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The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy. [ABSTRACT FROM AUTHOR]

Summary: Background: Composite tissue allotransplantation of hand, facial and other tissues is now a clinical reality. The terminology, treatment principles, drug combinations, dosage schedules and mechanisms of the immunosuppression medications on which contemporary transplant surgery is based are unfamiliar to plastic surgeons and most healthcare providers outside the field of transplantation medicine. With this in mind, the purpose of this manuscript is to provide plastic surgeons with a comprehensive and understandable review of key immunological principles relevant to composite tissue allotransplantation. Methods: We present an overview of the immunological basis of composite tissue allotransplantation aimed at the plastic surgery readership, based on our own experience plus manuscripts sourced from MEDLINE, EMBASE, text books, ancient manuscripts and illustrations. Results: In this manuscript we provide the reader with a brief history of composite tissue allotransplantation (CTA), a concise description of the immunological terminology, treatment approaches, risks associated with immunosuppressive therapy, risk acceptance, and current research avenues relating to contemporary CTA. Conclusion: Today, as transplant and reconstructive surgeons join forces to move hand and facial tissue allotransplantation into the clinical arena, it is important that plastic surgeons have an understanding of the major immunological principles upon which this new treatment is based. [Copyright &y& Elsevier]

Renal transplantation in high-risk patients is a growing phenomenon. More patients are progressing to endstage renal failure, in the setting of an increased incidence of diabetes mellitus and cardiovascular disease. Current organ shortages and the use of more marginal donors have affected both patient and graft survival. Acute rejection has been minimised under modern immunosuppression; however, patient and long-term allograft outcomes have not improved concurrently. Specific understanding of donor, recipient and allograft variables associated with stratification of patients as 'high risk for renal transplantation' is necessary to facilitate appropriate peri- and post-transplant pharmacotherapy. Induction and maintenance immunosuppression choices are different for high-risk patients and must be made to ensure optimal immunosuppression, while limiting patient and allograft toxicity. [ABSTRACT FROM AUTHOR]

PURPOSE: Immunosuppression used in transplantation is associated with an increased incidence of various cancers. Although the incidence of colorectal cancer in transplant patients seems to be equal to nontransplant population, the effects of immunosuppression on patients who develop colorectal cancer are not well defined. The purpose of this study was to define the characteristics and survival patterns of transplant patients developing tie novo colorectal cancer. METHODS: The Israel Penn International Transplant Tumor Registry was queried for patients with cob rectal cancer. Analysis included patient demographics, age at transplantation and colorectal cancer diagnosis, tumor stage, and survival. Age and survival rates were compared to United States population-based cob rectal cancer statistics using the National Cancer Institute Surveillance Epidemiology and End Results database. RESULTS: A total of 150 transplant patients with de novo colorectal cancer were identified: 93 kidney, 29 heart, 27 liver, and 1 lung. Mean age at transplantation was 53 years. Age at transplantation and coborectab cancer diagnosis was not significant for gender, race, or stage of disease. Compared to National Cancer Institute Surveillance Epidemiology and End Results database, transplantation patients had a younger mean age at colorectal cancer diagnosis (58 vs. 70 years; P < 0.001), and a worse five-year survival (overall, 44 vs. 62 percent, P < 0.001; Dukes A&B, 74 vs. 90 percent, P < 0.001; Dukes C, 20 vs. 66 percent, P < 0.001; and Dukes D, 0 vs. 9 percent, P = 0.08). CONCLUSIONS: Transplant patients develop colorectal cancer at a younger age and exhibit worse five-year survival rates than the general population. These data suggest that chronic immunosuppression results in a more aggressive tumor biology. Frequent posttransplantation colorectal cancer screening program may be warranted. [ABSTRACT FROM AUTHOR]

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 (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP 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. [ABSTRACT FROM AUTHOR]

Our previous Multicenter Trial to Transplant HCV‐infected Kidneys (MYTHIC) observed that 100% of hepatitis C virus (HCV)‐uninfected patients who received a kidney from an HCV‐infected deceased donor were cured of HCV with an 8‐week regimen of glecaprevir and pibrentasvir (G/P) initiated 2–5 days after transplantation. Following acute and chronic infection with HCV, immune system perturbations have been reported to persist even after viral clearance. The aim of this study was to determine whether HCV viremic kidney recipients in the MYTHIC study experience sustained changes in the soluble inflammatory milieu associated with HCV infection. Among nine patients with HCV viremia at day 3 post‐kidney transplant (post‐KT D3), IP‐10, IL‐10, MIP‐1β, and IL‐8 were significantly elevated from baseline. However, over the subsequent visits, there was a rapid, dramatic reduction back to baseline levels. Among seven patients who were not HCV viremic at post‐KT D3, the cytokine levels did not significantly change. HCV‐uninfected patients who received a kidney from an HCV‐viremic deceased donor and were treated with early G/P experienced only transient alterations in the soluble inflammatory milieu. These data provide reassuring evidence that there appear to be no persistent cytokine disturbances with transient HCV viremia accompanying HCV donor positive/recipient negative kidney transplant. [ABSTRACT FROM AUTHOR]

African-American and elderly kidney transplant recipients ( KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus ( LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 ( LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection ( BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [−1.48% (−5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [−1.29% (−5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [−13.82% (−27.22%, −0.31%)] and KTR ≥65 [−13.46% (−25.27%, −0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR ≥65 years old. [ABSTRACT FROM AUTHOR]

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens ( HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti- HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis ( PP), immunoadsorption ( IA), intravenous immunoglobulins ( IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection ( AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/ PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg. [ABSTRACT FROM AUTHOR]

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost‐containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher‐quality evidence for high single‐dose rATG, and dose‐rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target‐attainment or on ideal‐body‐weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost‐saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high‐cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost‐burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient‐specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost‐saving initiatives in the transplant population. [ABSTRACT FROM AUTHOR]

Abstract: The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin‐based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end‐stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow‐up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non‐ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) Cmax, Tmax, AUC, and half‐life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti‐HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals. [ABSTRACT FROM AUTHOR]

Competing Interests: E.S.W. received research grants from Bristol-Myers Squibb and Sanofi, and honoraria. R.R.A. received research grants from Bristol-Myers Squibb, Sanofi, and Veloxis and honoraria. A.A.V. received consulting fees from NDA Partners. T.M. received honoraria from Astellas Pharma, Inc, and Chugai Pharmaceutical Co. Ltd. At the time of study conduct, S.T. was a full-time employee of the University of Cincinnati/University of Cincinnati Physicians. At the time of publication, S.T. was a full-time employee of Veloxis Pharmaceuticals. The other authors declare no conflicts of interest.

BACKGROUND LCPT (Envarsus XR®) 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 AND 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 ≥75% 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.

The role of the transplant pharmacist is recognized by transplant programs, governmental groups, and professional organizations as an essential part of the transplant multidisciplinary team. This role has evolved drastically over the last decade with the advent of major advances in the science of transplantation and the growth of the field, which necessitate expanded pharmacy services to meet the needs of patients. Data now exist within all realms of the phases of care for a transplant recipient regarding the utility and benefit of a solid organ transplant (SOT) pharmacist. Furthermore, governing bodies now have the opportunity to use Board Certification in Solid Organ Transplant Pharmacotherapy as a mechanism to identify and recognize specialty knowledge and expertise within the field of SOT pharmacotherapy. The purpose of this paper is to provide an overarching review of the current and future state of SOT pharmacy while also identifying major changes to the profession, forthcoming challenges, and expected areas of growth., Competing Interests: Declaration of Competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lisa Potter reports a relationship with Takeda Pharmaceuticals USA Inc that includes: board membership. Lisa Potter reports a relationship with Veloxis Pharmaceuticals Inc that includes: funding grants and speaking and lecture fees. David Taber reports a relationship with Veloxis Pharmaceuticals Inc that includes: board membership and funding grants. David Taber reports a relationship with Takeda Pharmaceuticals USA Inc that includes: funding grants. David Taber reports a relationship with Merk that includes: funding grants. David Taber reports a relationship with CareDx Inc that includes: funding grants. Rita Alloway reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Rita Alloway reports a relationship with Nobelpharma Co Ltd that includes: funding grants. Rita Alloway reports a relationship with National Institutes of Health that includes: funding grants. Rita Alloway reports a relationship with Veloxis Pharmaceuticals Inc that includes: board membership and speaking and lecture fees. Rita Alloway reports a relationship with Sanofi that includes: speaking and lecture fees. The authors A. B. Lichvar, M. M. Chandran, B. R. Crowther, C. T. Doligalski, and A. J. C. Martinez of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. The following authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. L. M. M. Potter reported serving as an advisory board member for Takeda in Dec 2021. E. A. Cohen reported serving for the speaker bureau of Veloxis that ended in Dec 2021 and receiving an investigator-initiated research grant from Veloxis Pharmaceuticals. D. J. Taber reported serving as a board member of the Veloxis grant and advisory board, Takeda grant, Merck grant, and CareDx grant. R. R. Alloway reported BMS, Nobelpharma, Thinker NEXT grant, Veloxis advisory board, Veloxis, and Sanofi speaker bureau., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34 + stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to "standard-of-care" at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up., Methods: The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival., Results: Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P  < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02-1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor., Conclusion: The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Introduction. While use of (hepatitis C virus) HCV-viremic kidneys may result in net benefit for the average end-stage kidney disease (ESKD) patient awaiting transplantation, patients may have different values for ESKD-related health states. Thus, the best decision for any individual may be different depending on the balance of these factors. Our objective was to explore the feasibility of sampling health utilities from hemodialysis patients in order to perform patient-specific decision analyses considering various transplantation strategies. Study Design. We assessed utilities on a convenience sample of hemodialysis patients for health states including hemodialysis, and transplantation with either an HCV-uninfected kidney or an HCV-viremic kidney. We performed patient-specific decision analyses using each patient's age, race, gender, dialysis vintage, and utilities. We used a Markov state transition model considering strategies of continuing hemodialysis, transplantation with an HCV-unexposed kidney, and transplantation with an HCV-viremic kidney and HCV treatment. We interviewed 63 ESKD patients from four dialysis centers (Dialysis Clinic Inc., DCI) in the Cincinnati metropolitan area. Results. Utilities for ESKD-related health states varied widely from patient to patient. Mean values were highest for -transplantation with an HCV-uninfected kidney (0.89, SD: 0.18), and were 0.825 (SD: 0.231) and 0.755 (SD: 0.282), respectively, for hemodialysis and transplantation with an HCV-viremic kidney. Patient-specific decision analyses indicated 37 (59%) of the 63 ESKD patients in the cohort would have a net gain in quality-adjusted life years from transplantation of an HCV-viremic kidney, while 26 would have a net loss. Conclusions. It is feasible to gather dialysis patients' health state utilities and perform personalized decision analyses. This approach could be used in the future to guide shared decision-making discussions about transplantation strategies for ESKD patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)