Calculated Panel Reactive Antibody Research Articles

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P < 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

Cytomegalovirus Matching in Deceased Donor Kidney Allocation: Results From a U.S. National Simulation Model.

Cytomegalovirus (CMV) infects >60% of adults and can pose an independent risk factor for allograft loss and mortality in solid organ transplant recipients. The purpose of this study is to evaluate the impact of a nationwide implementation of CMV seromatching (donor/recipient: D-/R- and D+/R+) in the U.S. deceased donor kidney allocation system (KAS). Adult candidates on the U.S. kidney-only transplant waiting list and deceased donor kidneys offered to the U.S. transplant centers were considered. A discrete-event simulation model, simulating the pre-COVID-19 period from January 1, 2015, to January 1, 2018, was used to compare the performances of currently employed KAS-250 policy (without CMV matching) to various simulated CMV matching policies parameterized by calculated panel reactive antibody exception threshold. Outcomes included CMV serodistribution, waiting time, access to transplantation among various groups, transplant rate, graft survival, kidney discard rate, and antigen-mismatch distribution, stratified by CMV serostatus. CMV matching policy with a calculated panel reactive antibody exception threshold of 50% (namely, the CMV">50%" policy) strikes a better balance between benefits and drawbacks of CMV matching. Compared with KAS-250, CMV">50%" reduced CMV high-risk (D+/R-) transplants (6.1% versus 18.1%) and increased CMV low-risk (D-/R-) transplants (27.2% versus 13.1%); increased transplant rate for CMV R- patients (11.54 versus 12.57) but decreased for R+ patients (10.68 versus 10.48), yielding an increase in aggregate (11.09 versus 10.94); and reduced mean time to transplantation (by 6 wk); and reduced kidney discard rate (25.7% versus 26.2%). Our findings underscore the feasibility and potential advantages of a nationwide CMV seromatching policy in kidney transplantation.

Calibration of Priority Points for Sensitization Status of Kidney Transplant Candidates in the United States.

A primary change to the national organ allocation system in 2014 for deceased donor kidney offers was to weight candidate priority based on sensitization (i.e. calculated panel reactive antibody percentage [CPRA%]) using a sliding scale. Increased priority for sensitized patients could improve equity in access to transplantation for disadvantaged candidates. We sought to evaluate the effect of these weights using a contemporary cohort of adult US kidney transplant candidates. We used the national Scientific Registry of Transplant Recipients to evaluate factors associated with sensitization using multivariable logistic models and rates of deceased donor transplantation using cumulative incidence models accounting for competing risks and multivariable Cox models. We examined 270,912 adult candidates placed on the waiting list between Jan,2016-September,2023. Six-year cumulative incidence of deceased donor transplantation for candidates with cPRA%=[80-85) and [90-95) was 48% and 53% respectively, as compared to 37% for candidates with cPRA%=[0-20). In multivariable models, candidates with high cPRA% had the highest adjusted hazards for deceased donor transplantation. There was significant effect modification such that the association of high cPRA% with adjusted rates of deceased donor transplantation varied by region of the country, gender, race/ethnicity, prior dialysis time and blood type. Results indicate that the weighting algorithm for highly sensitized candidates may overinflate the need for prioritization and lead to higher rates of transplantation. Findings suggest re-calibration of priority weights for allocation is needed to facilitate overall equity in access to transplantation for prospective kidney transplant candidates. However, priority points should also account for subgroups of candidates who are disadvantaged for access to donor offers.

Waiting time for kidney transplantation based on calculated panel reactive antibodies: experience of a southern Brazilian center.

The aim of this study was to analyze the waiting list for kidney transplantation in our hospital according to candidate's panel reactive antibodies (cPRA) and its outcomes. One thousand six hundred forty patients who were on the waiting list between 2015 and 2019 were included. For the analysis, hazard ratios (HR) for transplant were estimated by Fine and Gray's regression model according to panel reactivity and HR for graft loss and death after transplantation. The mean age was 45.39 ± 18.22 years. Male gender was predominant (61.2%), but the proportion decreased linearly with the increase in cPRA (p < 0.001). The distribution of patients according to panels were: 0% (n = 390), 1% - 49% (n = 517), 50% - 84% (n = 269), and ≥ 85% (n = 226). Transplantation was achieved in 85.5% of the sample within a median time of 8 months (CI 95%: 6.9 - 9.1). The estimated HRs for transplantation during the follow-up were 2.84 (95% CI: 2.51 - 3.34), 2.41(95%CI: 2.07 - 2.80), and 2.45(95%CI: 2.08 - 2.90) in the cPRA range of 0%, 1%-49%, and 50%-84%, respectively, compared to cPRA ≥ 85 (p < 0.001). After transplantation, the HR for graft loss was similar in the different cPRA groups, but the HR for death (0.46 95% CI 0.24-0.89 p = 0.022) was lower in the 0% cPRA group when adjusted for age, gender, and presence of donor specific antibodies (DSA). Patients with cPRA below 85% are more than twice as likely to receive a kidney transplantation with a shorter waiting time. The risk of graft loss after transplantation was similar in the different cPRA groups, and the adjusted risk of death was lower in nonsensitized recipients.

Waiting time for kidney transplantation based on calculated panel reactive antibodies: experience of a southern Brazilian center

RESUMO Introdução: O objetivo foi analisar a lista de espera para transplante renal em nosso hospital segundo o painel de reatividade de anticorpos (PRAc) do candidato e seus desfechos. Métodos: Incluímos 1.640 pacientes em lista de espera entre 2015 e 2019. Para a análise, estimou-se a razão de risco (HR) para transplante pelo modelo de regressão de Fine e Gray conforme o painel de reatividade e HR para perda do enxerto e óbito após o transplante. Resultados: A idade média foi 45,39 ± 18,22 anos. Sexo masculino foi predominante (61,2%), mas a proporção diminuiu linearmente com o aumento do PRAc (p &lt; 0,001). A distribuição de pacientes conforme os painéis foi: 0% (n = 390), 1% – 49% (n = 517), 50% – 84% (n = 269), e ≥85% (n = 226). O transplante foi realizado em 85,5% da amostra em tempo mediano de 8 meses (IC 95%: 6,9 – 9,1). As HRs estimadas para transplante durante o acompanhamento foram 2,84 (IC 95%: 2,51 – 3,34), 2,41 (IC 95%: 2,07 – 2,80) e 2,45 (IC 95%: 2,08 – 2,90) no intervalo de PRAc de 0%, 1%–49% e 50%–84%, respectivamente, comparadas com PRAc ≥ 85 (p &lt; 0,001). Após o transplante, a HR para perda do enxerto foi semelhante nos diferentes grupos de PRAc, mas HR para óbito (0,46 IC 95% 0,24–0,89 p = 0,022) foi menor no grupo PRAc 0% quando ajustada para idade, sexo e presença de anticorpos doador específico (DSA). Conclusão: Pacientes com PRAc abaixo de 85% têm mais que o dobro de probabilidade de receber transplante renal com tempo de espera menor. Risco de perda do enxerto após o transplante foi semelhante nos diferentes grupos PRAc, e risco ajustado de óbito foi menor em receptores não sensibilizados.

Does temporary mechanical circulatory support with Impella 5.5 induce de novo human leukocyte antigen antibodies production in heart transplantation candidates?

Little is known about de novo human leukocyte antigen (HLA) antibody development with Impella 5.5 temporary mechanical circulatory assist support and downstream effects following heart transplantation in the new heart allocation system. 13 Impella and 17 control patients without device support were prospectively enrolled between December 2020 and June 2022. HLA antibodies with calculated panel reactive antibodies (cPRA) were assessed pre- and post-device implantation and within 1-year post-heart transplantation. Baseline prevalence of HLA antibodies and median cPRA were similar between groups. Patients in the study arm were on Impella support for a median of 7 days. No significant differences in HLA antibodies were observed post-device or post-heart transplant. One patient in the Impella arm developed rejection and required treatment. One Impella patient died due to infection and one control patient died due to primary graft dysfunction. Short-term use of Impella 5.5 in the new heart allocation system does not appear to increase risk of de novo HLA antibody development. Further studies are needed to validate these preliminary findings.

Subsequent kidney transplant after pediatric heart transplant: Prevalence and risk factors

Pediatric heart failure and transplantation carry associated risks for kidney failure and potential need for kidney transplant following pediatric heart transplantation (KT/pHT). This retrospective, United Network of Organ Sharing study of 10 030 pediatric heart transplants (pHTs) from 1987 to 2020 aimed to determine the incidence of waitlisting for and completion of KT/pHT, risk factors for KT/pHT, and risk factors for nonreceipt of a KT/pHT. Among pHT recipients, 3.4% were waitlisted for KT/pHT (median time of 14 years after pHT). Among those waitlisted, 70% received a KT/pHT, and 18% died on the waitlist at a median time of 0.8 years from KT/pHT waitlisting (median age of 20 years). Moderate-high sensitization at KT/pHT waitlisting (calculated panel reactive antibody, ≥20%) was associated with a lower likelihood of KT/pHT (adjusted hazard ratio, 0.67; 95% confidence interval, 0.47-0.95). Waitlisting for heart transplantation simultaneously with kidney transplant (adjusted hazard ratio, 3.73; 95% confidence interval, 2.01-6.92) was associated with increased risk of death on the KT/pHT waitlist. While the prevalence of KT/pHT is low, there is substantial mortality among those waitlisted for KT/pHT. These findings suggest a need to consider novel risk factors for nonreceipt of KT/pHT and death on the waitlist in prioritizing criteria/guidelines for simultaneous heart-kidney transplantation.

Influence of HLA-A, [sbnd]B, and -DRB1 genes and panel-reactive antibodies on the waitlist time for kidney transplantation in the state of Sao Paulo-Brazil

BackgroundBrazil ranks second in the absolute number of transplants. However, the supply remains insufficient to meet the demands, resulting in a lengthy waitlist. This study aimed to analyze whether the frequency of human leukocyte antigen (HLA) and the value of calculated panel reactive antibody (cPRA) would influence the waiting time for kidney transplantation. MethodsThe HLA-A, B, and -DRB1 frequencies and the cPRA value were analyzed in 11,186 kidney transplant candidates included in the waitlist from 2006 to 2016. ResultsThe most frequent alleles were HLA-A*02, HLA-B*35, and HLA-DRB1*13. The overall mean length of stay on the list was 986 ± 1001 days. The mean waiting time for the three most frequent alleles of the HLA-A and B loci showed no significant difference when compared with the least frequent alleles; however, for the HLA-DRB1 locus, the most frequent alleles showed a shorter waiting time. In the association between HLA and PRA, the average length of stay on the list increased according to the candidate's degree of sensitization, regardless of the analyzed HLA frequency. ConclusionThe length of stay on the waitlist is influenced by the frequency of the HLA alleles of the DRB1 locus and the degree of sensitization.

Demographic and Clinical Characteristics of Kidney Donors at First Check: A Single-Center Experience.

Kidney transplant is the best treatment for patients with end-stage kidney disease. In many regions of the world, including the Middle East, most kidney transplants are from living donors. In contrast to recipients, data for living donors remain scarce. Here, we describe living donor baseline characteristics at first hospital check at a single center in Baghdad, Iraq. We collected and analyzed demographic, laboratory, imaging, and histocompatibility data from donor records at the Nephrology and Renal Transplantation Center, Medical City-Baghdad, Baghdad, Iraq, from July 2022 to September 2022. We included 124 kidney donors (56.4% male) who donated their kidneys 1 to 3 years previous to our study, with a mean age of 34.84 ± 10.04 years and mean body mass index (weight in kilograms divided by height in meters squared) of 27.11 ± 2.12. Most donors donated their kidneys to a firstdegree relative (69.2%); blood group O was the most prevalent (47.5%). More than half of the donors were unemployed. Histocompatibility testing showed that 40% of the donors had >3 human leukocyte antigen mismatches with their recipients, and 30% of the recipients were high-risk sensitized patients with a calculated panel reactive antibody >50%. Regarding the virus status, 68.5% of the donors tested positive for cytomegalovirus immunoglobulin G, 8% of the transplants were high-risk cytomegalovirus status, and 43.5% tested positive for Epstein-Barr virus immunoglobulin G. Renal imaging showed that 75.8% of donors had a single artery and 24.1% had a double artery (26.6% double left, 40% double right, and 33.3% both). For living transplant procedures at a single center in Iraq, most were from related donors. Most donors are unemployed, which mandates future health and social support. High immunological and viral risks must not be ignored in a single center with living related donors.

Impact of imlifidase treatment on immunoglobulins in an HLA-hypersensitized lupus nephritis patient with anti-SSA/SSB antibodies after kidney transplantation: A case report

Bacterial recombinant cysteine protease Ides (imlifidase, Idefirix®, Hansa Biopharma) is used to prevent humoral transplant rejection in highly HLA-sensitized recipients, and to control IgG-mediated autoimmune diseases. We report the case of a 51 years old woman suffering from lupus nephritis with end stage kidney disease, grafted for the second time and pre-treated with imlifidase. The patient was HLA-hypersensitized (calculated Panel Reactive Antibodies [Abs], cPRA>99 %) and has three preformed Donor Specific Antibodies (DSA). Circulating immunoglobulins were monitored at initiation (0, 6, 36, 72 and 96 h), and at Ab recovery one and two months following imlifidase injection. From baseline, the higher depletion was reported after 36h for total IgG (−75 %) and IgG subclasses (−87 % for IgG1, IgG2 and IgG3, -78 % for IgG4), while no significant impact on IgA and IgM was observed. Anti-SSA 60 kDa and anti-SSB auto-Abs quickly decreased after imlifidase injection (−96 % for both after 36 h) as well as post-vaccinal specific IgG (−95 % for tetanus toxoid, −97 % for pneumococcus and −91 % for Haemophilus influenzae Abs after 36 h). At the Ab recovery phase, total IgG and anti-SSA60/SSB Abs reached their initial level at two months. Regarding alloreactive Abs, anti-HLA Abs including the three DSA showed a dramatic decrease after injection with 100 % depletion from baseline after 36 h as assessed by multiplex single bead antigen assay, leading to negative crossmatches using both lymphocytotoxicity (LCT) and flow cell techniques. DSA rebound at recovery was absent and remained under the positivity threshold (MFI = 1000) after 6 months. The findings from this case report are that imlifidase exerts an early depleting effect on all circulating IgG, while IgG recovery may depend in part from imlifidase's capacity to target memory B cells.

Donor-Specific Antibody Mean Fluorescence Intensity Threshold Predicts Platelet Transfusion Response in HLA-Alloimmunized Patients

Introduction:Patients with platelet transfusion refractoriness (PTR) due to HLA-alloimmunization respond to HLA-matched platelets. However, 4/4 HLA-matched platelets or platelets without donor-recipient antigenic mismatches are rarely available. Further, in severe HLA-alloimmunization, it is difficult to find donor products which do not contain antigens to which the recipient has developed antibodies ( i.e. antibody specificity prediction, ASP method). Hence, studies have evaluated platelet transfusion responsiveness in the presence of ≥1 donor specific antibodies (DSAs) to widen donor pools, a strategy termed permissive mismatching (PERMM). Using established semi-quantitative techniques for HLA-antibody detection, we sought to identify a cumulative DSA threshold which predicted platelet corrected count increment (CCI) failure despite PERMM. Methods:We retrospectively reviewed platelet transfusions among patients with HLA-alloimmunization and suspected PTR at the University of Washington/Fred Hutchinson Cancer Center from 2021-2023. HLA Class I antibodies were detected using a solid-phase single antigen bead assay (One Lambda) on the Luminex platform with individual antibody strengths measured by the mean fluorescence intensity (MFI). The calculated panel reactive antibodies (cPRA) were defined as the proportion of donors against whom recipients had antibodies. Transfusions were categorized as HLA matched, PERMM (DSA MFI&amp;gt;0), or random donor platelets (HLA-type unknown). CCI was calculated as described by Cohn ASH 2020. Results: Of 420 patients suspected to have PTR, 75 had cPRA &amp;gt; 50% and received ≥3 HLA-selected platelet transfusions. Of the 2726 transfusions these patients received, 1198 were excluded due to unavailability of post-transfusion platelet counts within 2 hours or due to multiple transfusions occurring between platelet counts. Ultimately, 1528 transfusions were analyzed (Panel A). In 1031 PERMM transfusions, the cumulative MFI was a stronger predictor of CCI at 2 hours than cPRA or the number of mismatched DSA (coefficients of determination or R2 of 7.3%, 2%, and 0.4%, respectively). We then examined the spectrum of cumulative MFIs to identify a threshold MFI predicting transfusion success/failure among the PERMM products. PERMM platelet transfusions in recipients with DSA MFIs of up to 5000 generated CCIs similar to HLA-matched platelets. However, CCI was significantly different between MFI &amp;lt;10,000 (median CCI 17,783) and MFI ≥10,000 (median CCI 3753) (Panel B). We then stratified data by splenomegaly, a significant non-immunologic cause of PTR (23.2% of transfusions, R2 15.8% for CCI prediction). Of the transfusions not affected by splenomegaly, 9.6% did not generate an adequate platelet response (defined as a CCI &amp;gt;5000) across all MFIs. This failure rate increased to 33.3%, 40.8%, and 52.8% among transfusions in recipients with MFIs &amp;gt;5000, &amp;gt;7500, and &amp;gt;10,000, respectively. After multiple testing correction, MFI of several individual DSAs (A1, A2, A24, A68, B8, B37, B39, B44, B51, B57, and B62) were also found to be significant predictors of CCI using linear regression ( n ranging 32-193, R2 ranging 6-33%). Conclusions: This is the largest study to date evaluating optimal MFI thresholds of DSAs for permissive HLA mismatching in the context of platelet transfusions. Cumulative DSA MFIs demonstrated a dose response effect with lower MFIs generating better CCIs. In our patient cohort overall, and when stratified by splenomegaly, we identified a threshold for cumulative DSA MFIs of 10,000, under which &amp;gt;50% of transfusions resulted in an adequate CCI. This MFI threshold (&amp;gt;10,000) has been implicated in HLA mismatched solid organ transplant rejections (Kallon, Transf. Med. 2020) as well as in a pooled analysis of smaller HLA-selected platelet transfusion studies conducted by our group (unpublished). If incorporated into a transfusion strategy, this MFI threshold may perform better than units chosen based on the number of mismatched DSAs alone or random donor platelets and widen the donor pool. Identifying the impact of specific HLA antibodies on CCIs needs further study. Studies are also underway to correlate cumulative DSA MFIs with complement activation (C1q levels) as a possible mechanistic explanation for the differences noted across the MFI threshold of 10,000 in our study.

IgM marks persistent IgG anti-human leukocyte antigen antibodies in highly sensitized heart transplant patients

Sensitization to human leukocyte antigens (HLA) is a persistent problem in heart transplant (HT) candidates. We sought to characterize the anti-HLA antibody and circulating B cell repertoire in a cohort of highly sensitized HT candidates. We assessed IgG and IgM anti-HLA antibodies using luminex single antigen bead assays in a cohort of 11 highly sensitized (HS; calculated panel reactive antibody ≥ 90%) and 3 mildly sensitized (MS) candidates. We also performed B cell receptor repertoire sequencing (BCRseq) in HS candidates and 33 non-candidate controls. HLA antibody strength was measured by mean fluorescence intensity (MFI). We found that IgM anti-HLA antibodies were present in all HS candidates, but with a lower breadth and strength as compared to IgG. When anti-HLA IgG specificities intersected with IgM, binding strength was higher. In contrast, there were IgM but no intersecting IgG specificities for the MS group. In four candidates in the HS group, IgG anti-HLA antibodies decreased in both breadth and strength after HT, but the decrease in strength was smaller if the IgG possessed a specificity that intersected with pre-transplant IgM. BCRseq revealed larger B cell clonotypes in HS candidates but similar diversity as compared to controls. IgM marks IgG anti-HLA antibodies with higher strength before HT and persistence after HT. The presence of IgM intersecting IgG for an anti-HLA specificity may be useful approach to determine which donor HLA should be avoided for a sensitized candidate.

Physician Preferences when Selecting Candidates for Lower-Quality Kidney Offers.

In the United States, more than 50% of kidneys in the lowest 15% quality range (those with Kidney Donor Profile Index >85) are discarded. Studies suggest that using more of these kidneys could benefit patients waiting for a transplant. This study assesses the trade-offs physicians make when selecting recipients for lower-quality kidneys. A discrete choice experiment (DCE) was administered to surgeons and nephrologists in the United States who are involved in kidney acceptance decisions. The DCE presented kidneys that varied in terms of Kidney Donor Profile Index, expected cold ischemia time, donor age, pump parameters, serum creatinine levels, glomerulosclerosis, donor diabetes status, and whether donation was made after circulatory death. Candidate characteristics included recipients' age, diabetes history, time on dialysis, ejection fraction, HLA mismatch, calculated panel reactive antibody, and Karnofsky performance score. Regression analysis was used to estimate acceptability weights associated with kidney and recipient characteristics. A total of 108 physicians completed the DCE. The likelihood of acceptance was significantly lower with deterioration of kidney quality, expected cold ischemia time at transplantation, and missing biopsy and pump information. Acceptance was prioritized for patients who were higher on the waiting list, younger recipients, those who have spent less time on dialysis, and those without a history of diabetes. Performance status (Karnofsky score) and calculated panel reactive antibody also had a statistically significant but smaller association. Finally, ejection fraction had a marginally significant association, and HLA match had no significant association with the acceptance of marginal kidneys. A group of respondents were found to be primarily concerned about cold ischemia time. In this DCE, physicians considered the recipient characteristics that inform expected post-transplant survival score when they decided whether to accept a marginal kidney for a given recipient.

ABO-adjusted cPRA metric for kidney allocation in an Asian-predominant population.

Recent studies showed that ABO-adjusted calculated panel reactive antibody (ABO-cPRA) may better reflect the histocompatibility level in a multi-ethnic population, but such data in Asians is not available. We developed an ABO-adjusted cPRA metric on a cohort of waitlist kidney transplant patients (n = 647, 99% Chinese) in Hong Kong, based on HLA alleles and ABO frequencies of local donors. The concordance between the web-based ABO-cPRA calculator and the impact on kidney allocation were evaluated. The blood group distribution for A, B, O and AB among waitlist kidney candidates were 26.2%, 27.5%, 40.1%, and 6.1%, and their chances of encountering incompatible blood group donors were 32.6%, 32.4%, 57.6%, and 0%, respectively. There is poor agreement between web-based ABO-cPRA calculator and our locally developed metrics. Over 90% of patients showed an increase in cPRA after ABO adjustment, most notably in those with cPRA between 70% and 79%. Blood group O patients had a much greater increase in cPRA scores after adjustment while patients of blood group A and B had similar increment. 10.6% of non-AB blood group waitlist patients had ABO-cPRA elevated to ≥80%. A local ABO-adjusted cPRA metric is required for Asian populations and may improve equity in kidney distribution for patients with disadvantageous blood groups. The result from the current study potentially helps other countries/localities in establishing their own unified ABO-cPRA metrics and predict the impact on kidney allocation.

Immune response, phenotyping and molecular graft surveillance in kidney transplant recipients following severe acute respiratory syndrome coronavirus 2 vaccination.

Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23%vs. 0.21% respectively, p = 0.13), GEP scores (9.85vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

Low incidence of de novo HLA antibodies after COVID-19 vaccination: A cohort study of patients awaiting kidney transplantation.

Antibodies against human leukocyte antigen (anti-HLA Abs) are associated with an increased risk of allograft loss. Herein, we report the prospective follow-up for anti-HLA Abs formation in 103 patients with end-stage kidney disease on the waiting list for transplantation who underwent COVID-19 vaccination. Sera were tested before and after vaccination using Luminex technology. The cohort comprised of 62 males and 41 females with a mean age of 56 ± 14 years. The patients received BNT162b2 (80.4%), mRNA-1273 (18.5%), AZD1222 (0.40%), or ChAdOx1-S (0.80%) vaccine. Patients were tested before and within 119 ± 50, 95 ± 46 and 25 ± 26 days after the first, second, and third dose of the vaccine, respectively. No significant change in calculated panel reactive antibody (cPRA) after vaccination was seen. Although 98.1% of patients had no change in anti-HLA Abs profile or cPRA after vaccination, two patients (1.9%) developed de novo anti-HLA Abs against class I or II HLA antigens. In those two patients, the cPRA changed from 0% and 63% at baseline to 9% and 90% after vaccination, respectively. Both patients received the BNT162b2 mRNA-based vaccine. The earliest detected anti-HLA Abs was 18 days after the first dose. In rare cases, new anti-HLA antibodies were observed after COVID-19 vaccination, with potential implications for transplantation. The low incidence of this phenomenon is outweighed by the clinical benefits of vaccination.

Immunoadsorption-Based HLA Desensitization in Patients Awaiting Deceased Donor Kidney Transplantation: An Interventional, Non-Randomised, Single Cohort Study.

Whether immunoadsorption (IADS) as part of desensitization protocols could facilitate deceased donor kidney transplantation (KT) in highly sensitized (HS) patients remains to be proven. We retrospectively analyzed our IADS based desensitization protocol for deceased donor KTs between 2013 and 2018. Fifteen HS patients (age 52years [40-56]) were included. Waiting time before IADS was 6years [5-10] and the interval between IADS initiation and KT was 5months [1-12] for the 14 transplanted patients. Nine patients had prior KT. Calculated panel reactive antibody decreased significantly during the protocol (99.3% [92.5-99.9] vs. 79.4% [56.7-81.9]; p = 0.004). Death-censored graft survival was 85.7% at 1 and 2years post-transplantation. One-year median plasma creatinine level was 135µmol/L [111-202]. Six developed active antibody mediated rejection (ABMR) at 1year, with a median delay of 13days [11-26]. Eight patients developed severe infections, including two fatal outcomes. Finally, compared to 93% of patients who received desensitization receiving a KT, only 43% of a control with similar characteristics underwent transplantation. However, no difference was found in overall probability of being alive with a functioning graft at the end of follow-up. The results indicate that our IADS-based desensitization strategy was not effective due to a high rate of ABMR and severe infectious complications which pose a challenge to its universalization.

Preemptive immune globulin therapy in sensitized lung transplant recipients

BackgroundSensitized lung transplant recipients are at increased risk of developing donor-specific antibodies, which have been associated with acute and chronic rejection. Perioperative intravenous immune globulin has been used in sensitized individuals to down-regulate antibody production. MethodsWe compared patients with a pre-transplant calculated panel reactive antibody ≥25% who did not receive preemptive immune globulin therapy to a historical control that received preemptive immune globulin therapy. Our cohort included 59 patients, 17 patients did not receive immune globulin therapy and 42 patients received therapy. ResultsDonor specific antibody development was numerically higher in the non-immune globulin group compared to the immune globulin group (58.8% vs 33.3%, respectively, odds ratio 2.80, 95% confidence interval [0.77, 10.79], p = 0.13). Median time to antibody development was 9 days (Q1, Q3: 7, 19) and 28 days (Q1, Q3: 7, 58) in the non-immune globulin and immune globulin groups, respectively. There was no significant difference between groups in the incidence of primary graft dysfunction at 72 h post-transplant or acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction at 12 months. ConclusionThese findings are hypothesis generating and emphasize the need for larger, randomized studies to determine association of immune globulin therapy with clinical outcomes.

Association between calculated panel reactive antibody and waitlist outcomes in the 2018 heart allocation system

The impact of heart transplant (HT) waitlist candidate sensitization on waitlist outcomes in the US is unknown. Adult waitlist outcomes in OPTN (October 2018-September 2022) by calculated panel reactive antibody (cPRA) were modeled to identify thresholds of clinical significance. The primary outcome was the rate of HT by cPRA category (low: 0-35, middle: >35-90, high: >90) assessed using multivariable competing risk analysis (compete: waitlist removal for death or clinical deterioration). The secondary outcome was waitlist removal for death or clinical deterioration. The elevated cPRA categories were associated with lower rates of HT. Candidates in the middle (35-90) and high cPRA categories (>90) had an adjusted 24% lower rate (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.80-0.92) and 61% lower rate (HR 0.39 95% CI. 0.33-0.47) of HT than the lowest category, respectively. Waitlist candidates in the high cPRA category listed in the top acuity strata (Statuses 1, 2) had increased rates of delisting for death or deterioration compared to those in the low cPRA category (adjusted HR 2.9, 95% CI 1.5-5.5), however, elevated cPRA (middle, high) was not associated with an increased rate of death and delisting when the cohort was considered as a whole. Elevated cPRA was associated with reduced rates of HT across all waitlist acuity tiers. Among HT waitlist candidates listed at the top acuity strata, the high cPRA category was associated with increased rates of delisting due to death or deterioration. Elevated cPRA may require consideration for critically ill candidates under continuous allocation.

Sex-Specific Outcomes of Candidates Listed as the Highest Priority Status for Heart Transplantation.

While sex differences in heart transplantation (HT) waitlist mortality have been previously described, waitlist and HT outcomes by sex of patients in the highest urgency strata (Status 1) since implementation of the 2018 allocation system change in the United States are unknown. We hypothesized that women listed as Status 1 may have worse outcomes due to adverse events on temporary mechanical circulatory support. The analysis included adult, single-organ HT waitlist candidates listed as Status 1 at any time while listed, after the HT allocation system change (from October 18, 2018 through March 31, 2022). The primary outcome was the rate of HT by sex, assessed using multivariable competing risk analysis where waitlist removal for death or clinical deterioration was the competing event. Post-HT survival by sex of waitlist candidates transplanted as a Status 1 was also compared. Of 1120 Status 1 waitlist candidates (23.8% women), women had a lower rate of HT compared to men (adjusted hazard ratio, 0.74 [95% CI, 0.62-0.88]; P<0.001) and a higher rate of delisting for death or medical unsuitability (adjusted hazard ratio, 1.48 [95% CI, 1.05-2.09]; P=0.026). Calculated panel reactive antibody did not account for all the harm observed. Post-HT survival of Status 1 candidates by sex was similar (adjusted hazard ratio, 1.13 [95% CI, 0.62-2.06]; P=0.70). Women have a lower rate of HT and higher rate of delisting for death or clinical deterioration at the highest urgent status, which appears to be mediated but not fully explained by calculated panel reactive antibody levels. Further investigation into the safety profile of temporary mechanical circulatory support devices in women is needed.