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.

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.

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.

Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-ß1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-ß1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-ß1-dependent effects on T cells.

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.

The Development of a Comprehensive Clinicopathologic Registry for Glomerular Diseases Using Natural Language Processing.

Background: Glomerulonephritis (GN) represents a common cause of chronic kidney disease, and treatment to slow or prevent progression of GN is associated with significant morbidity. Large patient registries have improved the understanding of risk stratification, treatment selection, and definitions of treatment response in GN, but can be resource-intensive, with incomplete patient capture. Objective: To describe the creation of a comprehensive clinicopathologic registry for all patients undergoing kidney biopsy in Manitoba, using natural language processing software for data extraction from pathology reports, as well as to describe cohort characteristics and outcomes. Design: Retrospective population-based cohort study. Setting: Tertiary care center in the province of Manitoba. Patients: All patients undergoing a kidney biopsy in the province of Manitoba from 2002 to 2019. Measurements: Descriptive statistics are presented for the most common glomerular diseases, along with outcomes of kidney failure and mortality for the individual diseases. Methods: Data from native kidney biopsy reports from January 2002 to December 2019 were extracted into a structured database using a natural language processing algorithm employing regular expressions. The pathology database was then linked with population-level clinical, laboratory, and medication data, creating a comprehensive clinicopathologic registry. Kaplan-Meier curves and Cox models were constructed to assess the relationship between type of GN and outcomes of kidney failure and mortality. Results: Of 2421 available biopsies, 2103 individuals were linked to administrative data, of which 1292 had a common glomerular disease. The incidence of yearly biopsies increased almost 3-fold over the study period. Among common glomerular diseases, immunoglobulin A (IgA) nephropathy was the most common (28.6%), whereas infection-related GN had the highest proportions of kidney failure (70.3%) and all-cause mortality (42.3%). Predictors of kidney failure included urine albumin-to-creatinine ratio at the time of biopsy (adjusted hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.24-1.65), whereas predictors of mortality included age at the time of biopsy (adjusted HR = 1.05, 95% CI = 1.04-1.06) and infection-related GN (adjusted HR = 1.85, 95% CI = 1.14-2.99, compared with the reference category of IgA nephropathy). Limitations: Retrospective, single-center study with a relatively small number of biopsies. Conclusions: Creation of a comprehensive glomerular diseases registry is feasible and can be facilitated through the use of novel data extraction methods. This registry will facilitate further epidemiological research in GN.

Contexte: La glomérulonéphrite (GN) est une cause courante d'insuffisance rénale chronique. Le traitement pour ralentir ou prévenir la progression de la GN est associé à une morbidité significative. Les vastes registres de patients ont permis de mieux comprendre la stratification des risques, la sélection du traitement et les définitions de la réponse au traitement en contexte de GN, mais ces registres exigent beaucoup de ressources et la saisie des données du patient peut être incomplète. Objectifs: Décrire, à l'aide d'un logiciel de traitement en langage naturel pour l'extraction des données des rapports pathologiques, la création d'un registre clinicopathologique complet pour tous les patients subissant une biopsie rénale au Manitoba, et décrire les caractéristiques et les résultats de la cohorte. Conception: Étude de cohorte rétrospective basée sur la population. Cadre: Centre de soins tertiaires de la province du Manitoba. Sujets: Tous les patients ayant subi une biopsie rénale entre 2002 et 2019 au Manitoba. Mesures: Des statistiques descriptives sont présentées pour les maladies glomérulaires les plus courantes, accompagnées des résultats d'insuffisance rénale et de mortalité pour les maladies individuelles. Méthodologie: Les données des rapports de biopsie sur un rein natif entre janvier 2002 et décembre 2019 ont été extraites d'une base de données structurée à l'aide d'un algorithme de traitement en langage naturel utilisant des expressions régulières. La base de données des pathologies a ensuite été reliée aux données cliniques, de laboratoire et de médicaments au niveau de la population, pour créer un registre clinicopathologique complet. Des courbes Kaplan-Meier et des modèles de Cox ont été construits pour évaluer la relation entre le type de GN et les résultats d'insuffisance rénale et de mortalité. Résultats: Des 2 421 biopsies réalisées, 2 103 concernaient des individus liés à des données administratives; de ceux-ci, 1 292 étaient atteints d'une maladie glomérulaire courante. L'incidence des biopsies annuelles a presque été multipliée par trois au cours de la période étudiée. Parmi les maladies glomérulaires courantes, la néphropathie à IgA était la plus fréquente (28,6 %). Les GN liées à une infection présentaient les proportions les plus élevées d'insuffisance rénale (70,3 %) et de mortalité toutes causes confondues (42,3 %). Les facteurs prédictifs de l'insuffisance rénale comprenaient le rapport albumine/créatinine urinaire au moment de la biopsie (rapport de risque corrigé [RRc]: 1,43; intervalle de confiance à 95 % [IC 95 %]: 1,24-1,65), alors que les facteurs prédictifs de la mortalité incluaient l'âge au moment de la biopsie (RRc: 1,05; IC 95 %: 1,04-1,06) et les GN liées à une infection (RRc: 1,85; IC 95 %: 1,14-2,99; par rapport à la catégorie de référence de la néphropathie à IgA). Limites: Étude rétrospective menée dans un seul centre sur un nombre relativement faible de biopsies. Conclusion: La création d'un registre complet des maladies glomérulaires est réalisable et peut être facilitée par l'utilisation de nouvelles méthodes d'extraction des données. Ce registre facilitera de futures recherches épidémiologiques sur la GN. Enregistrement de l'essai: ne s'applique pas, cette étude n'est pas un essai clinique.

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial.

BACKGROUND: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes. METHODS: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR. RESULTS: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06). CONCLUSIONS: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077).

Chronic kidney damage pathology score for systematic assessment of the non-neoplastic kidney tissue and prediction of post-operative renal function outcomes.

To establish a systematic histological assessment of non-neoplastic kidney (NNK) tissue at the time of nephrectomy to evaluate a patient's risk of developing post-operative renal dysfunction, a combined prospective pathologic assessment of the NNK and a retrospective clinical chart review was conducted. A blinded nephropathologist performed standardized assessment of glomerular sclerosis, tubulointerstitial fibrosis, arteriosclerosis, and hyaline arteriolosclerosis. Combined these formulated the chronic kidney damage pathology score (CKDPS). Multivariate logistic regression models were developed to assess the effect of CKDPS and other clinical factors on renal function up to 24 months following nephrectomy (partial or radical). 156 patients were included in the analysis with a median age of 60 years. 70% patients underwent radical nephrectomy. A history of hypertension and/or diabetes was present in 55.8% and 22.1%, respectively. Higher CKDPS (particularly glomerular global sclerosis and arteriosclerosis scores), radical nephrectomy, and reduced baseline estimated glomerular filtration rate (eGFR) were associated with worsening post-operative renal function outcomes. The systematic assessment of non-neoplastic kidney tissue at the time of renal surgery can help identify patients at risk of post-operative renal dysfunction. CKDPS represents a standardized and prognostically relevant histologic reporting system for non-neoplastic kidney tissue.

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.

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Two Cases of Sporadic Eosinophilic Solid and Cystic Renal Cell Carcinoma in Manitoba Population.

Two sporadic cases of eosinophilic solid and cystic renal cell carcinoma (ESC RCC), at our institution, are presented in this study to contribute to the growing literature on this novel renal neoplasm. The first patient was a 38-year-old female with two synchronous renal masses measuring 3.5 and 1.9 cm on preoperative imaging. The second patient was a 44-year-old female with an incidental renal mass measuring 4 cm. Both patients underwent uncomplicated radical nephrectomies. The 1.9 cm mass in the first patient was consistent with clear cell RCC. The dominant mass in the first patient and the tumor in the second patient had microscopic and macroscopic findings in keeping with ESC RCC including a tan appearance, abundant eosinophilic cytoplasm, and CK20+ and CK7- staining. Both patients had an uncomplicated course following surgery with no evidence of local recurrence or distant metastatic disease for 1 and 2 years for the first and second patient accordingly. These cases contribute to a growing body of literature regarding ESC RCC including, to our knowledge, the first reported case of synchronous ESC RCC and clear cell RCC. Further research about this novel renal neoplasm is needed.

Transplant Glomerulopathy: Importance of Ultrastructural Examination.

Background: Transplant glomerulopathy (TG) is a morphologic alteration in glomeruli of renal allografts, characterized by glomerular basement membrane reduplications. Summary: TG is associated with progressive chronic allograft dysfunction and proteinuria and is a diagnostic feature of chronic antibody-mediated rejection (ABMR) in patients positive for donor-specific antibodies, according to the Banff schema for renal allograft pathology. It is a definitive endpoint in clinical trials and interventional studies for ABMR, but the lesion can also occur in the absence of definitive alloimmune injury, as a consequence of chronic thrombotic microangiopathy, and in some cases in association with hepatitis C infection. This review discusses the pathophysiology and clinical presentation of TG, the diagnostic features by light microscopy, and focuses on the sequential ultrastructural stages of the lesion. The differential diagnosis of TG, and Banff grading of the lesion, are reviewed. Clinicopathological indications for performing routine ultrastructural examination of renal allograft biopsies are discussed. Key Messages: TG can be diagnosed at an early stage by electron microscopy, before histological features are apparent, emphasizing the importance of ultrastructural examination of renal allograft biopsies for an early diagnosis, when therapeutic intervention may be beneficial.

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.

Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell-mediated rejection in Canadian centers: Observations from the PROBE multicenter cohort study.

BACKGROUND: Early TCMR surveillance with protocol kidney biopsy is used differentially among pediatric kidney transplant centers. Little has been reported about actual center-based differences, and this variability may influence TCMR ascertainment, treatment, and monitoring more broadly. METHODS: Data from the PROBE multicenter study were used to identify patients from centers conducting ESB or LSIB. ESB was defined as >50% of patients having at least 1 surveillance biopsy in the first 9 months. Patients were compared for number of biopsies, rejection episodes, treatment, and follow-up monitoring. RESULTS: A total of 261 biopsies were performed on 97 patients over 1-2 years of follow-up. A total of 228 (87%) of biopsies were performed in ESB centers. Compared to LSIB centers, ESB centers had 7-fold more episodes of TCMR diagnosed on any biopsy [0.8 ± 1.2 vs 0.1 ± 0.4; P < .001] and a 3-fold higher rate from indication biopsies [0.3 ± 0.9 vs 0.1 ± 0.3; P = .04]. The proportion of rejection treatment varied based on severity: Banff borderline i1t1 (40%);>i1t1 and < Banff 1A (86%); and ≥ Banff 1A (100%). Biopsies for follow-up were performed after treatment in 80% of cases (n = 28) of rejection almost exclusively at ESB centers, with 17 (61%) showing persistence of TCMR (≥i1t1). CONCLUSIONS: Practice variation exists across Canadian pediatric renal transplant centers with ESB centers identifying more episodes of rejection. Additionally, treatment of Banff borderline is not universal and varies with severity regardless of center type. Lastly, follow-up biopsies are performed inconsistently and invariably show persistence of rejection.

Age and sex determine conversion from immediate-release to extended-release tacrolimus in a multi-center cohort of Canadian pediatric renal transplant recipients.

ER-Tac, taken once per day, is associated with improved adherence. This study examined the potential patient and clinical factors that influence clinicians to convert pediatric patients from immediate-release to ER-Tac. This prospective multi-center observational study followed Canadian pediatric kidney transplant recipients up to 5 years post-transplant. Cox Proportional Hazards Regression was used to examine the influence of factors on conversion to ER-Tac. Sixty-six participants were included in this analysis. For every additional year of age at the time of transplant, the likelihood of conversion was more than doubled (HR 2.54, CI 1.83, 3.54, P < 0.001). The impact of age reduced by three percent for every month after transplant (HR 0.97, CI 0.95, 0.98, P < 0.001). Girls were more likely to be converted than boys (HR 3.78, CI 1.35, 10.6, P 0.01). Adherence measures (MAM-MM and tacrolimus trough variability), individual barriers to adherence, renal function, HLA mismatch, and rejection were not significant predictors of conversion in the final regression model. ER-Tac was preferentially prescribed to older age and female patients. Female sex and adolescence are both associated with worse graft outcomes, but we found no link between individualized markers of adherence/graft risk and conversion. Clinicians appeared to be using demographic features to distinguish patients at perceived higher risk and converted accordingly, without a case-by-case evaluation of who is more susceptible to poor outcomes.

Langerhans Cell Histiocytosis Associated With Renal Cell Carcinoma Is a Neoplastic Process: Clinicopathologic and Molecular Study of 7 Cases.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.

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.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell-mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA-DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor-specific antibodies (P = .002). HLA-DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA-DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA-DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA-DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA-DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report.

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m2). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.