and to assess the impact of mean fluorescence intensity (MFI) evolution as detected by annual Luminex® screening. All 400 kidney transplant recipients with 731 dnDSA against the last graft (01/03/2000-31/05/2021) were included. Results: During 8.3 years of follow-up, ABMR occurred in 24.8% and graft loss in 33.3% of the cases, especially in patients with class I and II dnDSA, and those with multiple dnDSA. We observed frequent changes in MFI with 5-year allograft survivals post-dnDSA of 74.0% in patients with MFI reduction ≥ 50%, 62.4% with fluctuating MFI (MFI reduction ≥ 50% and doubling), and 52.7% with doubling MFI (log-rank p < 0.001). Interestingly, dnDSA in 168 (24.3%) cases became negative at some point during follow-up, and 38/400 (9.5%) patients became stable negative, which was associated with better graft survival. Multivariable analysis revealed the importance of MFI evolution and rejection, while class and number of dnDSA were not contributors in this model. Conclusion: In summary, we provide an in-depth analysis of the natural course of dnDSA after kidney transplantation, first evidence for the impact of MFI evolution on graft outcomes, and describe a relevant number of patients with a stable disappearance of dnDSA, related to better allograft survival.

On the clinical relevance of using complete high-resolution HLA typing for an accurate interpretation of posttransplant immune-mediated graft outcomes.

Complete and high-resolution (HR) HLA typing improves the accurate assessment of donor-recipient compatibility and pre-transplant donor-specific antibodies (DSA). However, the value of this information to identify de novo immune-mediated graft events and its impact on outcomes has not been assessed. In 241 donor/recipient kidney transplant pairs, DNA samples were re-evaluated for six-locus (A/B/C/DRB1/DQB1+A1/DPB1) HR HLA typing. De novo anti-HLA antibodies were assessed using solid-phase assays, and dnDSA were classified either (1) as per current clinical practice according to three-locus (A/B/DRB1) low-resolution (LR) typing, estimating donor HLA-C/DQ typing with frequency tables, or (2) according to complete six-locus HR typing. The impact on graft outcomes was compared between groups. According to LR HLA typing, 36 (15%) patients developed dnDSA (LR_dnDSA+). Twenty-nine out of 36 (80%) were confirmed to have dnDSA by HR typing (LR_dnDSA+/HR_dnDSA+), whereas 7 (20%) did not (LR_dnDSA+/HR_dnDSA-). Out of 49 LR_dnDSA specificities, 34 (69%) were confirmed by HR typing whereas 15 (31%) LR specificities were not confirmed. LR_dnDSA+/HR_dnDSA+ patients were at higher risk of ABMR as compared to dnDSA- and LR_dnDSA+/HR_dnDSA- (logRank < 0.001), and higher risk of death-censored graft loss (logRank = 0.001). Both LR_dnDSA+ (HR: 3.51, 95% CI = 1.25-9.85) and LR_dnDSA+/HR_dnDSA+ (HR: 4.09, 95% CI = 1.45-11.54), but not LR_dnDSA+/HR_dnDSA- independently predicted graft loss. The implementation of HR HLA typing improves the characterization of biologically relevant de novo anti-HLA DSA and discriminates patients with poorer graft outcomes.

Poor Outcomes in Patients With Transplant Glomerulopathy Independent of Banff Categorization or Therapeutic Interventions.

Background: Transplant glomerulopathy (TG) may indicate different disease entities including chronic AMR (antibody-mediated rejection). However, AMR criteria have been frequently changed, and long-term outcomes of allografts with AMR and TG according to Banff 2017 have rarely been investigated. Methods: 282 kidney allograft recipients with biopsy-proven TG were retrospectively investigated and diagnosed according to Banff'17 criteria: chronic AMR (cAMR, n = 72), chronic active AMR (cAAMR, n = 76) and isolated TG (iTG, n = 134). Of which 25/72 (34.7%) patients of cAMR group and 46/76 (60.5%) of cAAMR group were treated with antihumoral therapy (AHT). Results: Up to 5 years after indication biopsy, no statistically significant differences were detected among iTG, cAMR and cAAMR groups in annual eGFR decline (-3.0 vs. -2.0 vs. -2.8 ml/min/1.73 m2 per year), 5-year median eGFR (21.5 vs. 16.0 vs. 20.0 ml/min/1.73 m2), 5-year graft survival rates (34.1 vs. 40.6 vs. 31.8%) as well as urinary protein excretion during follow-up. In addition, cAMR and cAAMR patients treated with AHT had similar graft and patient survival rates in comparison with those free of AHT, and similar comparing with iTG group. The TG scores were not associated with 5-year postbiopsy graft failure; whereas the patients with higher scores of chronic allograft scarring (by mm-, ci- and ct-lesions) had significantly lower graft survival rates than those with mild scores. The logistic-regression analysis demonstrated that Banff mm-, ah-, t-, ci-, ct-lesions and the eGFR level at biopsy were associated with 5-year graft failure. Conclusions: The occurrence of TG is closely associated with graft failure independent of disease categories and TG score, and the long-term clinical outcomes were not influenced by AHT. The Banff lesions indicating progressive scarring might be better suited to predict an unfavorable outcome.

Pediatric Kidney Transplantation: Frameshift in Medical and Surgical Management. Does the Perioperative Setting Have an Impact on Transplant Outcome? A Single-Center Experience.

Introduction: Frameshift in medical management as well as in surgical thinking is putting the patient as a whole is the focus, rather than just the disease. To optimize the treatment of our pediatric transplant patients in our institution, we changed in 2013 the transplant program setting, treating, and operating all patients with pediatric transplant exclusively in a pediatric environment. The aim of this study was to analyze whether or not this change had an impact on patients safety, patient population, and patients and transplant outcome. Methods: In the retrospective analysis, we compared transplant outcome of two eras. Era1 (2008-2012) solely included patients treated in the adult facilities, era 2 (2013-2017) patients were exclusively treated in the pediatric environment. Results: There were 53 patients with renal transplant, with era 1 (28 patients) and era 2 (25 patients). Overall mortality was 5.6%. Median recipient age at transplantation was 13.2 years in era 1 and 8.59 years in era 2, median recipient weight at transplantation was 41.7 kg in era 1 vs. 26 kg in era 2, median size 149. 5 cm (era 1) vs. 123 cm in era2 (p = 0.05). The direct recipient/donor weight ratio remained stable in both eras, for recipients below 20 kg we saw a larger weight mismatch in era 1 (0.84 vs. 0.66). In the subgroup of patients with congenital anomalies of the kidney and urinary tract (CAKUT) those were significantly younger at onset of dialysis (p < 0.001) and at time of transplantation (p < 0.001), also they were less in body weight (p < 0.01), and body size (p < 0.001), this subgroup was larger in era 2. HLA mismatch data, serum creatinine, and GFR yield comparable results in both groups. Median time to detection of DSA was 46.2 month (3.8 years). Conclusion: Since children with ESRD at the time of transplant trend to be younger and smaller, it is crucial to ensure a medical environment that is able to address their particular challenges. Even in this recipient cohort, renal transplantation can be performed safely as outlined by our data.

Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients.

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor-treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain-specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo-activated programmed cell death 1-positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.

Determination of unacceptable HLA antigen mismatches in kidney transplant recipients.

With the introduction of the virtual allocation crossmatch in the Eurotransplant (ET) region in 2023, the determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients is of utmost importance for histocompatibility laboratories and transplant centers. Therefore, a joined working group of members from the German Society for Immunogenetics (Deutsche Gesellschaft für Immungenetik, DGI) and the German Transplantation Society (Deutsche Transplantationsgesellschaft, DTG) revised and updated the previous recommendations from 2015 in light of recently published evidence. Like in the previous version, a wide range of topics is covered from technical issues to clinical risk factors. This review summarizes the evidence about the prognostic value of contemporary methods for HLA antibody detection and identification, as well as the impact of UAM on waiting time, on which these recommendations are based. As no clear criteria could be determined to differentiate potentially harmful from harmless HLA antibodies, the general recommendation is to assign all HLA against which plausible antibodies are found as UAM. There is, however, a need for individualized solutions for highly immunized patients. These revised recommendations provide a list of aspects that need to be considered when assigning UAM to enable a fair and comprehensible procedure and to harmonize risk stratification prior to kidney transplantation between transplant centers.

Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching.

The EuroTransplant Kidney Allocation System (ETKAS) aims at allocating organs to patients on the waiting list fairly whilst optimizing HLA match grades. ETKAS currently considers the number of HLA-A, -B, -DR mismatches. Evidently, epitope matching is biologically and clinically more relevant. We here executed ETKAS-based computer simulations to evaluate the impact of epitope matching on allocation and compared the strategies. A virtual population of 400,000 individuals was generated using the National Marrow Donor Program (NMDP) haplotype frequency dataset of 2011. Using this population, a waiting list of 10,400 patients was constructed and maintained during simulation, matching the 2015 Eurotransplant Annual Report characteristics. Unacceptable antigens were assigned randomly relative to their frequency using HLAMatchmaker. Over 22,600 kidneys were allocated in 10 years in triplicate using Markov Chain Monte Carlo simulations on 32-CPU-core cloud-computing instances. T-cell epitopes were calculated using the www.pirche.com portal. Waiting list effects were evaluated against ETKAS for five epitope matching scenarios. Baseline simulations of ETKAS slightly overestimated reported average HLA match grades. The best balanced scenario maintained prioritisation of HLA A-B-DR fully matched donors while replacing the HLA match grade by PIRCHE-II score and exchanging the HLA mismatch probability (MMP) by epitope MMP. This setup showed no considerable impact on kidney exchange rates and waiting time. PIRCHE-II scores improved, whereas the average HLA match grade diminishes slightly, yet leading to an improved estimated graft survival. We conclude that epitope-based matching in deceased donor kidney allocation is feasible while maintaining equal balances on the waiting list.

Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies.

BACKGROUND: Donor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear. METHODS: We performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed. RESULTS: Analysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67-12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin. CONCLUSION: Donor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.