Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival.

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year making superiority trials unfeasible. IBOX, a quantitative composite of eGFR, proteinuria, anti-HLA DSA, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared to iBOX in a pooled cohort of 1534 kidney transplant recipients from four datasets, including two prospective randomized controlled trials. Discrimination analyses showed mean c-statistic differences between both iBOX compared to BPAR of 0.25 (95%CI: 0.17, 0.32) for full iBOX and 0.24 (95%CI: 0.16, 0.32) for abbreviated iBOX, indicating statistically significantly higher c-statistic values for the iBOX prognosis of death-censored graft survival. Mean (standard error) c-statistics were 0.81±0.03 for full iBOX, 0.80±0.03 for abbreviated iBOX, and 0.57±0.03 for BPAR. In calibration analyses, predicted graft loss events from both iBOX models were not significantly different from those observed. However, for BPAR, the predicted events were significantly (p<0.01) different (observed 64; predicted: 70 full iBOX; 76 abbreviated iBOX; 173 BPAR). IBOX at one-year post-transplant is superior to BPAR in the first year post-transplant in graft loss prognostic performance, providing valuable additional information facilitating the demonstration of superiority of novel immunosuppressive regimens.

A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

Effectiveness of mRNA Booster Vaccine Against Coronavirus Disease 2019 Infection and Severe Outcomes Among Persons With and Without Immune Dysfunction: A Retrospective Cohort Study of National Electronic Medical Record Data in the United States.

Background: Real-world evidence of coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) booster effectiveness among patients with immune dysfunction are limited. Methods: We included data from patients in the United States National COVID Cohort Collaborative (N3C) who completed ≥2 doses of mRNA vaccination between 10 December 2020 and 27 May 2022. Immune dysfunction conditions included human immunodeficiency virus infection, solid organ or bone marrow transplant, autoimmune diseases, and cancer. We defined incident COVID-19 BTI as positive results from laboratory tests or diagnostic codes 14 days after at least 2 doses of mRNA vaccination; and severe COVID-19 BTI as hospitalization, invasive cardiopulmonary support, and/or death. We used propensity scores to match boosted versus nonboosted patients and evaluated hazards of incident and severe COVID-19 BTI using Cox regression after matching. Results: Among patients without immune dysfunction, the relative effectiveness of booster (3 doses) after 6 months from the primary (2 doses) vaccination against BTI ranged from 69% to 81% during the Delta-predominant period and from 33% to 39% during the Omicron-predominant period. Relative effectiveness against BTI was lower among patients with immune dysfunction but remained statistically significant in both periods. Boosted patients had lower risk of COVID-19-related hospitalization (hazard ratios [HR] ranged from 0.5 [95% confidence interval {CI}, .48-.53] to 0.63 [95% CI, .56-.70]), invasive cardiopulmonary support, or death (HRs ranged from 0.46 [95% CI, .41-.52] to 0.63 [95% CI, .50-.79]) during both periods. Conclusions: Booster vaccines remain effective against severe COVID-19 BTI throughout the Delta- and Omicron-predominant periods, regardless of patients' immune status.

Impact of Centers for Medicare and Medicaid Services Final Rule on Organ Procurement Organization Metrics and Procedural Trends in the Procurement of Pancreata for Research.

OBJECTIVE: Pancreata recovered for research are included as a success (or positive) in the Centers for Medicare and Medicaid Services' (CMS) donation and organ transplantation rate metrics for recertification of organ procurement organizations (OPOs). MATERIALS AND METHODS: Given these metrics directly incentivize recovery of pancreata for research, this study tracks trends in recovery of pancreata for research across the implementation of the CMS metrics. RESULTS: In the 26 months before the December 2, 2020, publication of the CMS metrics, research pancreata as a percent of organs transplanted, including research pancreata, was 1.7% nationally, including as much as 10.8% of organs transplanted within any OPO. In the 26 months after the CMS metrics were published, research pancreata increased to 5.1% of organs counted as transplants nationally, including as much as 20.3% within any OPO. If research pancreata were excluded from the CMS metrics, 6 OPOs would change their CMS evaluation status for recertification purposes: 2 would move up a tier and 4 would move down a tier. CONCLUSIONS: Procurement of research pancreata has increased since the publication of the CMS performance metrics, OPOs vary in their recovery of pancreata for research, and recovery of pancreata for research can affect recertification of OPOs.

Advancing mouse models for transplantation research.

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs.

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.

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.

Prospective observational study to validate a next-generation sequencing blood RNA signature to predict early kidney transplant rejection.

The objective of this study was to validate the performance of Tutivia, a peripheral blood gene expression signature, in predicting early acute rejection (AR) post-kidney transplant. Recipients of living or deceased donor kidney transplants were enrolled in a nonrandomized, prospective, global, and observational study (NCT04727788). The main outcome was validation of the area under the curve (AUC) of Tutivia vs serum creatinine at biopsy alone, or Tutivia + serum creatinine at biopsy. Of the 151 kidney transplant recipients, the mean cohort age was 53 years old, and 64% were male. There were 71% (107/151) surveillance/protocol biopsies and 29% (44/151) for-cause biopsies, with a 31% (47/151) overall rejection rate. Tutivia (AUC 0.69 [95% CI: 0.59-0.77]) and AUC of Tutivia + creatinine at biopsy (0.68 [95% CI: 0.59-0.77]) were greater than the AUC of creatinine at biopsy alone (0.51.4 [95% CI: 0.43-0.60]). Applying a model cut-off of 50 (scale 0-100) generated a high- and low-risk category for AR with a negative predictive value of 0.79 (95% CI: 0.71-0.86), a positive predictive value of 0.60 (95% CI: 0.45-0.74), and an odds ratio of 5.74 (95% CI: 2.63-12.54). Tutivia represents a validated noninvasive approach for clinicians to accurately predict early AR, beyond the current standard of care.

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade.

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR.

The Impact of Ethnicity on Research Authorization at the Time of Organ Donation: A Single-Center Experience Among Deceased Donor Kidney Transplantation.

Objective: Research on deceased organ donors is needed to expand the donor organ supply. Little is known about the rate of research authorization among various groups. We aimed to determine the percentage of research authorization by the deceased donor family across different donor characteristics. Materials and Methods: We performed a retrospective review of deceased donors referred to one U.S. institution for kidney transplantation over a 12-month period. Organs were offered from multiple organ procurement organizations (OPO) across the United States. Stepwise logistic regression was performed to determine the predictors of research authorization. Results: From 10/2018 to 10/2019, 437 deceased donors were accepted for transplantation. 81.5% came from OPOs outside our donor service area and 18.5% from our local OPO. Overall, research authorization was declined in 24.0% of donors. Declined authorization was highest among Black donors (42.0%) compared to Whites (16.3%) and Hispanics (26.9%); p=0.000006. Donors <35 years had highest declined research authorization at 42.9% compared to older donors. There were no significant differences between individual OPOs. Conclusion: Deceased donor research authorization declined at the time of organ donation is higher among Black and younger donors. There is an immediate need for the transplant and donor community to develop best-practices to eliminate barriers to research in organ transplantation.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Sociodemographic Drivers of Donor and Recipient Gender Disparities in Living Kidney Donation in Australia.

Background: Females account for 60% of all living kidney donors worldwide. We defined the proportion of female to male donors for living donor kidney transplantation stratified by recipient gender, and explored the factors associated with female kidney donation. Methods: Data from the ANZDATA (Australian and New Zealand Dialysis and Transplantation) and ANZOD (Australian and New Zealand Organ Donor) registries (2002-2019) were used to identify the sociodemographic characteristics and their interactions associated with living donation from female donors. We derived the predicted probabilities from adjusted logistic models using marginal means. Results: Of 3523 living donor pairs, 2203 (63%) recipients were male, and 2012 (57%) donors were female. Male recipients were more likely to receive kidneys from female donors than male donors. Donor and recipient sex association was modified by donor-recipient relationship (P < 0.01), with sensitivity analysis suggesting that spousal donor-recipient pairs drive this interaction. Older recipients residing in regional or remote areas were more likely to receive kidneys from female donors compared with those from major cities (aged ≥60 years: 0.67 [0.63-0.71] vs. aged <60 years: 0.57 [0.53-0.60]). Conclusions: Factors associated with female donation include recipient sex, with spousal donors contributing to the interaction between recipient gender and donor-recipient relationship. Recipient age and location of residence have interactive effects on the likelihood of living donor transplantation from female donors.

Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

Hormone replacement therapy and COVID-19 outcomes in solid organ transplant recipients compared with the general population.

Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1135 SOTRs and 43 383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of major adverse renal or cardiac events (adjusted hazard ratio [aHR], 0.61; 95% confidence interval [CI], 0.57-0.65 for females; aHR, 0.70; 95% CI, 0.65-0.77 for males) and all secondary outcomes. In SOTR, HRT reduced the risk of acute kidney injury (aHR, 0.79; 95% CI, 0.63-0.98) and mortality (aHR, 0.49; 95% CI, 0.28-0.85) in males with COVID but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.