A Randomized Trial Comparing Imlifidase to Plasmapheresis in Kidney Transplant Recipients With Antibody-Mediated Rejection.

BACKGROUND: Antibody-mediated rejection (ABMR) poses a barrier to long-term graft survival and is one of the most challenging events after kidney transplantation. Removing donor specific antibodies (DSA) through therapeutic plasma exchange (PLEX) is a cornerstone of antibody depletion but has inconsistent effects. Imlifidase is a treatment currently utilized for desensitization with near-complete inactivation of DSA both in the intra- and extravascular space. METHODS: This was a 6-month, randomized, open-label, multicenter, multinational trial conducted at 14 transplant centers. Thirty patients were randomized to either imlifidase or PLEX treatment. The primary endpoint was reduction in DSA level during the 5 days following the start of treatment. RESULTS: Despite considerable heterogeneity in the trial population, DSA reduction as defined by the primary endpoint was 97% for imlifidase compared to 42% for PLEX. Additionally, imlifidase reduced DSA to noncomplement fixing levels, whereas PLEX failed to do so. After antibody rebound in the imlifidase arm (circa days 6-12), both arms had similar reductions in DSA. Five allograft losses occurred during the 6 months following the start of ABMR treatment-four within the imlifidase arm (18 patients treated) and one in the PLEX arm (10 patients treated). In terms of clinical efficacy, the Kaplan-Meier estimated graft survival was 78% for imlifidase and 89% for PLEX, with a slightly higher eGFR in the PLEX arm at the end of the trial. The observed adverse events in the trial were as expected, and there were no apparent differences between the arms. CONCLUSION: Imlifidase was safe and well-tolerated in the ABMR population. Despite meeting the primary endpoint of maximum DSA reduction compared to PLEX, the trial was unsuccessful in demonstrating a clinical benefit of imlifidase in this heterogenous ABMR population. TRIAL REGISTRATION: EudraCT number: 2018-000022-66, 2020-004777-49; ClinicalTrials.gov identifier: NCT03897205, NCT04711850.

The real unmet need: A multifactorial approach for identifying sensitized kidney candidates with low access to transplant.

BACKGROUND: At the start of 2020, the kidney waiting list consisted of 2526 candidates with a calculated panel reactive antibody (CPRA) of 99.9% or greater, a cohort demonstrated in published research to have meaningfully lower than average access to transplantation even under the revised kidney allocation system (KAS). METHODS: This was a retrospective analysis of US kidney registrations using data from the OPTN [Reference (https://optn.transplant.hrsa.gov/data/about-data/)]. The period-prevalent study cohort consisted of US kidney-alone registrations who waited at least 1 day between April 1, 2016, when HLA DQ-Alpha and DP-Beta unacceptable antigen data became available in OPTN data collection, to December 31, 2019. Poisson rate regression was used to model deceased donor kidney transplant rates per active year waiting and using an offset term to account for differential at-risk periods. Median time to transplant was estimated for each IRR group using the Kaplan-Meier method. Sensitivity analyses were included to address geographic variation in supply-to-demand ratios and differences in dialysis time or waiting time. RESULTS: In this study, we found 1597 additional sensitized (CPRA 50-<99.9%) candidates with meaningfully lower than average access to transplant when simultaneously taking into account CPRA and other factors. In combination with CPRA, candidate blood type, Estimated Post-Transplant Survival Score (EPTS), and presence of other antibody specificities beyond those in the current, 5-locus CPRA were found to influence the likelihood of transplant. CONCLUSION: In total, this suggests approximately 4100 sensitized candidates are on the waiting list who represent a community of disadvantaged patients who may benefit from progressive therapies and interventions to facilitate incompatible transplantation. Though associated with higher risks, such interventions may nevertheless be more attractive than remaining on dialysis with the associated accumulation of mortality risk over time.

Imlifidase for the treatment of anti-HLA antibody-mediated processes in kidney transplantation.

The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has therapeutic potential for HLA desensitization in kidney transplantation and antibody-mediated rejection. Data from clinical trials in kidney transplantation demonstrated rapid degradation of anti-HLA donor-specific antibodies facilitating HLA-incompatible transplantation, which led to conditional approval of imlifidase by the European Medicines Agency for desensitization in kidney transplant recipients of a deceased donor with a positive cross match. Important considerations arising from the early experiences with imilfidase on kinetics of donor-specific antibodies after administration, timing of complementary therapeutic monoclonal or polyclonal IgG antibodies, and interference with cross match assays should be recognized as imlifidase emerges as a therapeutic agent for clinical transplantation.

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

Transplant recipients are vulnerable to coverage denial under Medicare Part D.

Transplant immunosuppressants are often used off-label because of insufficient randomized prospective trial data to achieve organ-specific US Food and Drug Administration (FDA) approval. Transplant recipients who rely on Medicare Part D for immunosuppressant drug coverage are vulnerable to coverage denial for off-label prescriptions, unless use is supported by Centers for Medicare & Medicaid Services (CMS)-approved compendia. An integrated dataset including national transplant registry data and 3 years of dispensed pharmacy records was used to identify the prevalence of immunosuppression use that is both off-label and not supported by CMS-approved compendia. Numbers of potentially vulnerable transplant recipients were identified. Off-label and off-compendia immunosuppression regimens are frequently prescribed (3-year mean: lung 66.5%, intestine 34.2%, pancreas 33.4%, heart 21.8%, liver 16.5%, kidney 0%). The annual retail cost of these at-risk medications exceeds $30 million. This population-based study of transplant immunosuppressants vulnerable to claim denials under Medicare Part D coverage demonstrates a substantial gap between clinical practice, current FDA approval processes, and policy mandates for pharmaceutical coverage. This coverage barrier reduces access to life-saving medications for patients without alternative resources and may increase the risk of graft loss and death from medication nonadherence.

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients.

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

Meeting report: Consensus recommendations for a research agenda to address immunosuppressant nonadherence in organ transplantation.

Despite advances in the field of transplantation, immunosuppressant medication nonadherence (NA) remains a primary contributor to suboptimal long-term outcomes. Due to the multidimensional and multifactorial causes of medication NA, studies to date have focused on individual differing facets or single point barriers of NA with relative success. However, these successes have not proven to be sustainable, partly due to the intense resources needed for continued viability. This article provides a summary of a 2-day meeting held in April 2017 (Chicago, IL) prior to the American Transplant Congress in which a multidisciplinary group convened to identify the unmet research needs related to medication NA in transplantation. Thought leaders in the field presented the past, present, and future directions of medication NA with the primary outcome of designing, developing, and ranking targeted interventions into a dynamic research agenda to identify which interventions maintained effects over time. Break-out sessions were created based on the five World Health Organization (WHO) dimensions of adherence. Participants were then organized into the newly formed AST Transplant Pharmacy Adherence Consortium (AST TPAC) research group. This meeting report summarizes the content of the symposium, and the development, background, and future directions of the AST TPAC.

Racial differences in incident de novo donor-specific anti-HLA antibody among primary renal allograft recipients: results from a single center cohort study.

Controversy exists as to whether African American (AA) transplant recipients are at risk for developing de novo donor-specific anti-human leucocyte antigen (HLA) antibody (dnDSA). We studied 341 HLA-mismatched, primary renal allograft recipients who were consecutively transplanted between 3/1999 and 12/2010. Sera were collected sequentially pre- and post-transplant and tested for anti-HLA immunoglobulin G (IgG) via single antigen bead assay. Of the 341 transplant patients (225 AA and 116 non-AA), 107 developed dnDSA at a median of 9.2 months post-transplant. AA patients had a 5-year dnDSA incidence of 35%. This was significantly higher than the 5-year dnDSA incidence for non-AA patients (21%). DQ mismatch (risk) and receiving a living-related donor (LRD) transplant (protective) were transplant factors associated with dnDSA. Within the AA patient cohort, HLA-DQ mismatch, not-receiving a LRD transplant, nonadherence and BK viraemia were the most common factors associated with early dnDSA (occurring <24 months post-transplant). Nonadherence and pretransplant diabetes history were the strong precursors to late dnDSA. Despite the higher rates of dnDSA in the AA cohort, post-dnDSA survival was the same in AA and non-AA patients. This study suggests that DQ matching, increasing LRD transplantation in AA patients and minimizing under-immunosuppression will be key to preventing dnDSA.

Barriers to vaccination in renal transplant recipients.

Vaccine-preventable diseases remain at the forefront of challenges in the long-term care of renal transplant recipients (RTR). Although global vaccination campaigns targeting patients with end-stage renal disease or RTR are standard, rates of vaccination among renal transplant candidates and RTRs remain suboptimal. We highlight the multifactorial barriers leading to low vaccination rates in this vulnerable population.

Augmenting the Transplant Team With Artificial Intelligence: Toward Meaningful AI Use in Solid Organ Transplant.

Advances in systems immunology, such as new biomarkers, offer the potential for highly personalized immunosuppression regimens that could improve patient outcomes. In the future, integrating all of this information with other patient history data will likely have to rely on artificial intelligence (AI). AI agents can help augment transplant decision making by discovering patterns and making predictions for specific patients that are not covered in the literature or in ways that are impossible for humans to anticipate by integrating vast amounts of data (e.g. trending across numerous biomarkers). Similar to other clinical decision support systems, AI may help overcome human biases or judgment errors. However, AI is not widely utilized in transplant to date. In this rapid review, we survey the methods employed in recent research in transplant-related AI applications and identify concerns related to implementing these tools. We identify three key challenges (bias/accuracy, clinical decision process/AI explainability, AI acceptability criteria) holding back AI in transplant. We also identify steps that can be taken in the near term to help advance meaningful use of AI in transplant (forming a Transplant AI Team at each center, establishing clinical and ethical acceptability criteria, and incorporating AI into the Shared Decision Making Model).

Advances in personalized medicine and noninvasive diagnostics in solid organ transplantation.

Personalized medicine has been a mainstay and in practice in transplant pharmacotherapy since the advent of the field. Decisions pertaining to the diagnosis, selection, and monitoring of transplant pharmacotherapy are aimed toward the individual, the allograft, and the overall immunologic needs of the patient. Recent advances in pharmacogenomics, noninvasive biomarkers, and artificial intelligence (AI) technologies have the promise of transforming the way we individualize treatment and monitor allograft function. Pharmacogenomic testing can provide clinicians with additional data that can minimize toxicity and maximize therapeutic dosing in high-risk patients, leading to more informed decisions that may decrease the risk of rejection and adverse outcomes related to immunosuppressive therapies. Development of noninvasive strategies to monitor allograft function may offer safer and more convenient methods to detect allograft injury. Cell free DNA and gene expression profiling offer the potential to serve as "liquid biopsies" minimizing the risk to patients and providing clinicians with useful molecular data that may help individualize immunosuppression and rejection treatment. Use of big data in transplant and novel AI platforms, such as the iBox, hold tremendous promise in providing clinicians a "glimpse into the future" thereby allowing for a more individualized approach to immunosuppressive therapy that may minimize future adverse outcomes. Advances in diagnostics, laboratory science, and AI have made the application of personalized medicine even more tailored for solid organ transplant recipients. In this perspective, we summarize the current and emerging tools available, literature supporting use, and the horizon for future personalization of transplantation.

Prevalence of CYP3A5 Genomic Variances and Their Impact on Tacrolimus Dosing Requirements among Kidney Transplant Recipients in Eastern North Carolina.

To assess the prevalence of CYP3A5 genomic variances and their impact on tacrolimus (TAC) dosing requirements among kidney transplant recipients in eastern North Carolina, we conducted a single-center retrospective cohort study at a large tertiary care medical center. A total of 162 adults who received a kidney transplant between March 1, 2013, and February 28, 2015, and received oral TAC as part of their maintenance immunosuppression were enrolled. Of these patients, 85 patients expressed a genotype with a CYP3A5*1 variant (CYP3A5*1 group), and 77 patients expressed genotypes with other CYP3A5 variants (nonexpressor group). All patients were followed for 1 year posttransplantation. The primary end point was the TAC total daily dose (TDD) required to achieve the first therapeutic trough level based on the presence or absence of the CYP3A5*1 variant. The prevalence of different CYP3A5 variants across race/ethnicities in the study cohort was determined by CYP3A5 genotyping for each patient. The CYP3A5*1 and nonexpressor groups did not differ significantly with respect to sex, mean age, or mean weight. The CYP3A5*1 group was largely African American (93%, p≤0.0005) compared with other race/ethnicities. Among the CYP3A5*1 expressors compared with nonexpressors, the mean TAC TDD in milligrams at the first therapeutic TAC level was significantly higher (12 vs 8 mg/day, p≤0.001). Similarly, the mean TAC TDD in milligrams/kilogram was 50% greater among CYP3A5*1 expressors (0.15 vs 0.1 mg/kg/day, p≤0.0005). The predominant genotypic variants were CYP3A5*3/*3 (33%), CYP3A5*1/*3 (20%), and CYP3A5*1/*1 (19%). This study illustrates the prevalence of the CYP3A5*1 variant among African-American kidney transplant recipients and the effect of this gene expression on the TAC TDD. Patients with the CYP3A5*1 variant require higher TAC doses, on average, to achieve desirable drug levels. In addition, this study provides transplant clinicians with insight and support to dose TAC more aggressively in African-American kidney transplant recipients who may be at higher risk for both toxicities as well as poor clinical outcomes related to inadequate immunosuppression.

Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation.

PURPOSE: Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. SUMMARY: The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient's mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme-mediated drug interactions, (3) mental health-related medication use, (4) chronic pain-related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. CONCLUSION: Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented.

Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients.

BACKGROUND: With standard IgG donor-specific anti-HLA antibody (DSA) testing, it is unclear which immunoglobulin-G (IgG) DSA positive patients will fail. We looked further into the immune response by studying immunoglobulin-M (IgM) and IgG subclass 3 (IgG3) DSA to determine if these identify the IgG DSA patients at highest risk for allograft loss. METHODS: In 189 consecutively transplanted primary renal allograft recipients, sera were collected sequentially pre- and posttransplant. Of the 189, 179 patients had sera available to retrospectively test for anti-HLA IgG, IgM, and IgG3 antibodies via LABScreen single-antigen bead assay and were included in the study. All patients had a negative crossmatch. Per patient, all DSA (IgM, IgG3, and IgG) refers to the same serologic specificity. RESULTS: Overall, 100 (56%) patients developed an alloimmune response (IgM or IgG DSA positive, or both). Ninety-five patients developed IgM DSA and 47 patients developed IgG DSA. IgM DSA was detected in 42 of 47 patients with IgG DSA. IgM DSA alone did not increase the allograft loss risk, whereas IgG DSA did (P=0.002). Once IgG DSA appeared, IgM DSA persisted in 33 patients and an isotype switch to IgG3 positive DSA occurred in 25 patients. Patients with IgM persistent IgG3 positive DSA (n=19) were more likely to have allograft failure than those without (P=0.02). CONCLUSION: This study shows the evolution of the humoral immune response from IgM to IgG DSA posttransplant. We found that development of IgM persistent IgG3 positive DSA identifies the most dangerous IgG DSA subpopulation.