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.

Increased volume of organ offers and decreased efficiency of kidney placement under circle-based kidney allocation.

The newest kidney allocation policy kidney allocation system 250 (KAS250) broadened geographic distribution while increasing allocation system complexity. We studied the volume of kidney offers received by transplant centers and the efficiency of kidney placement since KAS250. We identified deceased-donor kidney offers (N = 907,848; N = 36,226 donors) to 185 US transplant centers from January 1, 2019, to December 31, 2021 (policy implemented March 15, 2021). Each unique donor offered to a center was considered a single offer. We compared the monthly volume of offers received by centers and the number of centers offered before the first acceptance using an interrupted time series approach (pre-/post-KAS250). Post-KAS250, transplant centers received more kidney offers (level change: 32.5 offers/center/mo, P < .001; slope change: 3.9 offers/center/mo, P = .003). The median monthly offer volume post-/pre-KAS250 was 195 (interquartile range 137-253) vs. 115 (76-151). There was no significant increase in deceased-donor transplant volume at the center level after KAS250, and center-specific changes in offer volume did not correlate with changes in transplant volume (r = -0.001). Post-KAS250, the number of centers to whom a kidney was offered before acceptance increased significantly (level change: 1.7 centers/donor, P < .001; slope change: 0.1 centers/donor/mo, P = .014). These findings demonstrate the logistical burden of broader organ sharing, and future allocation policy changes will need to balance equity in transplant access with the operational efficiency of the allocation system.

Association of transplant center market concentration and local organ availability with deceased donor kidney utilization.

Although there is a shortage of kidneys available for transplantation, many transplantable kidneys are not procured or are discarded after procurement. We investigated whether local market competition and/or organ availability impact kidney procurement/utilization. We calculated the Herfindahl-Hirschman Index (HHI) for deceased donor kidney transplants (2015-2019) for 58 US donation service areas (DSAs) and defined 4 groups: HHI ≤ 0.32 (high competition), HHI = 0.33-0.51 (medium), HHI = 0.53-0.99 (low), and HHI = 1 (monopoly). We calculated organ availability for each DSA as the number kidneys procured per incident waitlisted candidate, grouped as: <0.42, 0.42-0.69, >0.69. Characteristics of procured organs were similar across groups. In adjusted logistic regression, the HHI group was inconsistently associated with composite export/discard (reference: high competition; medium: OR 1.16, 95% CI 1.11-1.20; low 1.01, 0.96-1.06; monopoly 1.19, 1.13-1.26) and increasing organ availability was associated with export/discard (reference: availability <0.42; 0.42-0.69: OR 1.35, 95% CI 1.30-1.40; >0.69: OR 1.83, 95% CI 1.73-1.93). When analyzing each endpoint separately, lower competition was associated with higher export and only market monopoly was weakly associated with lower discard, whereas higher organ availability was associated with export and discard. These results indicate that local organ utilization is more strongly influenced by the relative intensity of the organ shortage than by market competition between centers.

Kidney nonprocurement in deceased donors with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in deceased organ donors and is associated with high rates of kidney discard by transplant centers. High discard rates may consequently drive nonprocurement of these kidneys by organ procurement organizations. We aimed to study the relationship between donor AKI and kidney nonprocurement. METHODS: Using U.S. registry data, we identified donors with at least one organ recovered from 2008 to 2018. We compared characteristics of donors with no kidneys procured across AKI stages, and used multivariable logistic regression to evaluate the relationship between AKI severity and kidney nonprocurement. RESULTS: Overall 14 543 kidneys from 7620 donors were not procured, among which 93% were from donors with AKI. For 6945 donors with no kidneys procured but an extrarenal organ recovered, most had stage 3 (51%), followed by stage 1 (27%) and stage 2 AKI (15%). Nonprocured stage 3 donors were the youngest and had the lowest Kidney Donor Risk Index of all nonprocured donors. Adjusted odds of kidney nonprocurement were 1.14 (95%CI 1.02-1.27) for stage 1, 1.25 (95%CI 1.12-1.41) for stage 2, and 10.37 (95%CI 9.30-11.56) for stage 3 donors, compared to non-AKI donors. Among donors with minimum creatinine <1.5 mg/dl, stage 2 and 3 AKI were still associated with significantly higher odds of nonprocurement. CONCLUSIONS: AKI severity is a strong risk factor for kidney nonprocurement. Efforts to address the organ shortage should focus on encouraging procurement and utilization of kidneys from deceased donors with severe AKI, given the large and rising prevalence of donor AKI and excellent transplant outcomes with these kidneys.

Patients with High Priority for Kidney Transplant Who Are Not Given Expedited Placement on the Transplant Waiting List Represent Lost Opportunities.

BACKGROUND: Kidney transplantation is associated with the best outcomes for most patients with ESKD. The national Kidney Allocation System prioritizes patients with Estimated Post-Transplant Survival (EPTS) scores in the top 20% for expedited access to optimal deceased donor kidneys. METHODS: We studied adults aged ≥18 years in the United States Renal Data System with top 20% EPTS scores who had been preemptively waitlisted or initiated dialysis in 2015-2017. We evaluated time to waitlist placement, transplantation, and mortality with unadjusted and multivariable survival models. RESULTS: Of 42,445 patients with top 20% EPTS scores (mean age, 38.0 years; 57% male; 59% White patients, and 31% Black patients), 7922 were preemptively waitlisted. Among 34,523 patients initiating dialysis, the 3-year cumulative waitlist placement incidence was 37%. Numerous factors independently associated with waitlisting included race, income, and having noncommercial insurance. For example, waitlisting was less likely for Black versus White patients, and for patients in the lowest-income neighborhoods versus those in the highest-income neighborhoods. Among patients initiating dialysis, 61% lost their top 20% EPTS status within 30 months versus 18% of patients who were preemptively listed. The 3-year incidence of deceased and living donor transplantation was 5% and 6%, respectively, for patients who initiated dialysis and 26% and 44%, respectively, for patients who were preemptively listed. CONCLUSIONS: Many patients with ESKDqualifying with top 20% EPTS status are not placed on the transplant waiting list in a timely manner, with significant variation on the basis of demographic and social factors. Patients who are preemptively listed are more likely to receive benefits of top 20% EPTS status. Efforts to expedite care for qualifying candidates are needed, and automated transplant referral for patients with the best prognoses should be considered. PODCAST: This article contains a podcast athttps://www.asn-online.org/media/podcast/JASN/2021_07_30_JASN2020081146.mp3.

Greater complexity and monitoring of the new Kidney Allocation System: Implications and unintended consequences of concentric circle kidney allocation on network complexity.

The deceased donor kidney allocation system in the United States has undergone several rounds of iterative changes, but these changes were not explicitly designed to address the geographic variation in access to transplantation. The new allocation system, expected to start in December 2020, changes the definition of "local allocation" from the Donation Service Area to 250 nautical mile circles originating from the donor hospital. While other solid organs have adopted a similar approach, the larger number of both kidney transplant centers and transplant candidates is likely to have different consequences. Here, we discuss the incredible increase in complexity in allocation, discuss some of the likely intended and unintended consequences, and propose metrics to monitor the new system.

Febrile neutropenia after kidney transplantation.

Neutropenia is common after kidney transplant. There are few data on febrile neutropenia episodes (FNE) after kidney transplant. We studied FNE in a single-center retrospective cohort of 1682 kidney transplant recipients. Neutropenia (absolute neutrophil count [ANC] <1000) occurred in 32% and FNE in 3%. There were 56 FNE. Median time to FNE was 143 days, and median time from onset of neutropenia to onset of FNE was 5.5 days. The most common sources of infection were urine, blood, and lungs, and in 20% of FNE no source was identified. No infectious organism was identified in 46% of FNE, and opportunistic infections were uncommon. Patient survival was similar among those with and without FNE, but FNE was associated with increased death-censored graft failure (DCGF). Following FNE, acute rejection occurred in 31% and DCGF in 15%, often in the setting of persistent reduced immunosuppression. In conclusion, FNE are common after kidney transplant and are associated with inferior long-term outcomes.

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.

Kidney nonprocurement in solid organ donors in the United States.

There are limited data on the nonprocurement of kidneys from solid organ donors. Analysis of Standard Transplant Analysis and Research files was undertaken on all deceased donors in the United States with at least 1 solid organ recovered. From 2000 to 2018, 21 731 deceased donor kidneys (averaging 1144 kidneys per year) were not procured. No kidneys were procured from 8% of liver donors, 3% of heart donors, and 3% of lung donors. Compared to donors with all kidneys procured, those with none procured were older and more likely obese, black, hypertensive, diabetic, hepatitis C positive, smokers, Public Health Service - Increased Risk designated, deceased after cardiac death, or deceased after cerebrovascular accident. Although these donors had lower quality kidneys (median Kidney Donor Risk Index (interquartile range) 1.9 (1.0) vs 1.2 (0.7)), there was substantial overlap in quality between nonprocured and procured kidneys. Nearly one third of nonprocurements were attributed to donor history. Donors with elevated terminal creatinine likely resulting from acute kidney injury (AKI) had higher odds of kidney nonprocurement. Nonprocurement odds varied widely across Organ Procurement and Transplantation Network regions, with a positive correlation between donor kidney nonprocurements and kidney discards at the donation service area level. These findings suggest current discard rates underestimate the underutilization of deceased donor kidneys and more research is needed to optimize safe procurement and utilization of kidneys from donors with AKI.

Tocilizumab for severe COVID-19 in solid organ transplant recipients: a matched cohort study.

The safety and efficacy of tocilizumab for the treatment of severe respiratory symptoms due to COVID-19 remain uncertain, in particular among solid organ transplant (SOT) recipients. Thus, we evaluated the clinical characteristics and outcomes of 29 hospitalized SOT recipients who received tocilizumab for severe COVID-19, compared to a matched control group who did not. Among a total of 117 total SOT recipients hospitalized with COVID-19, 29 (24.8%) received tocilizumab. The 90-day mortality was significantly higher among patients who received tocilizumab (41%) compared to those who did not (20%, P = .03). When compared to control patients matched by age, hypertension, chronic kidney disease, and administration of high dose corticosteroids, there was no significant difference in mortality (41% vs 28%, P = .27), hospital discharge (52% vs 72%, P = .26), or secondary infections (34% vs 24%, P = .55). Among patients who received tocilizumab, there was also no difference in mortality based on the level of oxygen support (intubated vs not intubated) at the time of tocilizumab initiation. In this matched cohort study, tocilizumab appeared to be safe but was not associated with decreased 90-day mortality. Larger randomized studies are needed to identify whether there are subsets of SOT recipients who may benefit from tocilizumab for treatment of COVID-19.

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.

Treatment of borderline infiltrates with minimal inflammation in kidney transplant recipients has no effect on allograft or patient outcomes.

In 2005, the Banff committee expanded the "borderline changes" category to include lesions with minimal (<10%) inflammation: "i0" borderline infiltrates. Clinical significance and optimal treatment of i0 borderline infiltrates are not known. Data suggest that i0 borderline infiltrates may have a more favorable prognosis than borderline infiltrates with higher grades of interstitial inflammation. In this single-center, retrospective, observational study, we assessed 90 renal transplant recipients with i0 borderline infiltrates on biopsies indicated for graft dysfunction. We studied the impact of treatment with corticosteroids on allograft function, allograft survival, and patient survival. We found no differences between treated and untreated groups with respect to eGFR at 4 weeks and 6 months after biopsy. Follow-up biopsies, available in 67% of patients, were negative for rejection in almost half of all cases, regardless of treatment status. The frequencies of persistent borderline infiltrates (38%) and higher-grade T cell-mediated rejection (1A or greater, 14%) on follow-up biopsies were similar between the two groups. There were no differences in rejection-free allograft survival, death-censored graft failure, or patient mortality among treated vs non-treated i0 borderline patients. Our findings suggest that the natural history of i0 borderline infiltrates, in relatively low immunologic risk patients, is not affected by corticosteroid treatment.

Role of oestrogen and its receptors in HEV-associated feto-maternal outcomes.

BACKGROUND: Pregnant women infected with HEV develops adverse pregnancy outcomes like, abortions, intrauterine fetal death, still births, neonatal deaths, preterm delivery and maternal mortality. AIM: To correlate oestrogen and its receptors ESR1α and ESR2ß levels with HEV-associated feto-maternal outcomes. MATERIAL & METHODS: A total of 142 pregnant women with HEV infection and 142 pregnant controls were included in study from Department of Obstetrics & Gynaecology and Department of Medicine, Maulana Azad Medical College (MAMC) and associated Lok Nayak Hospital (LNH), New Delhi. Three millilitre of blood sample was collected in plain for quantification of oestrogen, and its receptors ESR1α and ESR2ß using commercially available third-generation ELISA kits. RESULTS: The levels of oestrogen, ESR1α and ESR2ß were considerably higher in HEV-infected pregnant women (20.11 ± 18.19 ng/mL, 10.58 ± 3.27 ng/mL, 10.42 ± 4.71 ng/mL respectively) than pregnant controls (11.74 ± 6.42 ng/mL, 9.11 ± 1.63 ng/mL, 9.01 ± 1.18 ng/mL respectively)(P < 0.0001). It was found that oestrogen levels were significantly higher in pregnant women infected with HEV who had preterm delivery, low birth weight babies and fetal loss (19.64 ± 17.60 ng/mL, 19.71 ± 17.63 ng/mL, 33.62 ± 23.20 ng/mL respectively) than who had full term delivery, average birth weight babies and live babies (11.71 ± 8.77 ng/mL, 11.99 ± 9.44 ng/mL, 16.58 ± 14.98 ng/mL respectively)(P < 0.05). A significant negative correlation was observed between baby birth weight and oestrogen levels in HEV-infected pregnant women. CONCLUSION: The high level of oestrogen plays an important role in preterm delivery, low birth weight babies and fetal mortality in pregnant women with HEV infection through placental dysfunction. Moreover, oestrogen level is a significant predictor for preterm delivery and maternal mortality and ESR2ß levels is a significant predictor for maternal mortality in pregnant women infected with HEV.

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.

Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts.

Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.