Rita R. Alloway

Belatacept (BELA) pharmacokinetic (PK) studies informed dosing strategies used in phase 3 studies, where fixed mg/kg dosing compared a less intensive (LI) and more intensive (MI) regimen. The LI regimen was preferred due to a better risk/benefit profile. We compared PK parameters observed in the BELA Early Steroid Withdrawal Trial (BEST) with previous reports. BELA trough samples were analyzed using a validated quantitative enzyme‐linked immunoassay. Clearance (CL) was estimated with Bayesian estimation using a published BELA population PK model. Significantly higher CL was observed in subjects Trial Registration : ClinicalTrials.gov identifier: NCT 01729494

Background: LCPT (Envarsus XR (R)) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings. Material/Methods: Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as 375% agreement. Results: Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first -line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first -line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached. Conclusions: When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8⁺ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8⁺ T cell clonotypes (CD8_EXP). Gene expression of CD8_EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8_EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8_EXP into Jurkat 76 cells (TCR^–/–) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8_EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8_EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8_EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8_EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8⁺ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.

Background and objectives: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor–based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. Design, setting, participants, & measurements: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of 2 at 2 years. Results: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of 2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (PP=0.006; for belatacept/rATG versus tacrolimus/rATG, P2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample–proven acute rejection significantly higher. Clinical Trial registry name and registration number: Belatacept Early Steroid Withdrawal Trial, NCT01729494

Solid organ transplantation is a life‐saving procedure for patients with end‐stage organ disease. Over the past 70 years, tremendous progress has been made in solid organ transplantation, particularly in T‐cell‐targeted immunosuppression and organ allocation systems. However, humoral alloimmune responses remain a major challenge to progress. Patients with preexisting antibodies to human leukocyte antigen (HLA) are at significant disadvantages in regard to receiving a well‐matched organ, moreover, those who develop anti‐HLA antibodies after transplantation face a significant foreshortening of renal allograft survival. Historical therapies to desensitize patients prior to transplantation or to treat posttransplant AMR have had limited effectiveness, likely because they do not significantly reduce antibody levels, as plasma cells, the source of antibody production, remain largely unaffected. Herein, we will discuss the significance of plasma cells in transplantation, aspects of their biology as potential therapeutic targets, clinical challenges in developing strategies to target plasma cells in transplantation, and lastly, novel approaches that have potential to advance the field.

Significance Statement: Single-center trials and retrospective case series have reported promising outcomes transplanting kidneys from donors with hepatitis C virus (HCV) infection into HCV-negative recipients, although concerns remain about immunologic complications. In this first multicenter trial, 30 HCV-uninfected adults received a kidney from an HCV-viremic deceased donor and were cured of HCV with an 8-week regimen of coformulated glecaprevir and pibrentasvir initiated 2–5 days post-transplant. Three patients developed acute cellular rejection and three developed BK viremia near or >10,000 copies/ml that resolved after immunosupression reduction; none experienced severe adverse events associated with the antiviral treatment or HCV. Overall allograft function at 6 months was excellent. These findings demonstrate that HCV-viremic kidneys offer a valuable resource for transplantation and that donor-derived HCV can be effectively managed with early antiviral treatment. Background: Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. Methods: We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. Results: We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m² at 6 months. Conclusions: Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.