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.

Access to and Health Outcomes of Pediatric Solid Organ Transplantation for Indigenous Children in 4 Settler-colonial Countries: A Scoping Review.

Solid organ transplantation (SOT) is considered the optimal treatment for children with end-stage organ failure; however, increased efforts are needed to understand the gap surrounding equitable access to and health outcomes of SOT for Indigenous children. This scoping review summarizes the literature on the characteristics of access to and health outcomes of pediatric SOT among Indigenous children in the settler-colonial states of Canada, Aotearoa New Zealand, Australia, and the United States. A search was performed on MEDLINE, EMBASE, PsycINFO, and CINAHL for studies matching preestablished eligibility criteria from inception to November 2021. A preliminary gray literature search was also conducted. Twenty-four studies published between 1996 and 2021 were included. Studies addressed Indigenous pediatric populations within the United States (n = 7), Canada (n = 6), Aotearoa New Zealand (n = 5), Australia (n = 5), and Aotearoa New Zealand and Australia combined (n = 1). Findings showed that Indigenous children experienced longer time on dialysis, lower rates of preemptive and living donor kidney transplantation, and disparities in patient and graft outcomes after kidney transplantation. There were mixed findings about access to liver transplantation for Indigenous children and comparable findings for graft and patient outcomes after liver transplantation. Social determinants of health, such as geographic remoteness, lack of living donors, and traditional spiritual beliefs, may affect SOT access and outcomes for Indigenous children. Evidence gaps emphasize the need for action-based initiatives within SOT that prioritize research with and for Indigenous pediatric populations. Future research should include community-engaged methodologies, situated within local community contexts, to inform culturally safe care for Indigenous children.

Measuring wellbeing: A scoping review of metrics and studies measuring medical student wellbeing across multiple timepoints.

PURPOSE: Studies have demonstrated poor mental health in medical students. However, there is wide variation in study design and metric use, impairing comparability. The authors aimed to examine the metrics and methods used to measure medical student wellbeing across multiple timepoints and identify where guidance is necessary. METHODS: Five databases were searched between May and June 2021 for studies using survey-based metrics among medical students at multiple timepoints. Screening and data extraction were done independently by two reviewers. Data regarding the manuscript, methodology, and metrics were analyzed. RESULTS: 221 studies were included, with 109 observational and 112 interventional studies. There were limited studies (15.4%) focused on clinical students. Stress management interventions were the most common (40.2%). Few (3.57%) interventional studies followed participants longer than 12 months, and 38.4% had no control group. There were 140 unique metrics measuring 13 constructs. 52.1% of metrics were used only once. CONCLUSIONS: Unique guidance is needed to address gaps in study design as well as unique challenges surrounding medical student wellbeing surveys. Metric use is highly variable and future research is necessary to identify metrics specifically validated in medical student samples that reflect the diversity of today's students.

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.

Baseline Ethical Principles and a Framework for Evaluation of Policies: Recommendations From an International Consensus Forum.

To maintain public trust and integrity in organ and tissue donation and transplantation (OTDT), policymakers, governments, clinical leaders, and decision-makers must ensure that policies proposed to increase donation and transplant activity satisfy baseline ethical principles established by international agreement, declaration, and resolution. This article describes the output of the Baseline Ethical Domain group of an international forum designed to guide stakeholders in considering these aspects of their system. Methods: This Forum was initiated by Transplant Québec and co-hosted by the Canadian Donation and Transplantation Program partnered with multiple national and international donation and transplantation organizations. The domain working group members included administrative, clinical, and academic experts in deceased and living donation ethics and 2 Patient, Family, and Donor partners. Identification of internationally accepted baseline ethical principles was done after literature reviews performed by working group members, and a framework for consideration of existing or novel policies was completed over a series of virtual meetings from March to September 2021. Consensus on the framework was achieved by applying the nominal group technique. Recommendations: We used the 30 baseline ethical principles described in World Health Organization Guiding Principles, Declaration of Istanbul, and Barcelona Principles to generate an ethical framework-presented graphically as a spiral series of considerations-designed to assist decision makers in incorporating these ethical principles into practice and policy. We did not seek to determine what is ethical but instead described a method of evaluation for policy decisions. Conclusions: The proposed framework could be applied to new or existing OTDT policy decisions to facilitate the transformation of widely accepted ethical principles into practical evaluations. The framework includes adaptation for local contexts and could be applied broadly internationally.

The unfinished journey toward transplant equity: an analysis of racial/ethnic disparities for children after the implementation of the Kidney Allocation System in 2014.

BACKGROUND: Disparities in pediatric kidney transplantation (KT) result in reduced access and worse outcomes for minority children. We assessed the impact of recent systems changes on these disparities. METHODS: This is a retrospective cohort study of pediatric patients utilizing data from the US Renal Data System (n = 7547) and Scientific Registry of Transplant Recipients (n = 6567 waitlisted and n = 6848 transplanted patients). We compared access to transplantation, time to deceased donor kidney transplant (DDKT), and allograft failure (ACGF) in the 5 years preceding implementation of the Kidney Allocation System (KAS) to the 5 years post-KAS implementation 2010-2014 vs. 2015-2019, respectively. RESULTS: Compared to the pre-KAS era, post-KAS candidates were more likely to be pre-emptively listed (26.8% vs. 38.1%, p < 0.001), pre-emptively transplanted (23.8% vs. 28.0%, p < 0.001), and less likely to have private insurance (35.6% vs. 32.3%, p = 0.01), but these were not uniform across racial groups. Compared to white children, Black and Hispanic children had a lower likelihood of transplant listing within 2 years of first dialysis service (aHR 0.590.670.76 and 0.730.820.92, respectively) in the post-KAS era. Time to DDKT was comparable across all racial groups in the post-KAS era. Compared to white children, Black DDKT recipients have more 5-year ACGF (aHR 1.001.432.06 p = 0.05) while there was no difference in 3- or 5-year ACGF among LDKT recipients. CONCLUSIONS: After KAS implementation, there is equity in time to DDKT. Pre-KAS increased hazard of ACGF among Black children has decreased in the post-KAS era; however, persistent disparities exist in time to transplant listing among Black and Hispanic children when compared to white children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Compassion fatigue in pediatric nephrology-The cost of caring.

Compassion fatigue is the result of repeated vicarious trauma from caring for those who have suffered. Although not well-researched in pediatric nephrology to date, there is reason to believe that it is a real and sustained threat to the pediatric nephrology workforce. Interventions aimed at individuals, the profession, and the organizations in which pediatric nephrologists work can create spaces to discuss and ameliorate compassion fatigue. This will result in better care for patients, more stable pediatric nephrology divisions and a stronger, more resilient pediatric nephrology workforce.

A scoping review of the experiences and well-being of siblings of children with chronic kidney disease: implications for practice and research.

BACKGROUND: Children with chronic kidney disease (CKD) and their families deal with challenging circumstances. While numerous studies have shown that both patients and parents in these families can experience a variety of challenges and concerns, the experience of siblings is less well understood. The focus of this scoping review was on research addressing the experiences and well-being of siblings of children with CKD. METHODS: Following scoping review methodology, five databases were searched for peer-reviewed research or graduate theses published in English that addressed the experience or well-being of siblings aged 25 years or younger (biological, step or foster) of children with CKD; studies from any year or location were included. Two independent coders identified relevant studies. Findings were summarized and synthesized. RESULTS: Of the 2990 studies identified, 19 were chosen for full text review and eight fit the inclusion criteria. Five of the selected studies were qualitative, two were quantitative and one used mixed-methods. Four broad themes across studies were identified including family functioning, significant relationships, psychological well-being, and coping strategies. While there was some convergence between qualitative and quantitative findings, these linkages were weak. CONCLUSIONS: Several unmet needs of siblings were uncovered by this review. Sibling perceptions of differential parental treatment and desire for information about CKD emerged as priorities for practice. Using a strength-based approach in order to better understand sibling experiences and well-being was also recommended for future research. A higher resolution version of the Graphical abstract is available as Supplementary information.

Considering a COVID-19 vaccine mandate for pediatric kidney transplant candidates.

The world continues to face the effects of the SARS-CoV-2 pandemic. COVID-19 vaccines are safe and effective in protecting recipients, decreasing the risk of COVID-19 acquisition, transmission, hospitalization, and death. Transplant recipients may be at greater risk for severe SARS-CoV-2 infection. As a result, transplant programs have begun instituting mandates for COVID-19 vaccine for transplant candidacy. While the question of mandating COVID-19 vaccine for adult transplant candidates has garnered attention in the lay and academic press, these discussions have not explicitly addressed children who may be otherwise eligible for kidney transplants. In this paper we seek to examine the potential ethical justifications of a COVID-19 vaccine mandate for pediatric kidney transplant candidacy through an examination of relevant ethical principles, analogous cases of the use of mandates, differences between adult and pediatric kidney transplant candidates, and the role of gatekeeping in transplant vaccine mandates. At present, it does not appear that pediatric kidney transplant centers are justified to institute a COVID-19 vaccine mandate for candidates. Finally, we will offer suggestions to be considered prior to the implementation of a COVID-19 vaccine mandate.

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.

The COVID-19 pandemic and organ donation and transplantation: ethical issues.

BACKGROUND: The COVID-19 pandemic has had a significant impact on the health system worldwide. The organ and tissue donation and transplantation (OTDT) system is no exception and has had to face ethical challenges related to the pandemic, such as risks of infection and resource allocation. In this setting, many Canadian transplant programs halted their activities during the first wave of the pandemic. METHOD: To inform future ethical guidelines related to the COVID-19 pandemic or other public health emergencies of international concern, we conducted a literature review to summarize the ethical issues. RESULTS: This literature review identified three categories of ethical challenges. The first one describes the general ethical issues and challenges reported by OTDT organizations and transplantation programs, such as risks of COVID-19 transmission and infection to transplant recipients and healthcare professionals during the transplant process, risk of patient waitlist mortality or further resource strain where transplant procedures have been delayed or halted, and resource allocation. The second category describes ethical challenges related to informed consent in the context of uncertainty and virtual consent. Finally, the third category describes ethical issues related to organ allocation, such as social considerations in selecting transplant candidates. CONCLUSION: This literature review highlights the salient ethical issues related to OTDT during the current COVID-19 pandemic. As medical and scientific knowledge about COVID-19 increases, the uncertainties related to this disease will decrease and the associated ethical issues will continue to evolve.

Canadian Society of Transplantation White Paper: Ethical and Legal Considerations for Alcohol and Cannabis Use in Solid Organ Listing and Allocation.

Alcohol and cannabis use as a contraindication to organ transplantation is a controversial issue. Until recently, patients in Canada with alcohol-associated liver disease were required to demonstrate abstinence for 6 mo to receive a liver transplant. There is no equivalent rule that is applied consistently for cannabis use. There is some evidence that alcohol and cannabis use disorder pretransplant could be associated with worse outcomes posttransplantation. However, early liver transplantation for patients with alcohol-associated liver disease in France and in the United States has led to challenges of the 6-mo abstinence rule in Canada in the media. It has also resulted in several legal challenges arguing that the rule violates human rights laws regarding discrimination in the provision of medical services and that the rule is also unconstitutional (this challenge is still before the court). Recent legalization of cannabis use for adults in Canada has led to questions about the appropriateness of limiting transplant access based on cannabis use. The ethics committee of the Canadian Society of Transplantation was asked to provide an ethical analysis of cannabis and alcohol abstinence policies. Our conclusions were as follows: neither cannabis use nor the 6-mo abstinence rule for alcohol use should be an absolute contraindication to transplantation, and transplant could be offered to selected patients, further research should be conducted to ensure evidence-based policies; and the transplant community has a duty not to perpetuate stigma associated with alcohol and cannabis use disorders.

Patient-reported outcome measures in pediatric solid organ transplantation: Exploring stakeholder perspectives on clinical implementation through qualitative description.

PURPOSE: Patient-reported outcome measures (PROMs) are standardized instruments used to collect data about the subjective assessment of medical care from the patient perspective. Implementing PROMs within pediatric clinical settings has gained increasing importance as health services prioritize patient-centred pediatric care. This study explores the perspectives of pediatric solid organ transplant patients, caregivers, and healthcare practitioners (HCPs) on implementing PROMs into clinical practice. METHODS: Qualitative description methods were used to elicit stakeholder perspectives. Semi-structured interviews were conducted across five Canadian transplant centres. Purposive sampling was used to obtain maximum variation across age, gender, and transplant program for all participants, as well as discipline for HCPs. RESULTS: The study included a total of 63 participants [patients (n = 20), caregivers (n = 22) and HCPs (n = 21)]. Nearly all participants endorsed the implementation of PROMs to enhance pediatric transplant clinical care. Three primary roles for PROMs emerged: (1) to bring a transplant patient's overall well-being into the clinical care conversation; (2) to improve patient communication and engagement; and, (3) to inform the practice of clinical pediatric transplant care. Insights for effective implementation included completing electronic PROMs remotely and prior to clinical appointments by patients who are eight to 10 years of age or older. CONCLUSIONS: This study contributes to current research that supports the use of PROMs in clinical pediatric care and guides their effective implementation into practice. Future directions include the development, usability testing, and evaluation of a proposed electronic PROM platform that will inform future research initiatives.

Biomarker implementation: Evaluation of the decision-making impact of CXCL10 testing in a pediatric cohort.

BACKGROUND: Children are at high risk for subclinical rejection, and kidney biopsy is currently used for surveillance. Our objective was to test how novel rejection biomarkers such as urinary CXCL10 may influence clinical decision-making to indicate need for a biopsy. METHODS: A minimum dataset for standard decision-making to indicate a biopsy was established by an expert panel and used to design clinical vignettes for use in a survey. Pediatric nephrologists were recruited to review the vignettes and A) estimate rejection risk and B) decide whether to biopsy; first without and then with urinary CXCL10/Cr level. Accuracy of biopsy decisions was then tested against the biopsy results. IRA was assessed by Fleiss Kappa (κ) for binary choice and ICC for probabilities. RESULTS: Eleven pediatric nephrologists reviewed 15 vignettes each. ICC of probability assessment for rejection improved from poor (0.28, P < .01) to fair (0.48, P < .01) with addition of CXCL10/Cr data. It did not, however, improve the IRA for decision to biopsy (K = 0.48 and K = 0.43, for the comparison). Change in clinician estimated probability of rejection with additional CXCL10/Cr data was correlated with CXCL10/Cr level (r2  = 0.7756, P < .0001). Decision accuracy went from 8/15 (53.3%) cases to 11/15 (73.3%) with CXCL10/Cr, although improvement did not achieve statistical significance. Using CXCL10/Cr alone would have been accurate in 12/15 cases (80%). CONCLUSION: There is high variability in decision-making on biopsy indication. Urinary CXCL10/Cr improves probability estimates for risk of rejection. Training may be needed to assist nephrologists in better integrate biomarker information into clinical decision-making.

Management of Pediatric Kidney Transplant Patients During the COVID-19 Pandemic: Guidance From the Canadian Society of Transplantation Pediatric Group.

PURPOSE OF THE PROGRAM: To provide guidance on the management of pediatric kidney transplant patients during the COVID-19 pandemic. SOURCES OF INFORMATION: Program-specific documents, preexisting, and related to COVID-19; documents from provincial, national, and international kidney transplant societies/agencies and organ procurement agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature. METHODS: Challenges in the care of pediatric kidney transplant patients during the COVID-19 pandemic were highlighted within the Canadian Society of Transplantation (CST) Pediatric Group. It identified pediatric kidney transplant nephrologists (including a pediatric nephrologist ethicist) across the country and formed a workgroup. The initial guidance document was drafted and members of the workgroup reviewed and discussed all suggestions in detail via e-mail and virtual meetings. Disagreements were resolved by consensus. The document was reviewed by the CST Kidney Transplant Working Group, by the Canadian Society of Nephrology (CSN) COVID-19 Rapid Response Team (RRT), and an infectious disease expert. The suggestions were presented at an interactive webinar sponsored by CSN in collaboration with the CST and Canadian Association of Pediatric Nephrologists (CAPN), and attended by pediatric kidney health care professionals for further peer input. Final revisions were made based on feedback received. CJKHD editors reviewed the parallel process peer review and edited the manuscript for clarity. KEY FINDINGS: We identified 8 key areas of pediatric kidney transplant care that may be affected by the COVID-19 pandemic: (1) transplant activity, (2) outpatient clinic activity, (3) monitoring, (4) multidisciplinary care, (5) medications (immunosuppression and others), (6) patient/family education/support, (7) school and employment, and (8) management of pediatric kidney transplant patients who are COVID-19 positive. We make specific suggestions for each of these areas. LIMITATIONS: A full systematic review of available literature was not undertaken for the sake of expediency in development of this guideline. There is a paucity of literature to support evidence-based recommendations at this time. Instead, these guidelines were formulated based on expert opinion derived from available knowledge/experience and are subject to the biases associated with this level of evidence. The parallel review process that was created to expedite the publication of this work may not be as robust as standard arms' length peer review processes. IMPLICATIONS: These recommendations are meant to serve as a guide to pediatric kidney transplant directors, clinicians, and administrators for providing the best patient care in the context of limited resources while protecting patients and health care providers wherever possible by limiting exposure to COVID-19. We recognize that recommendations may not be applicable to all provincial/local health authority practices and that they may not be delivered to all patients given the time and resource constraints affecting the individual provincial/local health jurisdiction.