Management of the sensitized pediatric renal transplant candidate.

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.

Maximum surgical blood ordering schedule for elective surgical procedures in Omdurman teaching hospital, Sudan.

BACKGROUND: The need for blood during a surgical procedure is greater than what blood banks are able to provide. There is an excessive amount of blood being ordered for elective surgeries, surpassing the actual requirements. Only 30% of the cross matched blood is actually used in these surgeries. The accuracy of estimating the transfusion needs before a surgical procedure can be determined by looking at the cross match to transfusion ratio and the transfusion index. "These indicators play a crucial role in developing the maximum surgical blood ordering schedule; in this study, these indicators were tested." AIM OF STUDY: Is to determine the efficiency of blood ordering and transfusion practices for patients undergoing elective surgeries. METHODS: This study is a prospective cross-sectional hospital-based study done at Omdurman Teaching Hospital-Sudan. Conducted for the duration of 6 months period from July to December 2019.The study participants were patients who underwent elective surgical procedures in general surgery and Urology departments as total coverage sample over a period of study duration. Ethical clearance obtained from ethical committee of Sudan Medical Specialization Board. RESULTS: Two hundreds seven patients included in this study, the amount of blood units requested were 443-unit, cross matching for 98.6% (n 437) of units were done. Only 100 unit were Transfused (22,8%). The calculated CT ratio was 4.4, transfusion index was 1.6 and transfusion probability was 29.9%. CONCLUSION: Transfusion probability and transfusion index of the present study were optimal but comparatively higher than the standard guidelines as most of the cross matched blood was not utilized.

First use of imlifidase desensitization in a highly sensitized lung transplant candidate: a case report.

Lung transplant candidates who are highly sensitized against human leucocyte antigen present an ongoing challenge with regards to finding immunologically acceptable donors. Desensitization strategies aimed at reducing preformed donor-specific antibodies have a number of limitations. Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes, is a novel agent that has been used to convert positive crossmatches to negative in kidney transplant candidates, allowing transplantation to occur. We present the first case of imlifidase use for antibody depletion in a highly sensitized lung transplant candidate who went on to undergo a successful bilateral lung transplant.

Impact of allele-specific anti-human leukocyte antigen class I antibodies on organ allocation.

Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation.

Luminex Crossmatch in kidney transplantation.

The introduction of the Luminex Crossmatch assay (LumXm) which uses Luminex bead technology, consists of extracting the donor's Human Leukocyte Antigen (HLA) molecules from their lymphocytes, and binding them to fluorescent beads that are put in contact with recipient's serum. HLA donor-specific antibodies (DSA) are detected using a fluorescent conjugate. The goal of our study is to determine the benefits of using LumXm in a renal transplantation algorithm. We tested 78 recipients' sera using the LumXm, and the results were compared with the Luminex single antigen bead assay (SAB) for all sera, as well as the Flow Cytometry Crossmatch (FCXM) for 46 sera. We compared our results with those of SAB using 3 cutoffs, the first being the manufacturer's criteria where sensitivity and specificity were at 62.5% and 91.3% respectively for HLA class 1, and 88.5% and 50.0% respectively for HLA class 2. When using the third cutoff criteria (≥2 Adjusted values + MFI [Mean fluorescence intensity] >500 + Neg MFI < 500), the sensitivity increased to 69.0% for HLA class 1 and decreased to 84.0% for HLA class 2, while the specificity increased for HLA class 1 and 2. When comparing with FCXM, the 3 assays agreed in 55.8% of results for class 1 and 2 alike. However, major discrepancies were found for two groups in HLA class 1 and one in HLA class 2. The LumXm when used with other techniques to overcome its' weak points, can provide an interesting insight into the patient's HLA-DSA profile.

Successful combined auxiliary partial liver and intestinal transplantation in two highly sensitized, cross-match positive patients.

INTRODUCTION: Sensitization to human leukocyte antigen (HLA) creates an immunological barrier to intestinal transplantation (ITx). Current desensitization therapies are limited and ineffective in the most highly sensitized patients. A co-transplanted whole liver transplant can protect a kidney, heart, or intestinal allograft from antibody-mediated injury. Whether an auxiliary partial liver allograft provides effective protection for highly sensitized intestinal transplant recipients is unknown. METHODS: Two patients with strong HLA donor-specific antibody at high titer against their deceased donors underwent combined auxiliary partial liver and ITx across a positive cross-match. The left lateral lobes from the combined-graft recipients and the right liver lobes from the deceased donors were transplanted as a domino procedure to other four patients. RESULTS: Two combined-graft recipients have had an uneventful postoperative course without major complications at a 12- and 24-month follow-up, respectively. Intestinal graft function has been excellent with no evidence of humoral or cellular rejection. While a positive cross-match turned negative, titers of donor-specific HLA antibodies gradually declined over time after transplant. The left liver lobes procured from the combined-graft recipients were successfully transplanted into two pediatric patients (age 1.9, 2.4 years) and the right lobes from two deceased donors were successfully transplanted into two adult patients. All transplant procedures went well, without post-operative complications related to the splitting technique. CONCLUSION: Our results indicate that an auxiliary liver transplant can effectively protect a co-transplanted intestinal allograft against rejection and suggest that this combined procedure may serve as a useful therapeutic adjunct for a highly sensitized intestinal transplant candidate.

Liver Transplantation in Recipients With a Positive Crossmatch: A Retrospective Single-Center Match-Pair Analysis.

A positive crossmatch (XM+) is considered a contraindication to solid abdominal organ transplantation except liver transplantation (LT). Conflicting reports exist regarding the effects of XM+ on post-transplant outcomes. The goal of this retrospective single-center analysis is to evaluate the influence of XM+ on relevant outcome parameters such as survival, graft rejection, biliary and arterial complications. Forty-nine adult patients undergoing LT with a XM+ between 2002 and 2017 were included. XM+ LT recipients were matched 1:2 with crossmatch negative (XM-) LT recipients based on the balance of risk (BAR) score. Patient and graft survival were compared using Kaplan-Meier survival analysis and the log-rank test. Comparative analysis of clinical outcomes in XM+ and XM- groups were conducted. Patient and graft survival were similar in XM+ and XM- patients. Rejection episodes did not differ either. Recipients with a strong XM+ were more likely to develop a PCR+ CMV infection. A XM+ was not associated with a higher incidence of biliary or arterial complications. Donor age, cold ischemia time, PCR+ CMV infection and a rejection episode were associated with the occurrence of ischemic type biliary lesions. A XM+ has no effects on patient and graft survival or other relevant outcome parameters following LT.

Imlifidase for Kidney Transplantation of Highly Sensitized Patients With a Positive Crossmatch: The French Consensus Guidelines.

Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.

Contemporary outcomes of pediatric cardiac transplantation with a positive retrospective crossmatch.

BACKGROUND: A positive crossmatch (+ XM) has traditionally been associated with adverse outcomes following pediatric heart transplantation. However, more recent studies suggest that favorable intermediate-term outcomes may be achieved despite a + XM. This study's hypothesis is that children with a + XM have similar long-term survival, but higher rate of complications such as rejection, coronary allograft vasculopathy (CAV), and infection, compared to patients with a negative (-) XM. METHODS: The Pediatric Heart Transplant Society Registry (PHTS) database was queried from 2010-2021 for all patients <18 years of age with a known XM. Baseline demographics were compared between + XM and - XM groups using appropriate parametric and non-parametric group comparisons. Cox Proportional Hazards Modeling was used to identify risk factors for post-transplant graft loss, rejection, and CAV. RESULTS: Of 4599 pediatric heart transplants during the study period, XM results were available for 3914 (85%), of which 373 (9.5%) had a + XM. Univariate analysis showed lower 10-year survival for patients with + XM (HR = 1.3, p = .04). Multivariate analyses revealed no significant difference in 10-year survival in the 2 groups; however, time to first rejection (p = .0001) remained significantly shorter in the + XM group. CONCLUSIONS: Pediatric patients transplanted across a + XM experience earlier rejection; however, after multivariate adjustment, + XM is not independently associated with intermediate-term graft loss. The risk of heart transplantation against a + XM must be balanced with the ongoing risk of waitlist mortality.

Modifications to therapeutic plasma exchange to achieve rapid exchange on cardiopulmonary bypass prior to pediatric cardiac transplant.

BACKGROUND: Cardiac transplants increasingly occur following placement of ventricular assist devices (VADs). A strong association exists between human leukocyte antigen (HLA) sensitization and VAD placement; however, desensitization protocols that utilize therapeutic plasma exchange (TPE) are fraught with technical challenges and are at increased risk of adverse events. In response to increased VAD utilization in our pre-transplant population, we developed a new institutional standard for TPE in the operating room. METHODS: Through a multidisciplinary effort, we developed an institutional protocol for intraoperative TPE immediately prior to cardiac transplantation after cannulation onto cardiopulmonary bypass (CPB). All procedures used the standard TPE protocol on the Terumo Optia (Terumo BCT, Lakewood, CO, USA), but incorporated multiple modifications to limit patients' bypass times, and to coordinate with the surgical teams. These modifications included deliberate misidentification of replacement fluid and maximization of the citrate infusion rate. RESULTS: These adjustments allowed the machine to run at maximal inlet speeds, minimizing duration of TPE. To date, 11 patients have been treated with this protocol. All survived their cardiac transplantation operation. Hypocalcemia and hypotension were noted; however, none of these adverse events appeared to have clinical impact. Technical complications included unexpected fibrin deposition in the TPE circuit and air in the inlet line due to surgical manipulation of the CPB cannula. No thromboembolic complications occurred in any patient. CONCLUSION: We feel that this procedure can be rapidly and safely performed in HLA sensitized pediatric patients on CPB to limit the risk of antibody mediated rejection of their heart transplant.

Virtual crossmatching and epitope analysis in kidney transplantation: What the physician involved in kidney transplantation should know?

Solid-phase single antigen bead (SAB) assay for detection of anti-human leukocyte antigen (HLA) antibodies and high-resolution HLA typing have enabled tremendous progress in virtual crossmatch (VXM) technology in recent years. However, misinterpretation of the SAB assay may result in detrimental consequences after kidney transplantation. Meanwhile, epitope analysis could be an effective method to estimate immunizing eplets, which may provide ancillary information for better understanding of the SAB assay. To perform epitope analysis appropriately, it is necessary to understand the basic principles related to histocompatibility testing and the characteristics of the SAB assay. Therefore, knowledge of the properties and limitations of the SAB assay is critical. In this review, we aim to describe the fundamental concepts regarding immunobiological assessment, including HLA, anti-HLA antibodies, and SAB assay, and explain epitope analysis using examples.

Anti-Hla Donor-Specific Antibodies Are Associated to Infection and Not to the Engraftment Rate in Outpatient Haploidentical Hematopoietic Cell Transplantation.

Background: Recipients of a related haploidentical stem cell transplant (haplo-SCT) can have preformed antibodies to HLA donor's antigens. Objective: The aim of the study was to evaluate the engraftment rate and major clinical associations of anti-HLA donor-specific antibodies (DSA) at two mean fluorescence intensity (MFI) thresholds in recipients of an outpatient haplo-SCT. Methods: Seventy haplo-HCT recipients were analyzed. A virtual crossmatch was performed using the donor HLA typing and the recipient's anti-HLA DSA test results. Data for anti-HLA-A, -B, -C, and -DR were analyzed. Recipients with DSA ≥ 500 MFI were considered positive, and those with < 500 were considered negative; the same was adopted for MFI ≥ 1000. Results: Post-transplant infection was higher in recipients with DSA ≥ 500 MFI (84.6%, p = 0.041). First-year mortality was higher in DSA-positive patients ≥ 500 MFI, p = 0.004, and DSA ≥ 1000 MFI, p = 0.022, than in DSA-negative recipients. Graft failure in the first 100 days was not associated with DSA ≥ 500 or ≥ 1000 MFI. There was no difference in acute (a-GVHD) or chronic (c-GVHD) graft versus host disease between DSA-positive and negative patients. Conclusions: There was no association of anti-HLA DSA at MFI ≥ 500 and ≥ 1000 with graft failure, however, increased infection and 1st-year mortality were documented in related haplo-HCT at the MFI cutoffs studied.

Kidney transplantation: The journey across a century.

The Journey of kidney transplantation began a century ago with animal experiments and xenotransplants. The initial attempts of human to human kidney transplant were made by Yuri Voronoy, Jean Hamburger and several others between 1930 and 40s, but most of these were unsuccessful. The first successful live related kidney transplant between identical twins was performed at the Brigham Hospital in Boston in December 1953, by Joseph Murray and John P. Merrill, which paved the way for future live transplants. With the gradual improvement in the understanding of immunity and tolerance, the use of immunosuppression was attempted using irradiation and steroids, which gradually evolved over the decades to include azathioprine and cyclosporine. Discoveries of human leukocyte antigen by Dausset, complement dependent cross match by Paul Terasaki, and other developments in transplant immunology improved outcomes of kidney transplant. This journey was marked by new discoveries and improvements in surgical techniques including laparoscopic and robotic transplant surgery, better and safer immunosuppression, advances in transplant immunology, advent of the concept of brain death and deceased donor transplant program, and complicated transplants like transplants in highly sensitised recipients and ABO incompatible transplants. India was not far behind the rest of the world, and after a few unsuccessful attempts, the first successful transplant was done in CMC Vellore in 1971, which was followed by advancements in kidney transplants keeping in pace with the rest of the world.

Heart transplantation across preformed donor-specific antibody barriers using a perioperative desensitization protocol.

Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.

Evaluation of the Iranian panel reactive antibody calculator and potential usefulness: A retrospective study.

BACKGROUND AND OBJECTIVES: There are several cPRA websites based on large enough samples in Eurotransplant, the United Network for Organ Sharing (UNOS), and the Canadian Transplant Registry (CTR). On the other hand, those calculators can differ based on the ethnicity to which they are applied. We developed the Iranian PRA calculator and compared it with UNOS and CTR calculators. METHODS: The allele and haplotype frequencies of the Iranian donor pool were estimated using the HLA typing of 523 deceased Iranian kidney donors. The Organ Procurement and Transplantation Network formula was used to generate cPRA (cPRA frequency). We also used a computer script to compare the undesirable antigens of patients with the human leukocyte antigen (HLA) phenotype of donors (cPRA filtering). A total of 100 anti-HLA antibody profiles were determined in 100 sensitized individuals on the waiting list, and cPRA was estimated using various PRA calculators. RESULTS: Variable allelic frequencies were obtained from population heterogeneity in each calculator's donor panel. However, no significant changes in cPRA were identified between the Iranian calculator, UNOS, and the Canadian online calculators. Lin's concordance correlation coefficient of .98 showed that cPRA (freq) and cPRA (filter) values had almost perfect agreement. INTERPRETATION AND CONCLUSION: The cPRA values from the Iranian calculator are comparable to those from UNOS and CTR calculators. The donor filtering method was more useful because of factors like cost and flexibility. It also makes it easier to update cPRA on a regular basis.

Alloimmune Risk Stratification for Kidney Transplant Rejection.

Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient's circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non-HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.

Comparison of kidney transplant outcomes in HLA compatible and incompatible transplantation: A national cohort study.

BACKGROUND: Reports of HLA incompatible (HLAi) kidney transplant outcomes are inconclusive, especially in the context of lower level Donor Specific Antibodies (DSA). METHODS: Multi-centre national cohort study of HLAi kidney transplant recipients matched in 1:2 ratio with HLA compatible (HLAc) kidney transplant recipients. HLAi defined as DSA identified by Luminex. Antibody mediated rejection (AMR) and transplant-survival were analysed using Kaplan-Meier plots. Propensity score (PS) matching was used to compare recipient and transplant survival between groups. RESULTS: We included 61 HLAi and 122 HLAc recipients; mean age 46 years; 60% female. MFIT0 : 3327 (IQR 1352-6458), 23 (38%) were Flow cytometry crossmatch positive (FC-XMPOS ). DSAPOS /FC-XMPOS transplantation carried an increased risk of AMR at 1 year (52%) compared to DSAPOS /FC-XMNEG (27%) and HLAc (0%). Unadjusted death censored graft loss at 3 years was 13% (HLAi) and 8% (HLAc). Three-year patient survival was 95% in HLAc, 84% in DSAPOS /FC-XMNEG and 69% in DSAPOS /FC-XMPOS recipients; 58% of HLAi deaths were infection-related. HLA incompatibility was associated with a decreased 3-year survival in our PS-matched cohort. CONCLUSION: In kidney transplantation, DSA and positive FC-XM carries an increased risk of AMR. Despite inferior transplant and survival outcomes compared to HLAc transplantation, it remains a realistic option for highly sensitized patients facing prolonged waiting times and reduced survival on dialysis.

A multicenter prospective observational study on the use of type and screen method versus conventional type and crossmatch policy for pre-transfusion testing in the Indian population.

Despite knowing the benefits of the type and screen (TS) method in pre-transfusion testing (PTT), most transfusion centers in developing countries continue to be reluctant to adopt a TS strategy over the conventional type and antihuman globulin (AHG) crossmatch (TX) policy in their routine laboratory practice because of the cost of obtaining antibody screening reagents. To generate strong evidence, this multicenter, observational study was conducted in which we collected data prospectively over a 1-year period from six major blood centers in India. The primary objective of this study was to identify the discordance between TS and TX results. A secondary objective was to identify the allo-antibody specificity in patients with positive antibody detection tests. All patients with orders for red blood cell transfusion who met patient selection criteria were subjected to parallel testing by column agglutination technology (CAT) for both the antibody detection test (screen) using a commercial three-cell panel and for the AHG crossmatch. A total of 21,842 patients were tested. In 148 patients with incompatible crossmatches, samples from six patients gave negative results with the antibody detection test, whereas the antibody detection test was positive in samples from 118 patients among the 21,694 crossmatch-compatible cases. The TS approach achieved a positive percent agreement of 95.95 and was found to be significantly effective in preventing the transfusion of serologically incompatible blood. The risk associated with abbreviating the AHG crossmatch was found to be 0.009 percent. Most of the identified clinically significant alloantibodies were directed to Rh antigens (D>E>c>C>e), followed by anti-K and anti-M. This study has generated sufficient robust data for the Indian population by including patients from all major geographical areas of the country and concluded a satisfactory agreement level as well as non-inferiority to the current PTT policy. Therefore, TS policy can be implemented in developing countries with no compromise on blood safety, provided sufficient technical and infrastructural support are available.

Trends and impact on cold ischemia time and clinical outcomes using virtual crossmatch for deceased donor kidney transplantation in the United States.

For assessing human leukocyte antigen compatibility in deceased donor kidney transplantation, virtual crossmatch is used as an alternative to physical crossmatch and has potential to reduce cold ischemia time. The 2014 United States kidney allocation system prioritized highly sensitized candidates but led to increased shipping of kidneys. Using data from the Scientific Registry of Transplant Recipients, we evaluated changes in virtual crossmatch use with the new allocation policy and the impact of virtual crossmatch use on cold ischemia time and transplant outcomes. This was a retrospective cohort study of adult deceased donor kidney recipients in the United States (2011-2018) transplanted with either 9,632 virtual or 71,839 physical crossmatches. Before allocation change, only 9% of transplants were performed relying on a virtual crossmatch. After the 2014 allocation change, this increased by 2.4%/year so that 18% transplants in 2018 were performed with just a virtual crossmatch. There was significant variation in virtual crossmatch use among transplant regions (range 0.7-36%) and higher use was noted among large volume centers. Compared to physical crossmatches, virtual crossmatches were significantly associated with shorter cold ischemia times (mean 15.0 vs 16.5 hours) and similar death-censored graft loss and mortality (both hazard ratios HR 0.99) at a median follow-up of 2.9 years. Thus, our results show that virtual crossmatch is an attractive strategy for shortening cold ischemia time without negatively impacting transplant outcomes. Hence, strategies to optimize use and reduce practice variation may allow for maximizing benefits from virtual crossmatch.

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.