Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.

BACKGROUND: There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency. METHODS: This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described. RESULTS: There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease. CONCLUSION: Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.

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.

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.

Early progression of chronic histologic lesions in kidney transplant biopsies is not associated with HLA histocompatibility.

BACKGROUND: Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. METHODS: We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at three and twelve months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores (i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR) were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. RESULTS: More than one third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the three to the twelve-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 (OR = 1.10, 95%-CI: 1.03-1.18). Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95-% CI: 1.19-22.57) could be confirmed in our cohort. CONCLUSIONS: These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.

A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression.

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report.

The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.

hlaR: A rapid and reproducible tool to identify eplet mismatches between transplant donors and recipients.

Eplet mismatch load, both overall and at the single molecule level, correlates with transplant recipient outcomes. However, precise eplet assessment requires high-resolution HLA typing of both the donor and recipient. Anything less than high-resolution typing requires imputation of HLA types. The currently available methods to identify eplet mismatch are both tedious and demanding. Therefore, we developed a software package and user-friendly web application (hlaR), that simplifies the workflow of eplet analysis, provides functions to impute high-resolution from low-resolution data and calculates both overall and single molecule eplet mismatch for single or multiple donor recipient pairs. Compared to manual assessments using currently available tools (namely, HLAMatchMaker), hlaR resulted in only minimal discrepancy in eplet mismatches (mean absolute difference of 0.56 for class I and 0.86 for class II for unique sum across loci). Additionally, output of the single molecule eplet function compared well to manual calculation, with an average single antigen count increase of 0.19. Importantly, the hlaR tool permits rapid and reproducible imputation and eplet mismatch including comparison between eplet reference tables (e.g. HLAMatchMaker version 2 or 3). Users can import data from a spreadsheet rather than relying on keystroke entry of individual donor and recipient data, thus reducing the risk of data entry errors. The resulting improved scalability of the hlaR tool is highlighted by plotting analysis time against the size of the input dataset. The new hlaR tool can provide eplet mismatch data with a streamlined workflow. With decreased effort from the end user, eplet matching and mismatch load data can be further incorporated into both research and clinical use.

The negative impact of T cell-mediated rejection on renal allograft survival in the modern era.

The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.

Role of HLA molecular mismatch in clinical practice.

To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.

Effectiveness of T cell-mediated rejection therapy: A systematic review and meta-analysis.

The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2  statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.

Post-transplant diabetes mellitus in Canadian liver and renal transplant recipients.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) occurs in 10%-40% of liver and renal transplant recipients. Whether the risk factors for PTDM in liver and renal transplant recipients are similar and whether Indigenous Canadians, who have a high underlying prevalence of diabetes mellitus (DM), are at increased risk of developing PTDM have yet to be determined. OBJECTIVE: To describe and compare those variables associated with PTDM in adult Canadian liver and renal transplant recipients. METHODS: A retrospective chart review of adult liver and renal transplant recipients attending four transplant follow-up clinics in three Canadian provinces was undertaken. RESULTS: De novo PTDM was diagnosed in 184/905 (20.3%) liver and 179/390 (45.9%) renal transplant recipients. Older age, higher pre-transplant BMI, underlying immune-mediated liver disease, lower trough tacrolimus levels and longer duration of follow-up were independently associated with PTDM in liver transplant recipients and non-Caucasian race, higher pre-transplant BMI, and incidence of organ rejection in renal transplant recipients. Compared with Caucasians, Indigenous Canadians who had undergone renal transplantation had a significantly increased prevalence of PTDM (56.5% versus 40.0%, p = 0.035). The prevalence of PTDM in liver transplant recipients was similar in Indigenous Canadians and Caucasians (27.9% versus 20.1%, p = 0.215). CONCLUSIONS: The variables associated with PTDM differ in liver and renal transplant recipients. Compared with Caucasians, Indigenous Canadians undergoing renal transplantation are at increased risk of developing PTDM.

Training Programs for Fundamental and Clinician-Scientists: Balanced Outcomes for Graduates by Gender.

BACKGROUND: Women scientists are less likely to obtain Assistant Professorship and achieve promotion, and obtain less grant funding than men. Scientist/clinician-scientist training programs which provide salary awards as well as training and mentorship are a potential intervention to improve outcomes among women scientists. We hypothesized whether a programmatic approach to scientist/clinician-scientist training is associated with improved outcomes for women scientists in Canada when compared with salary awards alone. Trainees within the Kidney Research Scientist Core Education and National Training Program (KRESCENT), Canadian Child Health Clinician Scientist Program (CCHCSP), and the Canadian Institutes of Health Research (CIHR) salary award programs were evaluated. OBJECTIVE: To examine whether the structured KRESCENT training program with salary support improves academic success for women scientists relative to salary awards alone. DESIGN: Retrospective cohort study. SETTING: Canadian national research scientist and clinician-scientist training programs and salary awards. PARTICIPANTS: KRESCENT cohort (n = 59, 2005-2017), CCHCSP cohort (n = 58, 2002-2015), and CIHR (n = 571, 2005-2015) Salary Awardees for postdoctoral fellows (PDF) and new investigators (NI). MEASUREMENTS: National operating grant funding success, achieving an academic position as an Assistant Professor for PDF, or achieving promotion to Associate Professor for NI. METHODS: The gender distribution of each cohort was determined using first name and NamepediA and was examined for PDF and NI, followed by a description of trainee outcomes by gender and training level. RESULTS: KRESCENT and CIHR PDF were balanced (12/27, 44% men and 55/116, 47% women) while CCHCSP had a higher proportion of women (13/20, 65%). KRESCENT and CCHCSP NI retained women scientists (19/32, 59% and 22/38, 58% women), whereas CIHR NI had fewer women (165/455, 36% women vs 290/455, 64% men, P = 0.01). There was a high rate of NI operating grant success (91%-95%) with no gender differences in each cohort. There was a high proportion of CCHCSP PDF who achieved an Assistant Professorship (18/20, 90%) that may be due in part to a longer follow-up period (9.3 ± 3 years) compared with KRESCENT PDF (7/27, 26%, 0.88 ± 4.5 years), and these data were not available for CIHR PDF. Women KRESCENT NI showed increased promotion to Associate Professor (P = 0.02, 0.25 ± 3.2 years follow-up) and CCHCSP NI had high promotion rates (37/38, 97%, 6.9 ± 3.6 years follow-up) irrespective of gender. There was an overall trend toward more men pursuing biomedical research. LIMITATIONS: KRESCENT and CCHCSP training program cohort size and heterogeneity; assigning gender by first name may result in misclassification; lack of data on the respective applicant pools; and inability to examine intersectionality with gender, ethnicity, and sexual orientation. CONCLUSION: Overall trainee performance across programs is remarkable by community standards regardless of gender. KRESCENT and CCHCSP training programs demonstrated balanced success in their PDF and NI, whereas the CIHR awardees had reduced representation of women scientists from PDF to NI. This exploratory study highlights the utility of programmatic training approaches like the KRESCENT program as potential tools to support and retain women scientists in the academic pipeline during the challenging PDF to NI transition period.

CONTEXTE: Les chercheuses sont moins susceptibles que les hommes d'obtenir une promotion ou un poste de professeur adjoint, en plus d'obtenir moins de subventions. Des programmes de formation pour les chercheurs et chercheurs cliniciens offrant des bourses salariales ainsi que de la formation et du mentorat pourraient s'avérer pertinents pour améliorer la situation des femmes en sciences. Nous avons émis l'hypothèse qu'une approche programmatique de la formation des chercheurs et chercheurs cliniciens pourrait améliorer les résultats pour les chercheuses canadiennes comparativement aux bourses salariales seules. Pour ce faire, les stagiaires du Programme national de formation scientifique et d'encadrement des chercheurs spécialisés dans le domaine rénal (KRESCENT), du Programme canadien des cliniciens-chercheurs en santé de l'enfant (PCCCSE) et des programmes de bourses salariales des Instituts de recherche en santé du Canada (IRSC) ont été évalués. OBJECTIFS: Vérifier si le programme de formation structuré KRESCENT avec soutien salarial favorise le succès académique des scientifiques féminines par rapport aux bourses salariales uniquement. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Programmes nationaux de formation et de bourses salariales pour les chercheurs et les chercheurs cliniciens du Canada. SUJETS: La cohorte KRESCENT (n = 59; 2005-2017), la cohorte PCCCSE (n = 58; 2002-2015) et les récipiendaires d'une bourse salariale des IRSC (n = 571; 2005-2015) destinées aux boursiers postdoctoraux (BPD) et aux nouveaux chercheurs (NC). MESURES: Le succès du financement des subventions de fonctionnement nationales, l'obtention d'un poste de professeur adjoint à l'université pour les BPD ou l'obtention d'une promotion au poste de professeur agrégé pour les NC. MÉTHODOLOGIE: La répartition des genres dans chaque cohorte a été déterminée à l'aide du prénom et de Namepedia, et a été examinée en fonction du statut (BPD ou NC). Les résultats des stagiaires ont été décrits selon le genre et le niveau de formation. RÉSULTATS: Dans le cas des BPD, les cohortes KRESCENT et IRSC étaient plutôt équilibrées (44 % d'hommes [12/27] pour KRESCENT et 47 % [55/116] de femmes pour IRSC). Les femmes BPD étaient plus nombreuses dans la cohorte PCCCSE (13/20 [65 %]). Du côté des NC, les femmes étaient majoritaires dans les cohortes KRESCENT et PCCCSE (respectivement 59 % [19/32] et 58 % [22/38] de femmes) et les hommes étaient plus nombreux dans la cohorte IRSC (64 % d'hommes [290/455]; 36 % de femmes [165/455] [p = 0,01]). Nous avons observé un taux élevé de réussite des subventions de fonctionnement chez les NC (91 à 95 %) dans toutes les cohortes, sans égard au genre. Une forte proportion de BPD du PCCCSE avaient obtenu un poste de professeur adjoint (18/20 [90 %]); ceci pourrait s'expliquer en partie par le plus long suivi (9,3 ± 3 ans) comparativement aux BPD du KRESCENT (7/27 [26 %]; 0,88 ± 4,5 ans). Ces données n'étaient pas disponibles pour les BPD des IRSC. On a vu une augmentation des promotions à des postes de professeurs agrégés pour les nouvelles chercheuses de la cohorte KRESCENT (p = 0,02, pour 0,25 ± 3,2 ans de suivi). Les NC du PCCCSE présentaient un taux élevé de promotions (37/38 [97 %]; 6,9 ± 3,6 ans de suivi), indépendamment du genre. Une tendance globale pour un plus grand nombre d'hommes poursuivant des recherches biomédicales a été observée. LIMITES: Parmi les limites, on compte la taille et l'hétérogénéité des cohortes KRESCENT et PCCCSE; de possibles erreurs de classification dues à l'attribution du genre par le prénom; le manque de données sur les bassins respectifs de candidats; l'incapacité d'examiner l'intersectionnalité avec le genre, l'origine ethnique et l'orientation sexuelle. CONCLUSION: Le rendement global des stagiaires dans l'ensemble des programmes est remarquable, quel que soit leur genre, par rapport aux normes communautaires. Les programmes de formation de KRESCENT et PCCCSE ont démontré un succès équilibré chez leurs BPD et NC, tandis que les récipiendaires d'une bourse des IRSC ont montré une plus faible représentation de chercheuses tant chez les BPD et les NC. Cette étude exploratoire met en lumière la pertinence d'approches de formation programmatique comme le KRESCENT pour soutenir et retenir les scientifiques féminines dans le domaine académique pendant la difficile période de transition entre le statut de boursière postdoctorale et celui de nouvelle chercheuse.

Change in Estimated GFR and Risk of Allograft Failure in Patients Diagnosed With Late Active Antibody-mediated Rejection Following Kidney Transplantation.

BACKGROUND: There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx). METHODS: We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up. RESULTS: A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of -0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of -9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years. CONCLUSIONS: If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR.

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients.

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66-0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66-0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = -0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.

The role of non-HLA antibodies in solid organ transplantation: a complex deliberation.

PURPOSE OF REVIEW: There is tremendous interest in understanding when, if, and how non-HLA antibodies contribute to allograft injury. Numerous non-HLA target antigens have been identified and sensitization to these targets have been associated with delayed allograft function, rejection, and allograft failure. This review focuses on the clinical utility of HLA antibody testing, highlighting the strengths and limitations of current clinical studies, and the need for defining characteristics to inform non-HLA antibody pathogenicity. RECENT FINDINGS: Clinical studies continue to show associations between non-HLA antibodies and rejection and reduced allograft survival across multiple transplanted organ types. The worst clinical outcomes continue to be observed among recipients testing positive for both non-HLA and donor-specific HLA antibodies. Mechanistic insights from both animal and clinical studies support a model in which tissue injury accompanied by an inflammatory environment influence non-HLA antibody formation and pathogenicity. SUMMARY: Immune triggers that lead to non-HLA antibody formation and pathogenicity are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their affinity and strength (titer), target specificity, density of the target antigen, and synergy with donor-specific HLA antibodies.

More precise donor-recipient matching: the role of eplet matching.

PURPOSE OF REVIEW: A precise understanding of the alloimmune risk faced by individual recipients at the time of transplant is an unmet need in transplantation. Although conventional HLA donor-recipient mismatch is too imprecise to fulfil this need, HLA molecular mismatch increases the precision in alloimmune risk assessment by quantifying the difference between donors and recipients at the molecular level. RECENT FINDINGS: Within each conventional HLA mismatch the number, type, and position of mismatched amino acids create a wide range of HLA molecular mismatches between recipients and donors. Multiple different solid organ transplant groups from across the world have correlated HLA molecular mismatch with transplant outcomes including de novo donor-specific antibody development, antibody-mediated rejection, T-cell-mediated rejection, and allograft survival. SUMMARY: All alloimmunity is driven by differences between donors and recipients at the molecular level. HLA molecular mismatch may represent an advancement compared to traditional HLA antigen mismatch as a fast, reproducible, cost-effective way to improve alloimmune risk assessment at the time of transplantation to move the field towards precision medicine.