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ObjectivesWe sought to understand the demographic and clinical factors associated with variations in longitudinal antibody response following completion of two-dose regiment of BNT162b2 vaccination.DesignThis study is a 10-month longitudinal cohort study of healthcare workers and serially measured anti-spike protein IgG (IgG-S) antibody levels using mixed linear models to examine their associations with participant characteristics.SettingA large, multisite academic medical centre in Southern California, USA.ParticipantsA total of 843 healthcare workers met inclusion criteria including completion of an initial two-dose course of BNT162b2 vaccination, complete clinical history and at least two blood samples for analysis. Patients had an average age of 45±13 years, were 70% female and 7% with prior SARS-CoV-2 infection.ResultsVaccine-induced IgG-S levels remained in the positive range for 99.6% of individuals up to 10 months after initial two-dose vaccination. Prior SARS-CoV-2 infection was the primary correlate of sustained higher postvaccination IgG-S levels (partial R2=0.133), with a 1.74±0.11 SD higher IgG-S response (p

Kidney transplantation is the treatment of choice for patients with ESRD as it is associated with improved patient survival and better quality of life, especially in children. There are several barriers to a successful transplant including organ shortage, anatomic barriers, and immunologic barriers. One of the biggest immunologic barriers that precludes transplantation is sensitization, when patients have antibodies prior to transplantation, resulting in positive crossmatches with donor. 30%–40% of adult patients on the wait list are sensitized. There is a growing number of pediatric patients on the wait list who are sensitized. This poses a unique challenge to the pediatric transplant community. Therefore, attempts to perform desensitization to remove or suppress pathogenic HLA antibodies resulting in acceptable crossmatches, and ultimately a successful transplant, while reducing the risk of acute rejection, are much needed in these children. This review article aims to address the management of such patients both prior to transplantation, with strategies to overcome sensitization, and after transplantation with monitoring for allograft rejection and other complications. [ABSTRACT FROM AUTHOR]

Background: Tixagevimab−cilgavimab (Tix‐Cil) was authorized for prophylaxis against COVID‐19 in immunocompromised patients from December 2021 through January 2023. Real‐world effectiveness for solid organ transplant (SOT) recipients has been unclear. Methods: We enrolled 911 SOT recipients into a longitudinal COVID‐19 serology study, of whom 381 (42%) received ≥1 dose of Tix‐Cil. We collected and analyzed data on incident SARS‐CoV‐2 infections and antibody kinetics for all patients from January 2022 to March 2023, including periods dominated by Omicron BA and BQ subvariants. Results: Over 253 ± 131 days of follow‐up, there were 324 new‐onset SARS‐CoV‐2 infections: 117 (31%) in Tix‐Cil treated and 207 (39%) in Tix‐Cil untreated patients (p =.012). In analyses adjusting for demographic, clinical, and COVID‐19 exposure factors, any Tix‐Cil treatment was associated with lower infection risk (OR 0.52, 95% CI 0.27–0.96, p =.039) throughout the surveillance period including when more resistant BQ.1 and BQ.1.1 subvariants had emerged (12/1/2022 onwards). Among treated patients, receiving a Tix‐Cil dose was associated with substantial and sustained increase in anti‐spike IgG antibody and angiotensin‐converting enzyme 2 binding inhibition levels (Abbott Architect assay) that together also demonstrated association with lower infection risk (p =.042). During the full surveillance period, the frequency of infections requiring hospitalization was low overall (N = 26, 2.9% of the total cohort) and not significantly different between Tix‐Cil recipients (N = 12, 3.2% of treated patients) and non‐Tix‐Cil recipients (N = 14, 2.6% of untreated patients) with unadjusted p =.31 for between‐group difference. Conclusion: In a large cohort of SOT recipients, we found that Tix‐Cil reduced infection risk even amidst emergent Omicron subvariants. Additionally, the extent of measurable humoral response to Tix‐Cil may indicate relative effectiveness. Pre‐exposure monoclonal antibody therapy may represent a strategy that will continue to offer clinical benefit for immunocompromised persons who are known to derive limited protection from vaccinations. [ABSTRACT FROM AUTHOR]

Background: As COVID‐19‐positive donors are becoming more common, there is an increasing need for the transplant community to evaluate the safety and efficacy of organ transplant from a SARS‐CoV‐2‐infected donor. Methods: Here we describe outcomes of two pediatric kidney transplant recipients who were vaccinated against COVID‐19 and received their allograft from a SARS‐CoV‐2‐positive donor. Results: Both donors did not die from a COVID‐19‐related illness; the first donor had 1 week of COVID‐19 symptoms 4 weeks prior to donation and the second was asymptomatic. Donor 1 had a Ct of 33.4 at 3 days and Donor 2 with a Ct of 37.2 at 16 days prior to donation. The first recipient was positive for SARS‐CoV‐2 anti‐spike IgG on the day of transplant, but the second patient was negative and both patients received IVIg perioperatively. There was no evidence of SARS‐CoV‐2 transmission or compromised renal function at 86‐ and 80‐day post‐transplant, respectively. Conclusions: This case series suggests favorable short‐term outcomes with accepting SARS‐CoV‐2‐positive donors for pediatric renal transplantation, after thorough evaluation of the donor's risk for transmission, assessing the recipient's serologic status to SARS‐CoV‐2, and considering pre‐emptive measures to mitigate the risk for severe COVID‐19 should the recipient acquire donor‐derived SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Background The multiple mutations comprising the epsilon variant demonstrate the independent convergent evolution of severe acute respiratory syndrome coronavirus (SARS-CoV-2), with its spike protein mutation L452R present in the delta (L452R), kappa (L452R), and lambda (L452Q) variants. Methods Coronavirus disease 2019 (COVID-19) variants were detected in 1017 patients using whole-genome sequencing and were assessed for outcome and severity. The mechanistic effects of the epsilon versus non-epsilon variants were investigated using a multiomic approach including cellular response assays and paired cell and host transcriptomic and proteomic profiling. Results We found that patients carrying the epsilon variant had increased mortality risk but not increased hospitalizations (P <.02). Cells infected with live epsilon compared with non-epsilon virus displayed increased sensitivity to neutralization antibodies in all patients but a slightly protective response in vaccinated individuals (P <.001). That the epsilon SARS-CoV-2 variant is more infectious but less virulent is supported mechanistically in the down-regulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic messenger RNA processing with the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19–positive nasopharyngeal samples were transcriptomically profiled and revealed a differential innate immune response (P <.001) and an adjusted T-cell response in patients carrying the epsilon variant (P <.002). In fact, patients infected with SARS-CoV-2 and those vaccinated with the BNT162b2 vaccine have comparable CD4+/CD8+ T-cell immune responses to the epsilon variant (P <.05). Conclusions While the epsilon variant is more infectious, by altering viral processing, we showed that patients with COVID-19 have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated by this more transmissible variant in both vaccinated and unvaccinated patients. [ABSTRACT FROM AUTHOR]

A trial of felzartamab for the treatment of antibody-mediated rejection in kidney allografts showed promising results, but there were notable limitations in the study. The trial did not thoroughly examine interstitial fibrosis and tubular atrophy, which are important predictors of allograft failure. Additionally, the trial only included White and Asian patients, raising concerns about the potential adverse reactions in patients of African ancestry. Further research is needed to determine the efficacy of felzartamab in different racial groups and to better understand the mechanisms of fibrosis and tubular atrophy in kidney transplantation. [Extracted from the article]

Background: Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate endpoints, and for patient management as clinical decision support tools. However, the impact of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risk and noncompeting risk models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes., Methods: We included 11,046 kidney transplant recipients enrolled in 10 countries. We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox, Fine-Gray, and cause-specific Cox regression models. To this aim, we followed a detailed and transparent analytical framework for competing and noncompeting risk modelling, and carefully assessed the models' development, stability, discrimination, calibration, overall fit, clinical utility, and generalizability in external validation cohorts and subpopulations. More than 15 metrics were used to provide an exhaustive assessment of model performance., Results: Among 11,046 recipients in the derivation and validation cohorts, 1,497 (14%) lost their graft and 1,003 (9%) died with a functioning graft after a median follow-up post-risk evaluation of 4.7 years (IQR 2.7-7.0). The cumulative incidence of graft loss was similarly estimated by Kaplan-Meier and Aalen-Johansen methods (17% versus 16% in the derivation cohort). Cox and competing risk models showed similar and stable risk estimates for predicting long-term graft failure (average mean absolute prediction error of 0.0140, 0.0138 and 0.0135 for Cox, Fine-Gray, and cause-specific Cox models, respectively). Discrimination and overall fit were comparable in the validation cohorts, with concordance index ranging from 0.76 to 0.87. Across various subpopulations and clinical scenarios, the models performed well and similarly, although in some high-risk groups (such as donors over 65 years old), the findings suggest a trend towards moderately improved calibration when using a competing risk approach., Conclusions: Competing and noncompeting risk models performed similarly in predicting long-term kidney graft failure., (Copyright © 2024 by the American Society of Nephrology.)

Competing Interests: The author declares no funding or conflict of interest.

Exposure to HLA alloantigens through pregnancy, blood products, and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis/low-dose or high-dose intravenous Ig plus anti-CD20. However, these approaches are often unsuccessful because of the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B cells (B MEM ). This is especially significant for patients with a calculated panel reactive antibody of 99%-100%. Newer desensitization approaches, such as imlifidase (IgG endopeptidase), rapidly inactivate IgG molecules and create an antibody-free zone by cleaving IgG into F(ab'2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of B MEM and PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6 receptor (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of B MEM and PC donor-specific HLA antibody responses. Agents aimed at eliminating long-lived PCs (anti-CD38 and anti-B-cell maturation antigen×CD3) are likely to benefit highly HLA sensitized patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor IgG recycling will be important in desensitization. Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly HLA sensitized patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9 on-off ). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9 on-on Cadherin6 pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.