A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

Emerging phenotypes in kidney transplant rejection.

PURPOSE OF REVIEW: This review focuses on more recently emerging rejection phenotypes in the context of time post transplantation and the resulting differential diagnostic challenges. It also discusses how novel ancillary diagnostic tools can potentially increase the accuracy of biopsy-based rejection diagnosis. RECENT FINDINGS: With advances in reducing immunological risk at transplantation and improved immunosuppression treatment renal allograft survival improved. However, allograft rejection remains a major challenge and represent a frequent course for allograft failure. With prolonged allograft survival, novel phenotypes of rejection are emerging, which can show complex overlap and transition between cellular and antibody-mediated rejection mechanisms as well as mixtures of acute/active and chronic diseases. With the emerging complexity in rejection phenotypes, it is crucial to achieve diagnostic accuracy in the individual patient. SUMMARY: The prospective validation and adoption of novel molecular and computational diagnostic tools into well defined and appropriate clinical context of uses will improve our ability to accurately diagnose, stage, and grade allograft rejection.

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.

Banff Human Organ Transplant Consensus Gene Panel for the Detection of Antibody Mediated Rejection in Heart Allograft Biopsies.

The molecular refinement of the diagnosis of heart allograft rejection based on whole-transcriptome analyses faces several hurdles that greatly limit its widespread clinical application. The targeted Banff Human Organ Transplant gene panel (B-HOT, including 770 genes of interest) has been developed to facilitate reproducible and cost-effective gene expression analysis of solid organ allografts. We aimed to determine in silico the ability of this targeted panel to capture the antibody-mediated rejection (AMR) molecular profile using whole-transcriptome data from 137 heart allograft biopsies (71 biopsies reflecting the entire landscape of histologic AMR, 66 non-AMR control biopsies including cellular rejection and non-rejection cases). Differential gene expression, pathway and network analyses demonstrated that the B-HOT panel captured biologically and clinically relevant genes (IFNG-inducible, NK-cells, injury, monocytes-macrophage, B-cell-related genes), pathways (interleukin and interferon signaling, neutrophil degranulation, immunoregulatory interactions, endothelial activation) and networks reflecting the pathophysiological mechanisms underlying the AMR process previously identified in whole-transcriptome analysis. Our findings support the potential clinical use of the B-HOT-gene panel as a reliable proxy to whole-transcriptome analysis for the gene expression profiling of cardiac allograft rejection.

Finding the right context of use for molecular transplant diagnostics in kidney allograft biopsies.

Biopsy-based molecular diagnostics holds promise to increase diagnostic precision. In this issue of Kidney International, Beadle et al. describe a molecular classifier derived from the Banff Human Organ Transplant panel. This new molecular test specifically identifies biopsies associated with higher risk for allograft failure showing microvascular inflammation, but not considered diagnostic for antibody-mediated rejection by current Banff rules. This study marks a milestone toward defining a valuable context for use for biopsy-based molecular transplant diagnostics.

Progress toward Health System Readiness for Genome-Based Testing in Canada.

(1) Background: Genomic medicine harbors the real potential to improve the health and healthcare journey of patients, care provider experiences, and improve the health system efficiency-even reducing healthcare costs. There is expected to be an exponential growth in medically necessary new genome-based tests and test approaches in the coming years. Testing can also create scientific research and commercial opportunities beyond healthcare decision making. The purpose of this research is to generate a better understanding of Canada's state of readiness for genomic medicine, and to provide some insights for other healthcare systems. (2) Methods: A mixed-methods approach of a review of the literature and key informant interviews with a purposive sample of experts was used. The health system readiness was assessed using a previously published set of conditions. (3) Results: Canada has created some of the established conditions, but further action needs to be taken to improve the state of readiness for genome-based medicine. The important gaps to be filled are the need for linked information systems and data integration; evaluative processes that are timely and transparent; navigational tools for care providers; dedicated funding to facilitate rapid onboarding and support test development and proficiency testing; and broader engagement with innovation stakeholders beyond care providers and patients. These findings highlight the role of the organizational context, social influence, and other factors that are known to affect the diffusion of innovation within health systems.

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.

Diagnostic Potential of Minimally Invasive Biomarkers: A Biopsy-centered Viewpoint From the Banff Minimally Invasive Diagnostics Working Group.

With recent advances and commercial implementation of minimally invasive biomarkers in kidney transplantation, new strategies for the surveillance of allograft health are emerging. Blood and urine-based biomarkers can be used to detect the presence of rejection, but their applicability as diagnostic tests has not been studied. A Banff working group was recently formed to consider the potential of minimally invasive biomarkers for integration into the Banff classification for kidney allograft pathology. We review the existing data on donor-derived cell-free DNA, blood and urine transcriptomics, urinary protein chemokines, and next-generation diagnostics and conclude that the available data do not support their use as stand-alone diagnostic tests at this point. Future studies assessing their ability to distinguish complex phenotypes, differentiate T cell-mediated rejection from antibody-mediated rejection, and function as an adjunct to histology are needed to elevate these minimally invasive biomarkers from surveillance tests to diagnostic tests.

Quantitative scoring of progression in transplant glomerulopathy using digital pathology may be superior to Banff cg scoring.

Antibody-mediated rejection (ABMR) is a major cause of kidney allograft failure. Biopsy-based surrogate endpoints reflecting ABMR progression on sequential biopsies that predict long-term outcome offer the potential to make treatment trials for ABMR feasible. However, the Banff transplant glomerulopathy (TG) scoring system (chronic glomerular injury score [cg]) relies on relatively crude and arbitrary ordinal grades and has low inter-observer concordance that currently limits its usefulness as a surrogate endpoint for ABMR progression in clinical drug trials. Here, we describe and validate a novel quantitative method for quantifying progression of TG in ABMR. Using digital pathology in sequential biopsies from 75 patients at various stages of ABMR, we scored all capillaries in the most affected glomeruli for basement membrane duplication that were correlated with allograft function, outcome, Banff lesion scores, and gene expression. Our digital scoring reflected TG progression better than the categorical Banff cg score and correlated with Banff ABMR and chronicity lesions, but not transcript changes. In multivariate analysis, the delta change between biopsies with serum creatinine and mean percent duplicated glomerular basement membranes was significantly associated with graft loss. Neither the delta in any Banff lesion scores (including cg) nor in gene expression was associated with outcome. Receiver operating characteristic curve analysis showed that the digital pathology approach was superior to the conventional score for predicting graft failure. Thus, our digital pathology-based approach for scoring TG accurately assessed progression in TG. However, further validation as a potential surrogate endpoint in clinical trials for the treatment of ABMR is warranted.

2022 Joint Meeting On Transplantation: Canadian Society of Transplantation And Banff Foundation of Allograft Pathology.

The Canadian Society of Transplantation (CST) annual scientific meeting was held in Banff Alberta September 19-23, 2022. It provided a forum for the transplantation community to share ideas, leading practices, innovative science and educational content in transplant care. The meeting brought together members of the Banff Foundation for Allograft Pathology and the CST for a hybrid event, combining both in-person and virtual experiences, and helping the two societies reach a wider audience. With over 600 Canadian and International delegates attending, the 2022 Banff-CST Meeting received outstanding educational programming, but also rare opportunities to connect with transplantation professionals from all over the world.

Effective and Efficient Delivery of Genome-Based Testing-What Conditions Are Necessary for Health System Readiness?

Health systems internationally must prepare for a future of genetic/genomic testing to inform healthcare decision-making while creating research opportunities. High functioning testing services will require additional considerations and health system conditions beyond traditional diagnostic testing. Based on a literature review of good practices, key informant interviews, and expert discussion, this article attempts to synthesize what conditions are necessary, and what good practice may look like. It is intended to aid policymakers and others designing future systems of genome-based care and care prevention. These conditions include creating communities of practice and healthcare system networks; resource planning; across-region informatics; having a clear entry/exit point for innovation; evaluative function(s); concentrated or coordinated service models; mechanisms for awareness and care navigation; integrating innovation and healthcare delivery functions; and revisiting approaches to financing, education and training, regulation, and data privacy and security. The list of conditions we propose was developed with an emphasis on describing conditions that would be applicable to any healthcare system, regardless of capacity, organizational structure, financing, population characteristics, standardization of care processes, or underlying culture.

Seropositivity to SARS-CoV-2 in Alberta, Canada in a post-vaccination period (March 2021-July 2021).

BACKGROUND: The COVID-19 pandemic has necessitated the need to rapidly make public health decisions. We systematically evaluated SARS-CoV-2 seropositivity to understand local COVID-19 epidemiology and support evidence-based public health decision making. METHODS: Residual blood samples were collected for SARS-CoV-2 receptor binding domain (RBD) IgG testing over a 1-5 day period monthly from 26 February 2021-9 July 2021 from six clinical laboratories across the province of Alberta, Canada. Monthly crude and adjusted (for age and gender) seropositivity were calculated. Results were linked to provincial administrative, laboratory, and vaccine databases. RESULTS: 60,632 individual blood samples were tested. Vaccination data were available for 98.8% of samples. Adjusted RBD IgG positivity rose from 11.9% (95% confidence interval [CI] 11.9-12.0%) in March 2021 to 70.2% (95% CI 70.2-70.3%) in July 2021 (p < .0001). Seropositivity rose from 9.4% (95% CI 9.3-9.4%) in March 2021 to 20.2% (95% CI 20.1-20.2%) in July 2021 in unvaccinated Albertans. Unvaccinated seropositive individuals were from geographic areas with significantly (p < .001) lower median household income, lower proportion of married/common-law relationships, larger average household size and higher proportions of visible minorities compared to seronegative unvaccinated individuals. In July 2021, the age groups with the lowest and highest seropositivity in unvaccinated Albertans were those ≥80 years (12.0%, 95% CI 5.3-18.6%) and 20-29 years (24.2%, 95% CI 19.6-28.8%), respectively. Of seropositive unvaccinated individuals, 50.2% (95% CI 45.9-54.5%) had no record of prior SARS-CoV-2 molecular testing. CONCLUSIONS: Longitudinal surveillance of SARS-CoV-2 seropositivity with data linkage is valuable for decision-making during the pandemic.

Thirty years of the International Banff Classification for Allograft Pathology: the past, present, and future of kidney transplant diagnostics.

2021 marks the 30th anniversary of the original development of the Banff Classification of Kidney Allograft Pathology, when in August 1991 a group of pathologists and transplant clinicians led by Kim Solez and Lorraine Racusen met in Banff, Alberta, Canada, and established the first widely accepted criteria for the diagnosis of kidney transplant rejection and other lesions seen on kidney allograft biopsies. Since that time, Banff conferences have been held every 2 years at many sites around the world, resulting in several major revisions to the classification and expansion well beyond pure histopathology of kidney allografts to encompass other solid organ transplants, and with involvement of immunogeneticists, immunologists, other basic scientists, biostatisticians, and data scientists defining a very diverse and integrated Banff community. This approach with multidisciplinary international input, constantly incorporating new evidence from the scientific literature and from studies performed by Banff working groups while still maintaining the importance of a long-standing consensus process, has resulted in the Banff classification gaining overwhelming international acceptance as the main reference used for the scoring of kidney allograft biopsies in research studies, routine practice, and clinical trials. This review focuses on the major milestones in the development of the Banff classification of kidney allograft pathology and the evolution of the Banff process over the past 3 decades, with prospects for future advances and refinements.