Panel Reactive Antibody Research Articles

Long-term outcomes of heart re-transplantation from HCV-viremic donors based on UNOS registry

Abstract Background The use of hepatitis C virus (HCV) viremic donors increased the heart donor pool, and reduced waitlist time and mortality among first-time single-organ heart transplant (HT) candidates without compromising their post-transplant survival. The outcomes of heart re-transplantation (re-HT) with the use of HCV-viremic donor grafts have not been investigated. Methods Using the United Network of Organ Sharing (UNOS) Registry we analyzed all adult patients who underwent single-organ heart re-HT in the United States between January 1, 2016, and December 31, 2022. HCV-viremic donors were defined by a positive nucleic acid amplification test (NAT+). Graft survival rates between HCV-viremic and HCV-non-viremic donor graft recipients were compared using a log rank test. Results During the study period, of 18,259 HTs performed, 427 (2.3%) constituted single-organ heart re-transplantations. Recipients of NAT+ grafts (n=19) compared to NAT- grafts (n=408) were more often male (84.2% vs 61.3%, p=0.04). Otherwise, there were no significant differences between the two groups in age, ethnicity, BMI, blood type, history of diabetes rates or stroke, creatinine or bilirubin levels, reason for re-HT, hemodynamics, use of mechanical circulatory support, and waitlist time. Ischemic time, frequency of female donors, HLA, ABO, CMV mismatch rates, and calculated panel reactive antibodies levels were comparable across the two groups. There were no significant differences in demographics or comorbidities rates between HCV-viremic and HCV-non-viremic donors apart from the cause of death. Among the donors of HCV-viremic grafts brain anoxia was reported more often (89.5%) than among HCV-non-viremic donors (40%), p <0.01. Rates of acute rejection treated in the first year after re-HT were comparable across the two groups. Over a mean follow-up of 3.0±2.1 and 3.3±1.8 years after re-HT from NAT- and NAT+ organ donors, respectively, graft survival rate at 1 year was 82% vs. 95% (p=0.3) and at 3 years 79% vs. 89%, respectively (p=0.6) (Figure). Conclusion Graft survival rates at 1 and 3 years post-heart re-HT in adult recipients of HCV-viremic donor grafts were comparable to those of recipients of HCV-non-viremic donor grafts. The current study provides compelling preliminary evidence that HCV-viremic donors constitute a viable donor pool for patients in need of heart re-transplantation.

Case Report: Emergence of de novo Donor-Specific HLA antibodies post Pneumococcal & Varicella Zoster Vaccinations in Waitlisted Renal Transplant Candidate

Abstract Introduction/Objective In renal transplant waitlisted patients, vaccination series remains to be the standard of care for infection prevention. There is a need to investigate if any of these vaccines or their adjuvant components can induce de novo donor-specific antibodies (dnDSA) against human leukocyte antigens (HLA). These novel anti-HLA antibodies in renal transplant waitlisted patients can result in a positive flow cell crossmatch (FCXM) associated with an increased risk of renal transplant rejection. Methods/Case Report We present a 59-year-old renal transplant waitlisted patient who has had multiple negative T- cell and B-cell FCXM with no detection of dnDSA at baseline. We detected de-novo anti-HLA antibodies after he received pneumococcal conjugate (Pneum-C-13) and recombinant zoster vaccine (RZV). After vaccination, FCXM was positive for both T-cells and B-cells. HLA class I antibodies (A1, 23, 24, 80; B44, 45, 76) showed a panel reactive antibody (PRA) of 51%. Epitope analysis highlighted 166DG and 166ES as shared epitopes responsible for the entire specificity. The A1 dn-DSA had a mean fluorescence intensity (MFI) of 1800 and with shared A80 epitope MFI was 15,000 contributing to the strong positivity observed in T-cell and B-cell FCXM. New onset A1, and B44 DSA predicted high risk for transplant rejection with his sibling. His planned live donor renal transplant was halted and had to instead enter the kidney-paired donor program wherein he received his transplantation after 16 months. Results (if a Case Study enter NA) NA Conclusion Allosensitization risk secondary to RZV or Pneum-C-13 vaccines or their adjuvant components in renal transplant waitlisted patients must be considered as a potential risk for transplant rejection. Future studies can utilize monitoring of HLA-specific memory B-cells to provide crucial insights into the primary mechanism of action of dn-DSA anti-HLA antibody formation and suggest interventions to mitigate this memory B-cell activation.

Evaluation of Safety and Efficacy of Cell Therapy Based on Osteoblasts Derived from Umbilical Cord Mesenchymal Stem Cells for Osteonecrosis of the Femoral Head: Study Protocol for a Single-Center, Open-Label, Phase I Clinical Trial.

Although mesenchymal stem cells (MSCs) insertion has gained recent attention as a joint-preserving procedure, no study has conducted direct intralesional implantation of human umbilical cord-derived MSCs (hUCMSCs) in patients with ONFH. This is a protocol for a phase 1 clinical trial designed to assess the safety and exploratory efficacy of human umbilical cord-derived osteoblasts (hUC-Os), osteogenic differentiation-induced cells from hUCMSCs, in patients with early-stage ONFH. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 will be assigned to a low-dose (1 × 107 hUC-O cells, n = 3), medium-dose (2 × 107 cells, n = 3), and high-dose group (4 × 107 cells, n = 3) in the order of their arrival at the facility, and, depending on the occurrence of dose-limiting toxicity, up to 18 patients can be enrolled by applying the 3 + 3 escalation method. We will perform hUC-O (CF-M801) transplantation combined with core decompression and follow-up for 12 weeks according to the study protocol. Safety will be determined through adverse event assessment, laboratory tests including a panel reactive antibody test, vital sign assessment, physical examination, and electrocardiogram. Efficacy will be explored through the change in pain visual analog scale, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, ARCO stage, and also size and location of necrotic lesion according to Japanese Investigation Committee classification before and after the procedure. Joint preservation is important, particularly in younger, active patients with ONFH. Confirmation of the safety and efficacy of hUC-Os will lead to a further strategy to preserve joints for those suffering from ONFH and improve our current knowledge of cell therapy.

The Korean Organ Transplant Registry (KOTRY): Third Official Adult Heart Transplant Report.

The Korean Organ Transplant Registry (KOTRY) provided data for this third official report on adult heart transplantation (HT), including information from 709 recipients. Data from HTs performed at seven major centers in Korea between March 2014 and December 2020 were analyzed, focusing on immunosuppression, acute rejection, cardiac allograft vasculopathy (CAV), post-transplant survival, and mechanical circulatory support (MCS) usage. The median ages of the recipients and donors were 56.0 and 43.0 years, respectively. Cardiomyopathy and ischemic heart disease were the most common preceding conditions for HT. A significant portion of patients underwent HT at waiting list status 1 and 0. In the multivariate analysis, a predicted heart mass mismatch was associated with a higher risk of 1-year mortality. Patients over 70 years old had a significantly increased risk of 6-year mortality. The risk of CAV was higher for male donors and donors older than 45 years. Acute rejection was more likely in patients with panel reactive antibody levels above 80%, while statin use was associated with a reduced risk. The employment of left ventricular assist device as a bridge to transplantation increased from 2.17% to 22.4%. Pre-transplant extra-corporeal membrane oxygenation was associated with worse post-transplant survival. In this third KOTRY report, we analyzed changes in the characteristics of adult HT recipients and donors and their impact on post-transplant outcomes. The most notable discovery was the increased use of MCS before HT and their impact on post-transplant outcomes.

Cesarean Section Is a Risk Factor That Prevents Organ Transplantation by Increasing the Development of Anti-HLA Antibodies in Women.

In this study, prenatal and postnatal blood samples were taken from pregnant women who had 35 or more gestational weeks and had not developed anti-HLA positivity yet. The aim of this study was to evaluate the factors that may be effective in the development of panel reactive antibody (PRA) positivity during pregnancy. PRA testing was studied by taking the blood of 86 pregnant women 1month before birth. Blood was taken again 1month after birth from these women with prenatal PRA negative and it was checked whether PRA positivity developed. As a control group, 40 women without pregnancy were selected for the study. Of the 86 pregnant, 42 (48.8%) had cesarean sections, 44 (51.2%) had normal births, and PRA positivity developed in 14 (32.5%) of cesarean deliveries and three (8.0%) of normal births. In the control group, there were three (7.5%) PRA positivity. A statistically significant difference was found between cesarean delivery, normal delivery, and control group. Moreover, when compared with the control group, it was found statistically significant that all deliveries increased the development of HLA Class II antibodies. Cesarean delivery was associated with increased PRA positivity compared to normal birth. The new information presented in this study will pave the way for further research and enable healthcare professionals to consider both the individual's potential future need for organ transplantation and the positive impact on public health and more effective management of healthcare costs when making decisions regarding cesarean section.

Impact of Medicaid expansion on kidney transplantation in the State Oklahoma.

There is no data evaluating the impact of Medicaid expansion on kidney transplants (KT) in Oklahoma. To investigate the impact of Medicaid expansion on KT patients in Oklahoma. The UNOS database was utilized to evaluate data pertaining to adult KT recipients in Oklahoma in the pre-and post-Medicaid eras. Bivariate analysis, Kaplan Meier analysis was used to estimate, and cox proportional models were utilized. There were 2758 pre- and 141 recipients in the post-Medicaid expansion era. Post-expansion patients were more often non-United States citizens (2.3% vs 5.7%), American Indian, Alaskan, or Pacific Islander (7.8% vs 9.2%), Hispanic (7.4% vs 12.8%), or Asian (2.5% vs 8.5%) (P < 0.0001). Waitlist time was shorter in the post-expansion era (410 vs 253 d) (P = 0.0011). Living donor rates, pre-emptive transplants, re-do transplants, delayed graft function rates, kidney donor profile index values, panel reactive antibodies levels, and insurance types were similar. Patients with public insurance were more frail. Despite increased early (< 6 months) rejection rates, 1-year patient and graft survival were similar. In Cox proportional hazards model, male sex, American Indian, Alaskan or Pacific Islander race, public insurance, and frailty category were independent risk factors for death at 1 year. Medicaid expansion was not associated with graft failure or patient survival (adjusted hazard ratio: 1.07; 95%CI: 0.26-4.41). Medicaid expansion in Oklahoma is associated with increased KT access for non-White/non-Black and non-United States citizen patients with shorter wait times. 1-year graft and patient survival rates were similar before and after expansion. Medicaid expansion itself was not independently associated with graft or patient survival outcomes. Ongoing research is necessary to determine the long-term effects of Medicaid expansion.

Calculated Panel Reactive Antibody for an Organ-Sharing Zone: Concept and Execution Based on Data from North Kerala

Background Calculated-PRA (CPRA) is derived by virtually matching a recipient’s antibody profile against HLA antigens of a representative donor pool of a geographical region. Materials and Methods An android application–based CPRA calculator was created from HLA typing data (A/B/DR loci) of 712 consecutive living donors spanning over last 10 years from an organ-sharing region in Kerala. Only an open-source software was used. Results Our HLA data, compared with the National Marrow Donor Program (NMDP) 2011 database, show that the most common haplotype frequencies show comparable positions in order of prevalence. Available online PRA calculators like OPTN and Canadian CPRA show significant differences in PRA estimation when used in our population. This calculator provides a more accurate and realistic estimate of sensitization against the representative donor pool. Conclusion This CPRA tool can be customized for any allocation region using portable open-source software. The donor pool can be updated continually by populating data from multiple regional centers.

Impact of sex on clinical outcomes according to immunologic risk in spousal donor kidney transplantation.

The aim of this study is to investigate the impact of sex on the clinical outcomes of spousal donor kidney transplantation. We analyzed 456 spousal donor kidney transplantation recipients and categorized them into standard or high immunological risk groups according to panel-reactive antibody ≥50% or less. There were 366 recipients in the standard-risk group and 89 recipients in the high-risk group. When comparing biopsy-proven allograft rejection within 1 year from kidney transplantation, husband-to-wife recipients showed significantly higher incidence than wife-to-husband recipients in the high-risk group. By contrast, there was no significant difference between wife-to-husband and husband-to-wife recipients in the standard-risk group. Allograft function recovery was better in husband-to-wife recipients than in wife-to-husband recipients in each group, while husband-to-wife recipients in the high-risk group showed a more rapid decline than other recipients. The long-term patient and allograft survival rates showed no difference between husband-to-wife recipients and wife-to-husband recipients within the same groups. The husband-to-wife recipients with high immunological risk showed a higher risk of biopsy-proven allograft rejection compared to wife-to-husband recipients, so careful monitoring and management may be required.

Kidney re-transplantation in the ipsilateral iliac fossa: a surgeon's perspective on perioperative outcome.

Compared with primary transplantation, ipsilateral renal re-transplantation is associated with an increased risk of surgical complications and inferior graft outcomes. This study investigates whether an ipsilateral re-transplantation approach per se is an independent risk factor for surgical complications and early graft loss. In this retrospective, single-centre analysis, surgical complications and early graft outcomes of ipsilateral kidney re-transplantations from January 2007 to December 2017 were compared with primary transplantations and contralateral re-transplantations. Univariate and multivariate binary logistic regression analyses were performed to identify risk factors for surgical complications requiring surgical revision and graft loss within the first year after transplantation. Of the 1489 kidney transplantations, 51 were ipsilateral, 159 were contralateral re-transplantations and 1279 were primary transplantations. Baseline characteristics did not differ between the ipsilateral and contralateral re-transplant recipients except for current and highest panel reactive antibody levels. Major complications requiring surgical revision were significantly more frequent in ipsilateral re-transplantations (P=.010) than in primary transplantations but did not differ between ipsilateral and contralateral re-transplantations (P=.217). Graft loss within the first year after transplant was 15.7% in the ipsilateral versus 8.8% in the contralateral re-transplant group (P=.163) versus 6.4% in the primary transplantation group (P=.009). In a multivariate regression model, ipsilateral re-transplantation was not identified as an independent risk factor for complications requiring surgical revision or first-year graft loss. Ipsilateral renal re-transplantation is not a risk factor for inferior outcomes. Graft implantation into a pre-transplanted iliac fossa is a feasible and valid therapeutic option.

Refining cPRA calculation to improve HLA compatibility assessment in organ transplantation: A detailed picture of the Paris waiting list.

The determination of panel reactive antibodies (cPRA) scores plays a critical role in assessing the immunological compatibility between organ transplant recipients and potential donors. Traditional cPRA methods focus on a limited number of HLA loci using physical cytotoxicity tests. However, advancements such as the Luminex single antigen (LSA) assay, which uses mean fluorescence intensity (MFI) of individualised HLA antigens for antibody evaluation, provide a foundation for a more precise assessment. We developed cPRAdictor, a novel cPRA calculation tool using a large series of HLA-type individuals in France with NGS. cPRAdictor was applied to a cohort of 5962 kidney transplant candidates in Paris. We analysed how extending the range of HLA specificities could affect cPRA values. Implementing cPRAdictor revealed and allowed quantification of the significant discrepancies in cPRA values that appeared when HLA loci C and DP, and antigen-specific antibodies were taken into account. Notably, over 43% of the immunised transplant candidates showed an increase in calculated cPRA values when considering C/DP loci and antigen-specific antibodies, negatively impacting their eligibility and prioritisation in the transplantation programme. These findings highlight the necessity of revisiting cPRA calculation methodologies to include a broader spectrum of immunological data, as more exhaustive and precise information regarding anti-HLA antibodies in patients' sera and donor and recipient HLA typing are available prospectively. This will strongly improve both accuracy and equity at the organ allocation step, especially for highly sensitised candidates for whom organ offers are very limited in number.

Highly Sensitized Kidney Transplant Outcomes After the 2014 Kidney Allocation System Change.

Introduction: Kidney Allocation System (KAS) was implemented by United Network for Organ Sharing in 2014 to reduce allocation disparities. Research Questions: Outcomes of highly sensitized patients (calculated panel reactive antibody (cPRA) ≥ 97%) before and after KAS were compared to low-risk recipients (cPRA <10%) in the post-KAS era were examined. The impact on racial disparities was determined. Design: This was a retrospective study of national registry data. Two cohorts of adult candidates waitlisted for deceased donor transplantation during 3-year periods before and after KAS were identified. Results: Highly sensitized patients (N = 1238 and 4687) received a deceased donor kidney transplant between January 1, 2011 and December 31, 2013 and between January 1, 2015 and December, 31, 2017. Racial disparity for highly sensitized patients improved, yet remained significant (P < 0.001), with Black patients comprising 40% and 41% of the highly sensitized candidates and 28% and 34% of the recipients pre- and post-KAS. While posttransplant death-censored graft failure for highly sensitized recipients was similar overall, post-KAS was associated with improved graft survival in the first year after transplant (HR 0.56, 95% CI 0.40-0.78). When compared to contemporaneous lowrisk recipients, both death-censored and all-cause graft failure were similar for highly sensitized recipients and was associated with increased risk for death-censored graft failure beyond the first year (HR 1.39, 95% CI 1.11-1.73). Conclusion: The allocation system led to an increase in transplantation in highly sensitized candidates without compromising outcomes. Although KAS has led to more balanced transplant rates between highly sensitized Black and White patients, racial inequalities persist.

221.6: Development of a calculated panel reactive antibody calculator for the United Arab Emirates.

221.6: Development of a calculated panel reactive antibody calculator for the United Arab Emirates.

Anti-HLA Class II Antibodies Are the Most Resistant to Desensitization in Crossmatch-positive Living-donor Kidney Transplantations: A Patient Series.

In HLA-incompatible kidney transplantation, the efficacy of desensitization in terms of anti-HLA antibody kinetics is not well characterized. We present an overview of the course of anti-HLA antibodies throughout plasma exchange (PE) desensitization in a series of crossmatch-positive patients. All consecutive candidates in the Dutch HLA-incompatible kidney transplantation program between November 2012 and January 2022 were included. The eligibility criteria were a positive crossmatch with a living kidney donor and no options for compatible transplantation. Desensitization consisted of 5-10 PE with low-dose IVIg. A total of 16 patient-donor pairs were included. Patients had median virtual panel-reactive antibody of 99.58%. Cumulative donor-specific anti-HLA antibody (cumDSA) mean fluorescence intensity (MFI) was 31 399 median, and immunodominant DSA (iDSA) MFI was 18 677 for class I and 21 893 for class II. Median anti-HLA antibody MFI response to desensitization was worse in class II as compared with class I (P < 0.001), particularly for HLA-DQ. Class I cumDSA MFI decreased 68% after 4 PE versus 53% in class II. The decrease between the fifth and the 10th PE sessions was modest with 21% in class I versus 9% in class II. Antibody-mediated rejection occurred in 85% of patients, with the iDSA directed to the same mismatched HLA as before desensitization, except for 3 patients, of whom 2 had vigorous rebound of antibodies to repeated mismatches (RMMs). Rebound was highest (86%) in RMM-DSA with prior grafts removed (transplantectomy n = 7), lower (39%) in non-RMM-DSA (n = 30), and lowest (11%) for RMM-DSA with in situ grafts (n = 5; P = 0.018 for RMM-DSA transplantectomy versus RMM-DSA graft in situ). With a median follow-up of 59 mo, 1 patient had died resulting in a death-censored graft survival of 73%. Patients with class II DSA, and particularly those directed against HLA-DQ locus, were difficult to desensitize.

Introduction of the donor centre virtual crossmatch in Eurotransplant.

On 24 January 2023, Eurotransplant has introduced the virtual crossmatch for kidney and pancreas allocation as a better alternative for the physical Complement Dependent Cytotoxicity (CDC) crossmatches at the donor centre, which were associated with a longer cold ischaemia time and false positive reactions. For the time being, the physical CDC crossmatch at the recipient centre will remain in place as the final histocompatibility check. While Eurotransplant is certainly not the first organ allocation organisation to introduce virtual crossmatching, several novel aspects have been introduced, such as calculation of the virtual panel reactive antibody (vPRA) on 11 loci at the second-field level in addition to the serological broad and split level, electronic HLA typing data transmission using Histoimmunogenetics Markup Language (HML) file format, and the actual virtual crossmatch based on ambiguous, second-field HLA typing of the donor on all 11 loci. This short communication will focus on these novel aspects of the virtual crossmatch in Eurotransplant.

Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation

BackgroundThe safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined. MethodsA two-phase (I/II), monocentric open-label study was conducted to evaluate the M6 safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) Phase, we used four-weekly escalating doses of daratumumab. Phase II tested desensitization with 8 weekly infusions of 16mg/kg daratumumab. cPRA10000 was calculated considering only anti-HLA antibodies with MFI of > 10000. ResultsNine patients were enrolled in Phase I and 14 in Phase II. Safety analysis showed 4 serious non-treatment-emergent adverse events (NTEAEs), 36 mild treatment-emergent adverse events (TEAEs), mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at M3, with cPRA 10000 (P=0.003), number of anti-HLA (P<0.001), MFI max (P=0.053), and MFI sum (P<0.001), with complete return to baseline levels at M12. At M6, 46.15% [19.22%-74.87%] and 76.92% [46.19%-94.96%] of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10000, respectively. At M1, immune cells (T-reg, CD8+TEMRA, CD19+CD138+ B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications. ConclusionThe first use of daratumumab in desensitization demonstrated infusion-related AEs and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use.

Diagnostic Methods in the Determination of Immunological Risk in a Patient before Kidney Transplantation

Abstract Kidney transplantation is the treatment of choice in patients with an end-stage kidney disease (ESKD). Before kidney transplantation, it is important to assess the patient's immunological risk, which has an impact on graft survival after kidney transplantation. Human leukocyte antigens (HLA), also known as major histocompatibility complex (MHC) are responsible for the rejection of genetically different tissue by recognizing and distinguishing foreign proteins from self-proteins. HLA-typing and anti-HLA antibody screening are crucial to determine the donor/recipient mismatching. Diagnostic methods used for anti-HLA antibody detection and immunological risk assessment are complement-dependent cytotoxicity (CDC), flow cytometry crossmatch (FCXM), bead-based assays (Luminex technology), calculated panel-reactive antibody (cPRA), and algorithm “predicted Indirectly Recognizable HLA Epitopes“ (PIRCHE). The aim of these diagnostic tests is to minimize HLA mismatch between the donor and the recipient and prevent an early graft failure by the presence of HLA donor-specific antibodies (DSA).

Imlifidase in Highly Sensitized Kidney Transplant Recipients With a Positive Crossmatch Against a Deceased Donor

IntroductionImlifidase is authorized for desensitization of highly sensitized adult kidney transplant candidates with a positive crossmatch against a deceased donor. Here, we report on the results for the first 9 patients transplanted in this context who had at least 3 months of follow-up. MethodsThe eligibility criteria were: calculated panel reactive antibodies (cPRA) ≥ 98%, ≥ 3 years on the waiting list, immunodominant donor specific antibodies (iDSA) with mean fluorescence intensity (MFI) > 6,000 (and < 5,000 at 1:10 dilution) and a negative post-imlifidase complement-dependent cytotoxic crossmatch (CDCXM). ResultsAll 9 patients had been on dialysis for an average of 123±41 months, with cPRA at 99% (n=2) or 100% (n=7). At transplantation, the mean number of DSA was 4.3±1.4. The median iDSA MFI was 9,153 (6,430-16,980). Flow cytometry and CDC XMs before imlifidase were positive in 9 and 2 patients, respectively. After one injection of imlifidase all were negative. Patients received polyclonal antibodies, intravenous immunoglobulins, rituximab, tacrolimus, and mycophenolate. Five patients had a DSA rebound within the first 14 days: 2 had concomitant clinical antibody-mediated rejection (ABMR), 2 had subclinical ABMR, and 1 had isolated positive C4d staining. No ABMR was observed in patients without rebound. CKD-EPI eGFR was 56±22 mL/min/1.73m2 at the last follow-up (7±2.8 months). No graft loss or death were observed. Four patients developed at least one infection. ConclusionThese real-life data demonstrate that the use of imlifidase to desensitize highly sensitized patients can have an acceptable short-term efficacy and safety profile in selected patients.

New Therapies for Highly Sensitized Patients on the Waiting List.

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.

Significant Long-Term Prevention of High Sensitization After Kidney Allograft Failure by Maintaining Calcineurin Inhibitor-Based Immunosuppression.

Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0%vs. 85.5%, p < 0.001) and 24 months (61.0%vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4%vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6%vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9%vs. 18.6%, p=0.003, OR=0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406vs. 813 days, p = 0.001) without an increased risk of complications. CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.

Outcomes of Deceased Donor Kidney Recipients From the Same Donor Based on Donor-Recipient Sex Discordance.

Outcomes of deceased donor kidney transplant (DDKT) recipients from the same donor with donor-recipient sex discordance have been studied with inconsistent results. Adult DDKT where both kidneys from the same donor occurred at our center in two different recipients of different sexes were included. Outcomes were analyzed separately for male and female donors, based on the concordance or discordance between donor-recipient sex: Male-male (M-m) versus Male to female (M-f) or vice versa, F-f versus F-m. Acute rejection (AR) and uncensored graft failure were primary outcomes of interest. The univariate and multivariate risks for AR and graft failure were conducted using the Cox proportional hazards model and log-rank tests. A total of 130 donors, 84 male and 46 female fulfilled our selection criteria and were transplanted in 260 recipients. With respect to the concordant groups (M-m or F-f), sex discordance was not significantly associated with the risk of rejection in multivariate analysis (M-f vs. M-m HR 1.15 [0.53-2.53, P=0.72]; F-m vs. F-f HR 1.77 [0.71-4.39, P=0.23]). Sex discordance was also not significantly associated with graft failure in multivariate analysis. Interestingly, risk factors for AR differed among male donors and female donors. The higher calculated panel reactive antibodies (cPRA) and nonwhite recipients were at increased risk for AR in F-m, but not in M-f. Donor-recipient sex discordance was not significantly associated with AR or graft failure. Risk factors for AR may differ across male and female donors.