The John Charnley Award: The Impact of Human Leukocyte Antigen (HLA) Genotype on Bacterial Infection Rates and Successful Eradication in Total Hip Arthroplasty.

BACKGROUND: Genetics plays an important role in several medical domains, however, the influence of human leukocyte antigen (HLA) genotype on the development of periprosthetic joint infection (PJI) in total hip arthroplasty (THA) remains unknown. The primary aim of this study was to determine if HLA genotype is associated with the development of bacterial PJI in THA. Secondarily, we evaluated the association between HLA genotype and PJI treatment success. METHODS: A retrospective, matched, case-control study was performed using prospectively collected data from a single institution. A total of 49 patients who underwent primary THA were included, with a mean follow-up of 8.5 years (range, 4.2 to 12.9). The 23 cases (PJI) and 26 controls (no PJI) were matched for age, sex, follow-up, body mass index (BMI), primary diagnosis, and comorbidities (P > 0.05). High-resolution genetic analysis targeting 11 separate HLA loci was performed in all patients using serum samples. The HLA gene frequencies and carriage rates were determined and compared between cohorts. A subgroup analysis of PJI treatment success (18) and failure (5) was performed. Statistical significance was set at P = 0.10 for genetic analysis and at 0.05 for all other analyses. RESULTS: There were four HLA alleles that were significantly associated with the development of PJI. The 3 at-risk alleles included HLA-C*06:02 (OR [odds ratio] 5.25, 95% CI [confidence interval] 0.96 to 28.6, P = 0.064), HLA-DQA1*04:01 (P = 0.096), and HLA-DQB1*04:02 (P = 0.096). The single protective allele was HLA-C*03:04 (OR 0.12, 95% CI 0.01 to 1.10, P = 0.052). There were no specific HLA alleles that were associated with treatment success or failure. CONCLUSION: This study suggests that there are at-risk and protective HLA alleles associated with the development of PJI in THA. To our knowledge, this is the first study to demonstrate an association between patient HLA genotype and the development of PJI. A larger study of the subject matter is necessary and warranted.

Clinical relevance of HLA-DQ eplet mismatch and maintenance immunosuppression with risk of allosensitization after kidney transplant failure.

The optimal immunosuppression management in patients with a failed kidney transplant remains uncertain. This study analyzed the association of class II HLA eplet mismatches and maintenance immunosuppression with allosensitization after graft failure in a well characterized cohort of 21 patients who failed a first kidney transplant. A clinically meaningful increase in cPRA in this study was defined as the cPRA that resulted in 50% reduction in the compatible donor pool measured from the time of transplant failure until the time of repeat transplantation, death, or end of study. The median cPRA at the time of failure was 12.13% (interquartile ranges = 0.00%, 83.72%) which increased to 62.76% (IQR = 4.34%, 99.18%) during the median follow-up of 27 (IQR = 18, 39) months. High HLA-DQ eplet mismatches were significantly associated with an increased risk of developing a clinically meaningful increase in cPRA (p = 0.02) and de novo DQ donor-specific antibody against the failed allograft (p = 0.02). We did not observe these associations in patients with high HLA-DR eplet mismatches. Most of the patients (88%) with a clinically meaningful increase in cPRA had both a high DQ eplet mismatch and a reduction in their immunosuppression, suggesting the association is modified by immunosuppression. The findings suggest HLA-DQ eplet mismatch analysis may serve as a useful tool to guide future clinical studies and trials which assess the management of immunosuppression in transplant failure patients who are repeat transplant candidates.

Canadian Kidney Transplant Professionals' Perspectives on Precision Medicine and Molecular Matching in Kidney Allocation.

Background: Antibody-mediated rejection is an important cause of kidney transplant loss. A new strategy requiring application of precision medicine tools in transplantation considers molecular compatibility between donors and recipients and holds the promise of improved immunologic risk, preventing rejection and premature graft loss. The objective of this study was to gather Canadian transplant professionals' perspectives on molecular compatibility in kidney transplantation. Methods: Seventeen Canadian transplant professionals (14 nephrologists, 2 nurses, and 1 surgeon) participated in semistructured interviews in 2021. The interviews were digitally recorded, transcribed, and analyzed using the qualitative description approach. Results: Participants identified fair access to transplantation as the most important principle in kidney allocation. Molecular compatibility was viewed as a promising innovation. However, participants were concerned about increased waiting times, negative impact on some patients, and potential problems related to the adequacy of information explaining this new technology. To mitigate the challenges associated with molecular matching, participants suggested integrating a maximum waiting time for molecular-matched kidneys and expanding the program nationally/internationally. Conclusions: Molecular matching in kidney transplantation is viewed as a promising technology for decreasing the incidence of antibody-mediated rejection and improving graft survival. Further studies are needed to determine how to ethically integrate this technology into the kidney allocation algorithm.

Are patients with primary glomerular disease at increased risk of malignancy?

Over the past decade, several observational studies and case series have provided evidence suggesting a connection between glomerular diseases (GN) and the development of malignancies, with an estimated risk ranging from 5%-11%. These malignancies include solid organ tumors as well as hematologic malignancies such as lymphoma and leukemia. However, these risk estimates are subject to several sources of bias, including unmeasured confounding from inadequate exploration of risk factors, inclusion of GN cases that were potentially secondary to an underlying malignancy, misclassification of GN type, and ascertainment bias arising from an increased likelihood of physician encounters compared to the general population. Consequently, population-based studies that accurately evaluate the cancer risk in GN populations are lacking. While it is speculated that long-term use of immunosuppressive medications and GN disease activity measured by proteinuria and estimated glomerular filtration rate may be associated with cancer risk in patients with GN, the independent role of these risk factors remains largely unknown. The presence of these knowledge gaps could lead to (i) lack of awareness of cancer as a potential chronic complication of GN, (ii) under-utilization of routine screening practices in clinical care that allow early diagnosis and treatment of malignancies, and (iii) under-recognition of modifiable risk factors to decrease the risk of de novo malignancies over time. This review summarizes the current evidence on the risk of cancer in patients with GN, explores the limitations of prior studies, and discusses methodological challenges and potential solutions for obtaining accurate estimates of cancer risk and identifying modifiable risk factors unique to GN populations.

NephroCAGE-German-Canadian Consortium on AI for Improved Kidney Transplantation Outcome: Protocol for an Algorithm Development and Validation Study.

BACKGROUND: Recent advances in hardware and software enabled the use of artificial intelligence (AI) algorithms for analysis of complex data in a wide range of daily-life use cases. We aim to explore the benefits of applying AI to a specific use case in transplant nephrology: risk prediction for severe posttransplant events. For the first time, we combine multinational real-world transplant data, which require specific legal and technical protection measures. OBJECTIVE: The German-Canadian NephroCAGE consortium aims to develop and evaluate specific processes, software tools, and methods to (1) combine transplant data of more than 8000 cases over the past decades from leading transplant centers in Germany and Canada, (2) implement specific measures to protect sensitive transplant data, and (3) use multinational data as a foundation for developing high-quality prognostic AI models. METHODS: To protect sensitive transplant data addressing the first and second objectives, we aim to implement a decentralized NephroCAGE federated learning infrastructure upon a private blockchain. Our NephroCAGE federated learning infrastructure enables a switch of paradigms: instead of pooling sensitive data into a central database for analysis, it enables the transfer of clinical prediction models (CPMs) to clinical sites for local data analyses. Thus, sensitive transplant data reside protected in their original sites while the comparable small algorithms are exchanged instead. For our third objective, we will compare the performance of selected AI algorithms, for example, random forest and extreme gradient boosting, as foundation for CPMs to predict severe short- and long-term posttransplant risks, for example, graft failure or mortality. The CPMs will be trained on donor and recipient data from retrospective cohorts of kidney transplant patients. RESULTS: We have received initial funding for NephroCAGE in February 2021. All clinical partners have applied for and received ethics approval as of 2022. The process of exploration of clinical transplant database for variable extraction has started at all the centers in 2022. In total, 8120 patient records have been retrieved as of August 2023. The development and validation of CPMs is ongoing as of 2023. CONCLUSIONS: For the first time, we will (1) combine kidney transplant data from nephrology centers in Germany and Canada, (2) implement federated learning as a foundation to use such real-world transplant data as a basis for the training of CPMs in a privacy-preserving way, and (3) develop a learning software system to investigate population specifics, for example, to understand population heterogeneity, treatment specificities, and individual impact on selected posttransplant outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48892.

Validation of next-generation sequencing-based chimerism testing for accurate detection and monitoring of engraftment in hematopoietic stem cell transplantation.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for various hematological disorders. The success of allo-HSCT depends on the engraftment of donor cells and the elimination of recipient cells monitored through chimerism testing. We aimed to validate a next-generation sequencing (NGS)-based chimerism assay for engraftment monitoring and to emphasize the importance of including the most prevalent cell subsets in proficiency testing (PT) programs. We evaluated the analytical performance of NGS-based chimerism testing (AlloSeq-HCT and CareDx) with a panel of targeted 202 informative single-nucleotide polymorphisms (SNPs) (i.e., linearity and precision, analytical sensitivity and specificity, system accuracy, and reproducibility). We further compared the performance of our NGS panel with conventional short tandem repeat (STR) analysis in unfractionated whole blood and cell-subset-enriched CD3 and CD66. Our NGS-based chimerism monitoring assay has an impressive detection limit (0.3% host DNA) for minor alleles and analytical specificity (99.9%). Pearson's correlation between NGS- and STR-based chimerism monitoring showed a linear relationship with a slope of 0.8 and r = 0.973. The concordance of allo-HSCT patients using unfractionated whole blood, CD3, and CD66 was 0.95, 0.96, and 0.54, respectively. Utilization of CD3+ cell subsets for mixed chimerism detection yielded an average of 7.3 ± 7-fold higher donor percentage detection compared to their corresponding unfractionated whole blood samples. The accuracy of the NGS assay achieved a concordance of 98.6% on blinded external quality control STR samples. The reproducibility series showed near 100% concordance with respect to inter-assay, inter-tech, inter-instrument, cell flow kits, and AlloSeq-HCT software versions. Our study provided robust validation of NGS-based chimerism testing for accurate detection and monitoring of engraftment in allo-HSCT patients. By incorporating the cell subsets (CD3 and CD66), the sensitivity and accuracy of engraftment monitoring are significantly improved, making them an essential component of any PT program. Furthermore, the implementation of NGS-based chimerism testing shows potential to streamline high-volume transplant services and improve clinical outcomes by enabling early relapse detection and guiding timely interventions.

Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy.

Next-Generation Sequencing (NGS) has transformed clinical histocompatibility laboratories through its capacity to provide accurate, high-throughput, high-resolution typing of Human Leukocyte Antigen (HLA) genes, which is critical for transplant safety and success. As this technology becomes widely used for clinical genotyping, histocompatibility laboratories now have an increased capability to identify novel HLA alleles that previously would not be detected using traditional genotyping methods. Standard guidelines for the clinical verification and reporting of novelties in the era of NGS are greatly needed. Here, we describe the experience of a clinical histocompatibility laboratory's use of NGS for HLA genotyping and its management of novel alleles detected in an ethnically-diverse population of British Columbia, Canada. Over a period of 18 months, 3,450 clinical samples collected for the purpose of solid organ or hematopoietic stem cell transplantation were sequenced using NGS. Overall, 29 unique novel alleles were identified at a rate of ∼1.6 per month. The majority of novelties (52%) were detected in the alpha chains of class II (HLA-DQA1 and -DPA1). Novelties were found in all 11 HLA classical genes except for HLA-DRB3, -DRB4, and -DQB1. All novelties were single nucleotide polymorphisms, where more than half led to an amino acid change, and one resulted in a premature stop codon. Missense mutations were evaluated for changes in their amino acid properties to assess the potential effect on the novel HLA protein. All novelties identified were confirmed independently at another accredited HLA laboratory using a different NGS assay and platform to ensure validity in the reporting of novelties. The novel alleles were submitted to the Immuno Polymorphism Database-Immunogenetics/HLA (IPD-IMGT/HLA) for official allele name designation and inclusion in future database releases. A nationwide survey involving all Canadian HLA laboratories confirmed the common occurrence of novel allele detection but identified a wide variability in the assessment and reporting of novelties. In summary, a considerable proportion of novel alleles were identified in routine clinical testing. We propose a framework for the standardization of policies on the clinical management of novel alleles and inclusion in proficiency testing programs in the era of NGS-based HLA genotyping.

Regulatory T Cell Biomarkers Identify Patients at Risk of Developing Acute Cellular Rejection in the First Year Following Heart Transplantation.

BACKGROUND: Acute cellular rejection (ACR), an alloimmune response involving CD4+ and CD8+ T cells, occurs in up to 20% of patients within the first year following heart transplantation. The balance between a conventional versus regulatory CD4+ T cell alloimmune response is believed to contribute to developing ACR. Therefore, tracking these cells may elucidate whether changes in these cell populations could signal ACR risk. METHODS: We used a CD4+ T cell gene signature (TGS) panel that tracks CD4+ conventional T cells (Tconv) and regulatory T cells (Treg) on longitudinal samples from 94 adult heart transplant recipients. We evaluated combined diagnostic performance of the TGS panel with a previously developed biomarker panel for ACR diagnosis, HEARTBiT, while also investigating TGS' prognostic utility. RESULTS: Compared with nonrejection samples, rejection samples showed decreased Treg- and increased Tconv-gene expression. The TGS panel was able to discriminate between ACR and nonrejection samples and, when combined with HEARTBiT, showed improved specificity compared with either model alone. Furthermore, the increased risk of ACR in the TGS model was associated with lower expression of Treg genes in patients who later developed ACR. Reduced Treg gene expression was positively associated with younger recipient age and higher intrapatient tacrolimus variability. CONCLUSIONS: We demonstrated that expression of genes associated with CD4+ Tconv and Treg could identify patients at risk of ACR. In our post hoc analysis, complementing HEARTBiT with TGS resulted in an improved classification of ACR. Our study suggests that HEARTBiT and TGS may serve as useful tools for further research and test development.

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.

Clinical application of immune repertoire sequencing in solid organ transplant.

Background: Measurement of T cell receptor (TCR) or B cell receptor (BCR) gene utilization may be valuable in monitoring the dynamic changes in donor-reactive clonal populations following transplantation and enabling adjustment in therapy to avoid the consequences of excess immune suppression or to prevent rejection with contingent graft damage and to indicate the development of tolerance. Objective: We performed a review of current literature to examine research in immune repertoire sequencing in organ transplantation and to assess the feasibility of this technology for clinical application in immune monitoring. Methods: We searched MEDLINE and PubMed Central for English-language studies published between 2010 and 2021 that examined T cell/B cell repertoire dynamics upon immune activation. Manual filtering of the search results was performed based on relevancy and predefined inclusion criteria. Data were extracted based on study and methodology characteristics. Results: Our initial search yielded 1933 articles of which 37 met the inclusion criteria; 16 of these were kidney transplant studies (43%) and 21 were other or general transplantation studies (57%). The predominant method for repertoire characterization was sequencing the CDR3 region of the TCR ß chain. Repertoires of transplant recipients were found to have decreased diversity in both rejectors and non-rejectors when compared to healthy controls. Rejectors and those with opportunistic infections were more likely to have clonal expansion in T or B cell populations. Mixed lymphocyte culture followed by TCR sequencing was used in 6 studies to define an alloreactive repertoire and in specialized transplant settings to track tolerance. Conclusion: Methodological approaches to immune repertoire sequencing are becoming established and offer considerable potential as a novel clinical tool for pre- and post-transplant immune monitoring.

Patient and Caregiver Experience Decision Factors in Treatment Decision Making: Results of a Systematic Literature Review of Multiple Myeloma Decision Aids.

OBJECTIVES: Decision-aids (DAs) may facilitate shared decision-making for patients and caregivers, by providing evidence-based information to assist healthcare professionals, patients, and caregivers in making choices about aspects of care, and/or highlighting decision factors to discuss with the potential of altering the treatment decision. These decision factors may not be well integrated in DAs. METHODS: A systematic literature review was conducted in the field of multiple myeloma (MM) on peer-reviewed publications, extended with a gray literature search. Data on whether and how patient and caregiver experience elements, other than survival and physical quality of life, were mentioned as decision factors in the identified MM DAs were extracted and analyzed qualitatively. RESULTS: Seventy MM DAs were found and analyzed; 51% of DAs mentioned any patient non-routinely assessed experience decision factors and only 17% mentioned any caregiver-related information. One hundred and forty potential decision factors were extracted, deduplicated and categorized into the following categories: 1) financial, 2) mode of administration / transportation issues, 3) personal beliefs and values, 4) emotional and social quality of life, 5) other medical information, 6) availability of social support, 7) caregiver burden. None of the DAs presented a comprehensive framework on all seven categories of decision factors being consider when mapping patient and caregiver experience value elements in MM. CONCLUSIONS: Based on available DAs, we recommend a set of patient and caregiver experience decision factors that have the potential to affect treatment choices of patients with MM, which should be included in DAs, including MM clinical guidelines.

A Systematic Review of Kidney Transplantation Decision Modelling Studies.

BACKGROUND: Genome-based precision medicine strategies promise to minimize premature graft loss after renal transplantation, through precision approaches to immune compatibility matching between kidney donors and recipients. The potential adoption of this technology calls for important changes to clinical management processes and allocation policy. Such potential policy change decisions may be supported by decision models from health economics, comparative effectiveness research and operations management. OBJECTIVE: We used a systematic approach to identify and extract information about models published in the kidney transplantation literature and provide an overview of the status of our collective model-based knowledge about the kidney transplant process. METHODS: Database searches were conducted in MEDLINE, Embase, Web of Science and other sources, for reviews and primary studies. We reviewed all English-language papers that presented a model that could be a tool to support decision making in kidney transplantation. Data were extracted on the clinical context and modelling methods used. RESULTS: A total of 144 studies were included, most of which focused on a single component of the transplantation process, such as immunosuppressive therapy or donor-recipient matching and organ allocation policies. Pre- and post-transplant processes have rarely been modelled together. CONCLUSION: A whole-disease modelling approach is preferred to inform precision medicine policy, given its potential upstream implementation in the treatment pathway. This requires consideration of pre- and post-transplant natural history, risk factors for allograft dysfunction and failure, and other post-transplant outcomes. Our call is for greater collaboration across disciplines and whole-disease modelling approaches to more accurately simulate complex policy decisions about the integration of precision medicine tools in kidney transplantation.

Systematic literature review of health economic models developed for multiple myeloma to support future analyses.

AIMS: The goal of this study was to review the economic evaluations of health technologies in multiple myeloma (MM) and provide guidance and recommendations for future health economic analyses. MATERIALS AND METHODS: A systemic literature review (SLR) was conducted on original economic assessment studies and structured review papers focusing on the studies in MM. The search was limited to English language papers published from 1 January 2000 onwards. Publications not applying any type of modelling methodology to describe disease progression and patient pathways over a specific time horizon were excluded. RESULTS: A total of 2,643 publications were initially identified, of which 148 were eligible to be included in the full-text review phase. From these, 49 publications were included in the final analysis. Most published health economic analyses supported by models came from high-income countries. Evaluations from middle-income countries were rarely published. Diagnostic technologies were rarely modelled and integrated care had not been modelled. Very few models investigated MM treatments from a societal perspective and there was a relative lack of evaluations regarding minimal residual disease (MRD). LIMITATIONS: Limitations of the publications included differences between trial populations and modelled populations, justification of methods, lack of confounder analyses, and small trial populations. Limitations of our study included the infeasibility of comparing MM economic evaluations due to the significant variance in modelled therapeutic lines and indications, and the relative scarcity of published economic evaluations from non-high-income countries. CONCLUSIONS: As published economic models lacked many of the elements of the complex and heterogeneous patient pathways in MM and they focused on single decision problems, a thorough, open-source economic whole disease modelling framework is needed to assess the economic value of a wide range of technologies across countries with various income levels with a more detailed view on MM, by including patient-centric and societal aspects.

Viral load kinetics and the clinical consequences of cytomegalovirus in kidney transplantation.

Background: Despite advances in clinical management, cytomegalovirus (CMV) infection remains a serious complication and an important cause of morbidity and mortality following kidney transplantation. Here, we explore the importance of viral load kinetics as predictors of risk and potential guides to therapy to reduce transplant failure in a large longitudinal Genome Canada Transplant Consortium (GCTC) kidney transplant cohort. Methods: We examined the relationship between CMV infection rates and clinical characteristics, CMV viral load kinetics, and graft and patient outcomes in 2510 sequential kidney transplant recipients in the British Columbia Transplant Program. Transplants were performed between January 1, 2008, and December 31, 2018, were managed according to a standard protocol, and were followed until December 31, 2019, representing over 3.4 million days of care. Results: Longitudinal CMV testing was performed in 2464 patients, of whom 434 (17.6%) developed a first episode of CMV viremia at a median of 120 (range: 9-3906) days post-transplant. Of these patients, 93 (21.4%) had CMV viremia only and 341 (78.6%) had CMV viremia with clinical complications, of whom 21 (4.8%) had resulting hospitalization. A total of 279 (11.3%) patients died and 177 (7.2%) patients lost their graft during the 12 years of follow-up. Patients with CMV infection were at significantly greater risk of graft loss (p=0.0041) and death (p=0.0056) than those without. Peak viral load ranged from 2.9 to 7.0 (median: 3.5) log10 IU/mL, the duration of viremia from 2 to 100 (15) days, and the viral load area under the curve from 9.4 to 579.8 (59.7) log10 IU/mL × days. All three parameters were closely inter-related and were significantly increased in patients with more severe clinical disease or with graft loss (p=0.001). Duration of the first CMV viremic episode greater than 15 days or a peak viral load ≥4.0 log10 IU/mL offered simple predictors of clinical risk with a 3-fold risk of transplant failure. Conclusion: Viral load kinetics are closely related to CMV severity and to graft loss following kidney transplantation and provide a simple index of risk which may be valuable in guiding trials and treatment to prevent transplant failure.

Dissecting the impact of molecular T-cell HLA mismatches in kidney transplant failure: A retrospective cohort study.

Introduction: Kidney transplantation is the optimal treatment in end-stage kidney disease, but de-novo donor specific antibody development continues to negatively impact patients undergoing kidney transplantation. One of the recent advances in solid organ transplantation has been the definition of molecular mismatching between donors and recipients' Human Leukocyte Antigens (HLA). While not fully integrated in standard clinical care, cumulative molecular mismatch at the level of eplets (EMM) as well as the PIRCHE-II score have shown promise in predicting transplant outcomes. In this manuscript, we sought to study whether certain T-cell molecular mismatches (TcEMM) were highly predictive of death-censored graft failure (DCGF). Methods: We studied a retrospective cohort of kidney donor:recipient pairs from the Scientific Registry of Transplant Recipients (2000-2015). Allele level HLA-A, B, C, DRB1 and DQB1 types were imputed from serologic types using the NMDP algorithm. TcEMMs were then estimated using the PIRCHE-II algorithm. Multivariable Accelerated Failure Time (AFT) models assessed the association between each TcEMM and DCGF. To discriminate between TcEMMs most predictive of DCGF, we fit multivariable Lasso penalized regression models. We identified co-expressed TcEMMs using weighted correlation network analysis (WGCNA). Finally, we conducted sensitivity analyses to address PIRCHE and IMGT/HLA version updates. Results: A total of 118,309 donor:recipient pairs meeting the eligibility criteria were studied. When applying the PIRCHE-II algorithm, we identified 1,935 distinct TcEMMs at the population level. A total of 218 of the observed TcEMM were independently associated with DCGF by AFT models. The Lasso penalized regression model with post selection inference identified a smaller subset of 86 TcEMMs (56 and 30 TcEMM derived from HLA Class I and II, respectively) to be highly predictive of DCGF. Of the observed TcEMM, 38.14% appeared as profiles of highly co-expressed TcEMMs. In addition, sensitivity analyses identified that the selected TcEMM were congruent across IMGT/HLA versions. Conclusion: In this study, we identified subsets of TcEMMs highly predictive of DCGF and profiles of co-expressed mismatches. Experimental verification of these TcEMMs determining immune responses and how they may interact with EMM as predictors of transplant outcomes would justify their consideration in organ allocation schemes and for modifying immunosuppression regimens.

Beyond medicines' barriers: exploring the true cost of multiple myeloma.

AIM: The goal of this research was to quantify and qualify all the costs associated with multiple myeloma (MM) from a healthcare and societal perspective and to highlight certain costs that are often underestimated. MATERIALS AND METHODS: The study used a mixed methods approach that consisted of three phases: a systemic literature review (SLR), a virtual roundtable discussion based on the results of the SLR, and an online survey. RESULTS: In total, 4321 records were identified by literature and snowball searches. After applying the eligibility criteria, 49 articles were included in the narrative summary. As combination treatments have become the mainstay of MM treatment, drug costs have become the most important component of the total healthcare costs. Collected evidence suggests that optimizing treatment pathways, besides prolonging patient survival and maintaining quality of life, has the potential to generate cost savings for all stakeholders (payers and patients). Improved patient access to new therapies that can improve outcomes may reduce the "financial toxicity" of MM by decreasing patients' and caregivers' productivity loss due to better prognosis and it also has the potential of reducing patients' direct health care payments. LIMITATIONS: Heterogeneity of research objectives of included studies, costing methods, and applied measurement units limited the comparability of cost data between studies. Data for more than half of the world's population, including China, Russia, the Middle East, and Africa were not investigated. CONCLUSION: While treatment costs are burdensome for healthcare systems, it is only one of several items that make up the True Cost of MM. Understanding these burdens is one way to argue for optimized treatment pathways and improve patient outcomes by tearing down access barriers.

Comprehensive Immune Profiling of a Kidney Transplant Recipient With Peri-Operative SARS-CoV-2 Infection: A Case Report.

To date there is limited data on the immune profile and outcomes of solid organ transplant recipients who encounter COVID-19 infection early post-transplant. Here we present a unique case where the kidney recipient's transplant surgery coincided with a positive SARS-CoV-2 test and the patient subsequently developed symptomatic COVID-19 perioperatively. We performed comprehensive immunological monitoring of cellular, proteomic, and serological changes during the first 4 critical months post-infection. We showed that continuation of basiliximab induction and maintenance of triple immunosuppression did not significantly impair the host's ability to mount a robust immune response against symptomatic COVID-19 infection diagnosed within the first week post-transplant.

On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss.

INTRODUCTION: To mitigate risks related to human leukocyte antigen (HLA) incompatibility, we assessed whether certain structurally defined HLA targets present in donors but absent from recipients, known as eplet mismatches (EMM), are associated with death-censored graft failure (DCGF). METHODS: We studied a cohort of 118,313 American 0% panel reactive antibodies (PRA) first kidney transplant recipients (2000 to 2015) from the Scientific Registry of Transplant Recipients. Imputed allele-level donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were converted to the repertoire of EMM. We fit survival models for each EMM with significance thresholds corrected for false discovery rate and validated those in an independent PRA > 0% cohort. We conducted network-based analyses to model relationships among EMM and developed models to select the subset of EMM most predictive of DCGF. RESULTS: Of 412 EMM observed, 119 class I and 118 class II EMM were associated with DCGF. Network analysis showed that although 210 eplets formed profiles of 2 to 12 simultaneously occurring EMMs, 202 were singleton EMMs that were not involved in any profile. A variable selection procedure identified 55 single HLA class I and II EMMs in 70% of the dataset; of those, 15 EMMs (9 singleton and 6 involved in profiles) were predictive of DCGF in the remaining dataset. CONCLUSION: Our analysis distinguished increasingly smaller subsets of EMMs associated with increased risk of DCGF. Validation of these EMMs as important predictors of transplant outcomes (in contrast to acceptable EMMs) in datasets with measured allele-level genotypes will support their role as immunodominant EMMs worthy of consideration in organ allocation schemes.

Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury.

In kidney transplantation, the use of minimally invasive damage biomarkers that are more sensitive and specific than plasma creatinine will be crucial to enable early, actionable detection or exclusion of structural kidney damage due to acute or chronic rejection. Donor-derived cell-free DNA (dd-cfDNA), which can be quantified, for example, through next-generation sequencing, droplet digital PCR and quantitative PCR, is a candidate biomarker with great potential for enabling comprehensive monitoring of allograft injury. dd-cfDNA has a favourable overall diagnostic performance for the detection of rejection and its high negative predictive value might be especially useful for avoiding unnecessary biopsies. Elevated dd-cfDNA levels have been shown to be detectable before graft injury can be clinically identified using current diagnostic methods. Moreover, dd-cfDNA falls rapidly to baseline levels after successful treatment for rejection owing to its short half-life. dd-cfDNA can detect graft injury caused by immune activation owing to insufficient immunosuppression and might therefore also help guide immunosuppression dosing. The fractional abundance of dd-cfDNA can be affected by changes in the recipient cfDNA (for example, due to infection or physical exercise) but the use of absolute quantification of dd-cfDNA overcomes this limitation. Serial dd-cfDNA determinations might therefore facilitate cost-effective personalized clinical management of kidney transplant recipients to reduce premature graft loss.