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In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely "microvascular inflammation/injury donor-specific antibodies-negative and C4d negative" and "probable antibody-mediated rejection," into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell-mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell-mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft., Methods: We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function., Results: There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases., Conclusions: The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: From population studies, solid organ transplant recipients are at increased risk of mortality from RT-PCR confirmed COVID-19 infection. The risk factors associated with infection acquisition and mortality in transplant recipients using serological data have not been reported., Methods: From 1725 maintenance transplant recipients, 855 consecutive patients were screened for SARS-CoV-2 antibodies. Serological screening utilized assays to detect both the N protein and receptor binding domain antibodies. Thirty-three of 855 (3.9%) of the screened patients had prior infection confirmed with RT-PCR. Twenty-one additional patients from our 1725 maintenance cohort with RT-PCR confirmed infection were included in our analysis., Results: Eighty-nine of 855 (10.4%) patients tested positive for SARS-CoV-2 antibodies. Fifty-nine of 89 (66.3%) cases were patients newly identified as exposed, while 30/89 (33.7%) seropositive patients had previous infection confirmed by RT-PCR. A diagnosis of SARS-CoV-2 (RT-PCR or Ab+) was associated with being from a noncaucasoid background, P = 0.015; having a diagnosis of diabetes, P = 0.028 and a history of allograft rejection, P < 0.01. Compared with the RT-PCR+ cohort, patients with serological-proven infection alone were more likely to be receiving tacrolimus monotherapy, P < 0.01, and less likely to have a diagnosis of diabetes, P = 0.012. Seventeen of 113 (15.0%) of all patients with infection (RT-PCR and Ab+) died. Risk factors associated with survival were older age, odds ratio (OR): 1.07 (1.00-1.13), P = 0.041; receiving prednisolone, OR: 5.98 (1.65-21.60), P < 0.01 and the absence of diabetes, OR: 0.27 (0.07-0.99), P = 0.047., Conclusions: This study identifies risk factors and outcome for COVID-19 infection incorporating data on serologically defined infection and highlights the important contribution of immunosuppression regimen on outcomes., Competing Interests: The authors declare no funding and conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The risk of COVID-19 infection in transplant recipients (TRs) is unknown. Patients on dialysis may be exposed to greater risk of infection due to an inability to isolate. Consideration of these competing risks is important before restarting suspended transplant programs. This study compared outcomes in kidney and kidney/pancreas TRs with those on the waiting list, following admission with COVID-19 in a high-prevalence region., Methods: Audit data from all 6 London transplant centers were amalgamated. Demographic and laboratory data were collected and outcomes included mortality, intensive care (ITU) admission, and ventilation. Adult patients who had undergone a kidney or kidney/pancreas transplant, and those active on the transplant waiting list at the start of the pandemic were included., Results: One hundred twenty-one TRs and 52 waiting list patients (WL) were admitted to hospital with COVID-19. Thirty-six TR died (30%), while 14 WL patients died (27% P = 0.71). There was no difference in rates of admission to ITU or ventilation. Twenty-four percent of TR required renal replacement therapy, and 12% lost their grafts. Lymphocyte nadir and D-dimer peak showed no difference in those who did and did not die. No other comorbidities or demographic factors were associated with mortality, except for age (odds ratio of 4.3 [95% CI 1.8-10.2] for mortality if aged over 60 y) in TR., Conclusions: TRs and waiting list patients have similar mortality rates after hospital admission with COVID-19. Mortality was higher in older TRs. These data should inform decisions about transplantation in the COVID era., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: De novo DQ donor-specific antibody (DSA) are associated with antibody-mediated rejection and allograft loss. Given the lack of effective treatment of de novo DQ DSA, their prevention is vital if there is to be an improvement of long-term allograft survival. Using the HLA Matchmaker program, DQ epitope matching has been shown to be superior to HLA antigen mismatching in predicting de novo DQ DSA development. Whether DQ epitopes determined by Terasaki may more accurately predict de novo DQ development over HLA antigen matching is not known., Methods: We retrospectively analyzed the immunogenicity of the different HLA antigens, DQB1 alleles and DQB1 Teraskai epitopes (TerEp) in a large cohort of renal transplant recipients, by comparing patient mismatches with de novo DSA development., Results: Patients mismatched at a DQB1 allele were at significantly higher risk of developing de novo DSA compared with other mismatched HLA antigens. Patients mismatched at the DQ7 allele appear to be at specific risk. For patients mismatched at a single DQB1 allele, the risk of de novo DQ DSA development increases with the number of TerEp mismatches. However, the immunogenicity of the different DQ TerEps does not appear to be equal. Patients who develop antibodies against TerEps are at increased risk of adverse allograft outcomes, specifically antibody-mediated rejection., Conclusions: Epitope mismatch burden, determined by TerEps, helps predict risk of de novo DQ DSA development and offers an alternative approach to predict an alloimmune response.

Background: Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronic antibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basement membrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies (dnDSA) as an early marker to predict long-term antibody-mediated injury., Methods: This is a retrospective cohort study with 151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean number of BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development were estimated in survival analyses., Results: We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25 PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, in patients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a mean PTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation. The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score added significantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone., Conclusions: Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronic antibody-mediated injury.

Introduction: Microarray studies have shown elevated transcript levels of endothelial and natural killer (NK) cell-associated genes during antibody-mediated rejection (AMR) of the renal allograft. This study aimed to assess the use of quantitative real-time polymerase chain reaction as an alternative to microarray analysis on a subset of these elevated genes., Methods: Thirty-nine renal transplant biopsies from patients with de novo donor-specific antibodies and eighteen 1-year surveillance biopsies with no histological evidence of rejection were analyzed for expression of 11 genes previously identified as elevated in AMR., Results: Expression levels of natural killer markers were correlated to microcirculation inflammation and graft outcomes to a greater extent than endothelial markers. Creating a predictive model reduced the number of gene transcripts to be assessed to 2, SH2D1b and MYBL1, resulting in 66.7% sensitivity and 89.7% specificity for graft loss., Discussion: This work demonstrates that elevated gene expression levels, proposed to be associated with AMR, can be detected by established quantitative real-time polymerase chain reaction technology, making transition to the clinical setting feasible. Transcript analysis provides additional diagnostic information to the classification schema for AMR diagnosis but it remains to be determined whether significant numbers of centres will validate transcript analysis in their laboratories and put such analysis into clinical use.

Background: Mixed rejection in kidney transplantation consists of histologic and/or serological evidence of both cellular and humoral components. As it is not confined to a distinct category in the Banff classification, how to best manage these patients is not clear. The aim of this study was to determine the incidence and outcome of morphological T-cell-mediated rejection (TCMR) with a humoral component, defined as the presence of either DSA or C4d, compared with the outcome of pure TCMR., Methods: We retrospectively studied 922 consecutive renal transplant recipients and analyzed patients with TCMR according to the evidence of a humoral component., Results: A total of 147 cases of morphological TCMR were analyzed. Of these, 92 (62.6%) had "pure" TCMR and 55 (37.4%) had "mixed" TCMR on the index biopsy. On univariant analysis, diffuse C4d (odds ratio [OR]=10.9, 95% confidence interval [CI]=1.8-66.9, P=0.01) and DSA positivity at the time of index biopsy (OR=2.8, 95% CI=1.2-6.6, P=0.02) were associated with allograft loss, whereas arteritis (OR=0.5, 95% CI=0.2-1.2, P=0.11) and glomerulitis (OR=0.9, 95% CI=0.4-2.1, P=0.8) were not. Arteritis was associated with subsequent antibody-mediated rejection (OR=4.9, 95% CI=1.1-20.8, P=0.03), and glomerulitis was associated with the development of transplant glomerulopathy (OR=10.7, 95% CI=3.1-37.1, P<0.01). On the multivariate analysis, only patients with C4d and DSA were at risk of graft failure (OR=4.9, 95% CI=2.0-12.0, P<0.01) in the medium term., Conclusion: TCMR with a humoral component has a worse prognosis when compared with pure TCMR. As such, it is important to test for alloantibody in cases of morphological TCMR to optimize patient management. Such cases might benefit from more aggressive immunotherapy.

BACKGROUND.: Donor-specific anti-HLA antibodies (DSA) are a major cause of alloimmune injury. Transplant recipients with negative complement-dependent cytotoxic crossmatch (CDC-XM) and donor cell-based flow cytometric crossmatch (flow-XM) but low level DSA (i.e., by Luminex) have worse outcomes compared with nonsensitized patients. The aim of this study was to establish whether complement-activating ability in this low-level DSA, present before transplantation, as determined by this technique is important in dictating pathogenicity. METHODS.: We retrospectively studied 52 patients with preformed DSA detected by single-antigen flow cytometric fluorescent beads (SAFBs). Patients were transplanted using a steroid-sparing regimen consisting of alemtuzumab induction, 1 week of corticosteroids and tacrolimus monotherapy.Fifteen (29%) of 52 patients experienced antibody-mediated rejection (AMR), whereas 37 (71%) patients did not. There were no demographic differences between patients with AMR and those without. Pretransplant sera were retested using a modified (SAFB) assay, which detects the presence of the complement fragment C4d as a result of DSA-induced complement activation. RESULTS.: C4d+DSA were detected in 10 (19%) of 52 patients. Biopsy-proven AMR occurred in 7 (70%) of the 10 patients with C4d+DSA and in 8 (19%) of 42 patients with C4d-DSA. AMR-free survival was worse in patients with C4d+DSA (P<0.001). CONCLUSIONS.: The ability of preformed, low-level, DSA to trigger C4d fixation in vitro in patients with negative conventional crossmatch tests is predictive for AMR. C4d SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression.

Background: Chronic antibody-mediated rejection is an important cause of late graft failure. Developing an early marker of the disease may allow diagnosis and treatment before irreversible graft damage has occurred. The aim of this study was to assess whether, on electron microscopy examination, peritubular capillary (PTC) basement membrane multilayering precedes and predicts the development of transplant glomerulopathy (TG)., Methods: We used a vintage matched case-control method. Sixteen case-control pairs were created among all renal transplant patients from October 2005. Cases were patients who developed TG, and controls were patients with a late (>36 months) posttransplant (indication or surveillance) biopsy without TG. Electron microscopy was carried out on a biopsy taken earlier in the posttransplantation period for both cases and controls., Results: For every additional PTC of 25 examined with three or more layers in the early biopsy, the risk of having TG in the later biopsy was increased by 1.4-fold (95% confidence interval, 1.1-1.9; P=0.015). For every PTC of 25 with five or more layers, the risk was increased by 1.6-fold (95% confidence interval, 1.0-2.7; P=0.063). Thus, the risk of future TG increased substantially with every additional PTC of 25 showing multilayering in the early biopsy., Conclusions: Peritubular capillary basement membrane multilayering on electron microscopy is a useful marker of early chronic antibody-mediated damage, and information can be obtained by assessing PTC with three to four layers of basement membrane in addition to those with five or more layers. This finding must be validated in a prospective study.

Background: The importance of human leukocyte antigen (HLA) matching in renal transplantation is well recognized, with HLA-DR compatibility having the greatest influence. De novo DQ donor-specific antibodies (DSAbs) are the predominant HLA class II DSAb after transplantation. The aim of this study was to establish the incidence and outcomes after the development of DQ DSAbs along with the impact of class II HLA mismatch on their development., Methods: We retrospectively analyzed 505 patients who received a renal-alone transplant between 2005 and 2010. We excluded patients who received an ABO- and HLA-incompatible allograft, which we defined as those with a positive crossmatch or preformed DSAbs detected by single-antigen beads only., Results: Of 505 patients, 92 (18.2%) developed DSAbs, with 50 (54.3%) of these 92 patients having DQ DSAbs. Patients who developed DQ DSAbs were at significant risk for antibody-mediated rejection, transplant glomerulopathy, and allograft loss (P<0.0001). Of 505 patients, 108 (21.4%) were matched at both the DR and DQ loci, 284 (56.2%) were mismatched at both loci, 38 (7.5%) were matched at DR alone, and 75 (14.9%) were matched at DQ alone. Patients mismatched at both DR and DQ were at risk for developing class II DSAbs when compared with those mismatched at either DR or DQ alone, P=0.001, and were at risk for antibody-mediated rejection, P=0.001., Conclusions: DQ DSAbs are associated with inferior allograft outcomes. This study shows the importance of establishing the DQ match before transplantation to define immunologic risk.

Background: Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days., Methods: One hundred twenty-three live or deceased donor renal transplant recipients were randomized 2:1 to receive alemtuzumab/tacrolimus or daclizumab/tacrolimus/mycophenolate. The primary endpoint was survival with a functioning graft at 1 year., Results: Both regimens produced equivalent, excellent outcomes with the primary outcome measure of 97.6% in the alemtuzumab arm and 95.1% in the daclizumab arm at 1 year (95% confidence interval of difference 6.9% to -1.7%) and at 2 years 92.6% and 95.1%. Rejection was less frequent in the alemtuzumab arm with 1- and 2-year rejection-free survival of 91.2% and 89.9% compared with 82.3% and 82.3% in the daclizumab arm. There were no significant differences in terms of the occurrence of opportunistic infections., Conclusion: Alemtuzumab induction with tacrolimus maintenance monotherapy and short-course steroid use provides a simple, safe, and effective immunosuppressive regimen for renal transplantation.

Background: Antibody-mediated rejection (AMR) is associated with allograft loss. Identification of factors associated with poor outcome has not been extensively studied., Methods: We retrospectively studied 469 patients who received a negative crossmatch renal transplant with alemtuzumab induction. Forty-eight of 469 (10.2%) patients were treated for AMR. Thirty of 48 (62.5%) of the cases fulfilled the Banff criteria for definite AMR, whereas 18 of 48 (37.5%) were categorized as suspicious for AMR (tissue injury with C4d staining or donor-specific antibodies [DSAbs]). Sensitization, high human leukocyte antigen, and -DR mismatch were risk factors for the development of AMR (P = 0.0016, 0.001, and 0.012, respectively)., Results: Allograft survival was inferior in the AMR group (70.2%) compared with the nonrejector group (97.0%) (P<0.001). Forty-two of 48 (87.5%) of patients with acute AMR had DSAbs. Patients with CII DSAbs at the time of AMR, whether alone or in combination with CI DSAbs had the worst allograft survival (P = 0.014). Both the mean cumulative and immunodominant mean fluorescence index were higher in those patients who subsequently lost their grafts (P<0.001). Patients with diffuse C4d staining had inferior allograft survival than those with focal C4d or no staining (P = 0.02). There was no significant difference in survival by histological grade but a trend to inferior outcomes in those with vascular involvement (P = 0.06). Those patients who met the full Banff criteria had worse survival than those with suspicion for AMR only (P = 0.04)., Conclusion: This study identifies patients at risk of graft failure from AMR. These patients may benefit from newer therapeutic strategies including the use of eculizumab or bortezomib.