Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

Influence of donor sex and age on graft outcome in kidney transplantation.

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.

P32: a sex- and gender-sensitive model for evidence-based precision medicine: from knowledge generation to implementation in the field of kidney transplantation.

Precision medicine emerged as a promising approach to identify suitable interventions for individual patients with a particular health concern and at various time points. Technology can enable the acquisition of increasing volumes of clinical and "omics" data at the individual and population levels and support advanced clinical decision making. However, to keep pace with evolving societal realities and developments, it is important to systematically include sex- and gender-specific considerations in the research process, from the acquisition of knowledge to implementation. Building on the foundations of evidence-based medicine and existing precision medicine frameworks, we propose a novel evidence-based precision medicine framework in the form of the P32model, which considers individual sex-related (predictive [P1], preventive [P2], and personalized [P3] medicine) and gender-related (participatory [P4], psychosocial [P5], and percipient [P6] medicine) domains and their intersection with ethnicity, geography, and other demographic and social variables, in addition to population, community, and public dimensions (population-informed [P7], partnered with community [P8], and public-engaging [P9] medicine, respectively). Through its ability to contextualize and reflect on societal realities and developments, our model is expected to promote consideration of diversity, equity, and inclusion principles and, thus, enrich science, increase reproducibility of research, and ensure its social impact.

A multinational cohort study uncovered sex differences in excess mortality after kidney transplant.

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.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

BACKGROUND: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS: This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION: Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

Adding epitope compatibility to deceased donor kidney allocation criteria: recommendations from a pan-Canadian online public deliberation.

BACKGROUND: The widening supply-demand imbalance for kidneys necessitates finding ways to reduce rejection and improve transplant outcomes. Human leukocyte antigen (HLA) epitope compatibility between donor and recipient may minimize premature graft loss and prolong survival, but incorporating this strategy to deceased donor allocation criteria prioritizes transplant outcomes over wait times. An online public deliberation was held to identify acceptable trade-offs when implementing epitope compatibility to guide Canadian policymakers and health professionals in deciding how best to allocate kidneys fairly. METHODS: Invitations were mailed to 35,000 randomly-selected Canadian households, with over-sampling of rural/remote locations. Participants were selected for socio-demographic diversity and geographic representation. Five two-hour online sessions were held from November-December 2021. Participants received an information booklet and heard from expert speakers prior to deliberating on how to fairly implement epitope compatibility for transplant candidates and governance issues. Participants collectively generated and voted on recommendations. In the final session, kidney donation and allocation policymakers engaged with participants. Sessions were recorded and transcribed. RESULTS: Thirty-two individuals participated and generated nine recommendations. There was consensus on adding epitope compatibility to the existing deceased donor kidney allocation criteria. However, participants recommended including safeguards/flexibility around this (e.g., mitigating declining health). They called for a transition period to epitope compatibility, including an ongoing comprehensive public education program. Participants unanimously recommended regular monitoring and public sharing of epitope-based transplant outcomes. CONCLUSIONS: Participants supported adding epitope compatibility to kidney allocation criteria, but advised safeguards and flexibility around implementation. These recommendations provide guidance to policymakers about incorporating epitope-based deceased donor allocation criteria.

Public values and guiding principles for implementing epitope compatibility in kidney transplantation allocation criteria: results from a Canadian online public deliberation.

BACKGROUND: Epitope compatibility in deceased donor kidney allocation is an emerging area of precision medicine (PM), seeking to improve compatibility between donor kidneys to transplant candidates in the hope of avoiding kidney rejection. Though the potential benefits of using epitope compatibility are promising, the implied modification of deceased organ allocation criteria requires consideration of significant clinical and ethical trade-offs. As a matter of public policy, these trade-offs should consider public values and preferences. We invited members of the Canadian public to participate in a deliberation about epitope compatibility in deceased donor kidney transplantation; to identify what is important to them and to provide recommendations to policymakers. METHODS: An online public deliberation was conducted with members of the Canadian public, in which participants were asked to construct recommendations for policymakers regarding the introduction of epitope compatibility to kidney allocation criteria. In the present paper, a qualitative analysis was conducted to identify the values reflected in participants' recommendations. All virtual sessions were recorded, transcribed, and analyzed using NVivo 12 software. RESULTS: Thirty-two participants constructed nine recommendations regarding the adoption of epitope compatibility into deceased donor kidney allocation. Five values were identified that drove participants' recommendations: Health Maximization, Protection/Mitigation of Negative Impacts, Fairness, Science/Evidence-based Healthcare, and Responsibility to Maintain Trust. Conflicts between these values were discussed in terms of operational principles that were required for epitope compatibility to be implemented in an acceptable manner: the needs for Flexibility, Accountability, Transparent Communication and a Transition Plan. All nine recommendations were informed by these four principles. Participant deliberations were often dominated by the conflict between Health Maximization and Fairness or Protection/Mitigation of Negative Impacts, which was discussed as the need for Flexibility. Two additional values (Efficient Use of Resources and Logic/Rationality) were also discussed and were reasons for some participants voting against some recommendations. CONCLUSIONS: Public recommendations indicate support for using epitope compatibility in deceased donor kidney allocation. A flexible approach to organ allocation decision-making may allow for the balancing of Health Maximization against maintaining Fairness and Mitigating Negative Impacts. Flexibility is particularly important in the context of epitope compatibility and other PM initiatives where evidence is still emerging.

Severity of COVID-19 among solid organ transplant recipients in Canada, 2020-2021: a prospective, multicentre cohort study.

BACKGROUND: Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada. METHODS: We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen. RESULTS: A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n = 190), compared with not needing (n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5-69.5 yr v. median 55.5 yr, IQR 47.5-66.5; p < 0.001) and number of comorbidities (median 3, IQR 2-3 v. median 2, IQR 1-3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n = 48) were more likely to have severe disease with a high mortality rate (n = 15, 31.3%) compared with recipients of other organ transplants, including kidney (n = 48, 14.8%), heart (n = 1, 4.4%), liver (n = 9, 11.4%) and kidney-pancreas (n = 3, 12.0%) transplants (p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.07) and number of comorbidities (OR 1.63, 95% CI 1.30-2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly. INTERPRETATION: Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

An Analysis by the European Committee on Organ Transplantation of the Council of Europe Outlining the International Landscape of Donors and Recipients Sex in Solid Organ Transplantation.

Discrepancies in donation and transplantation by sex and gender have previously been reported. However, whether such differences are invariably the inevitable, unintended outcome of a legitimate process has yet to be determined. The European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) is the committee that actively promotes the development of ethical, quality and safety standards in the field of transplantation in Europe. Whilst the ultimate objective is to shed light on the processes underlying potential gender inequities in transplantation, our initial goal was to represent the distribution by sex among organ donors and recipients in the CD-P-TO Member States and observer countries. Our survey confirms previous evidence that, in most countries, men represent the prevalent source of deceased donors (63.3% in 64 countries: 60.7% and 71.9% for donation after brain and circulatory death, respectively). In contrast, women represent the leading source of organs recovered from living kidney and liver donors (61.1% and 51.2% in 55 and 32 countries, respectively). Across countries, most recovered organs are transplanted into men (65% in 57 countries). These observations may be explained, at least in part, by the higher burden of certain diseases in men, childbearing related immune sensitization in women, and donor-recipient size mismatch. Future research should establish whether gender-related socially-constructed roles and socioeconomic status may play a detrimental role reducing the access of women to transplantation.

Age- and sex-mediated differences in T lymphocyte populations of kidney transplant recipients.

BACKGROUND: Graft failure rates increase through childhood and adolescence, decline in adulthood, and are higher in female than male kidney transplant recipients (KTR) until middle age. We aimed to describe age- and sex-related differences in T-cell subsets among KTR to determine which differences may help to explain the differences in kidney graft failure rates. METHODS: Effector T (Teff)-cell and regulatory T (Treg)-cell phenotypes in PBMCs from healthy controls and KTR, who were at least 1 year post-transplant with stable graft function under immunosuppression, were analyzed by flow cytometry. The effects of age, sex, and status (KTR or control) were analyzed using linear regressions. RESULTS: We enrolled 20 male and 21 female KTR and 20 male and 20 female controls between 3 and 29 years of age. CD3+ T-cell frequencies were not associated with age or sex but were higher in KTR than controls. There were no differences in CD4+ and CD8+ frequencies. Th1 (IFNγ+ IL-4- IL-17A-) and Th17 (IL-17A+) frequencies within the CD4+ T-cell population were higher at older ages. The frequencies of FOXP3 + Helios + Treg cells in CD4+ CD25+ CD127- T cells were lower in females than males and in KTR than controls. CONCLUSIONS: Increasing frequencies of Th1 and Th17 cells with increasing age mirrors the increasing graft failure rates from childhood to young adulthood. Importantly, sex differences in frequencies of circulating Treg cells may suggest a role in the sex differences in graft failure rates.

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.

Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

BACKGROUND: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients. METHODS: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada. Patients were enrolled between June 2015 and March 2018 and followed for 6 months. Adherence was assessed at baseline, 3, and 6 months using the BAASIS© self-report tool. Patients were classified as adherent if no doses were missed in the prior 4 weeks. Transplant program directors and nurses completed questionnaires regarding care organization and processes. RESULTS: Of the 270 participants, 99 were followed in pediatric programs and 171 in adult programs. Median age was 20.3 years, and median time since transplant was 5 years. At baseline, 71.5% were adherent. Multivariable mixed effects logistic regression models with program as a random effect identified two program-level factors as independently associated with better adherence: minimum number of prescribed blood draws per year for those >3 years post-transplant (per 1 additional) (OR 1.12 [95% CI 1.00, 1.26]; p = .047), and average time nurses spend with patients in clinic (per 5 additional minutes) (OR 1.15 [1.03, 1.29]; p = .017). CONCLUSION: Program-level factors including protocols with a greater frequency of routine blood testing and more nurse time with patients were associated with better medication adherence. This suggests that interventions at the program level may support better adherence.

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation.

The development of donor-specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post-transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor-specific antibodies post-transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet-based donor:recipient matching, including unavailability of allele-level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping methods, compilation of large data sets with allele-level genotypes, and standardization of methods to verify eplets as determinants of immune-mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

Nonalcoholic Fatty Liver Disease and the Development of Metabolic Comorbid Conditions in Patients With Human Immunodeficiency Virus Infection.

BACKGROUND: Cardiovascular and liver disease are main causes of death in people with human immunodeficiency virus (HIV) (PWH). In HIV-uninfected patients, nonalcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbid conditions in PWH. METHODS: We included PWH undergoing a screening program for NAFLD using transient elastography. NAFLD was defined as a controlled attenuation parameter ≥248 dB/m with exclusion of other liver diseases. Incident diabetes, hypertension, dyslipidemia, and chronic kidney disease were investigated using survival analysis and Cox proportional hazards. RESULTS: The study included 485 HIV-monoinfected patients. During a median follow-up of 40.1 months (interquartile range, 26.5-50.7 months), patients with NAFLD had higher incidences of diabetes (4.74 [95% confidence interval, 3.09-7.27] vs 0.87 [.42-1.83] per 100 person-years) and dyslipidemia (8.16 [5.42-12.27] vs 3.99 [2.67-5.95] per 100 person-years) than those without NAFLD. With multivariable analysis, NAFLD was an independent predictor of diabetes (adjusted hazard ratio, 5.13; 95% confidence interval, 2.14-12.31) and dyslipidemia (2.35; 1.34-4.14) development. CONCLUSIONS: HIV-monoinfected patients with NAFLD are at higher risk of incident diabetes and dyslipidemia. Early referral strategies and timely management of metabolic risk may improve outcomes.

Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.

Renal resistance thresholds during hypothermic machine perfusion and transplantation outcomes - a retrospective cohort study.

Renal resistance (RR), of allografts undergoing hypothermic machine perfusion (HMP), is considered a measure of organ quality. We conducted a retrospective cohort study of adult deceased donor kidney transplant (KT) recipients whose grafts underwent HMP. Our aim was to evaluate whether RR is predictive of death-censored graft failure (DCGF). Of 274 KT eligible for analysis, 59% were from expanded criteria donor. RR was modeled as a categorical variable, using a previously identified terminal threshold of 0.4, and 0.2 mmHg/ml/min (median in our cohort). Hazard ratios (HR) of DCGF were 3.23 [95% confidence interval (CI): 1.12-9.34, P = 0.03] and 2.67 [95% CI: 1.14-6.31, P = 0.02] in univariable models, and 2.67 [95% CI: 0.91-7.86, P = 0.07] and 2.42 [95% CI: 1.02-5.72, P = 0.04] in multivariable models, when RR threshold was 0.4 and 0.2, respectively. Increasing risk of DCGF was observed when RR over the course of HMP was modeled using mixed linear regression models: HR of 1.31 [95% CI: 1.07-1.59, P < 0.01] and 1.25 [95% CI: 1.00-1.55, P = 0.05], in univariable and multivariable models, respectively. This suggests that RR during HMP is a predictor of long-term KT outcomes. Prospective studies are needed to assess the survival benefit of patients receiving KT with higher RR in comparison with staying wait-listed.