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Introduction: The rising prevalence of global end-stage renal disease (ESRD) is a significant health concern, especially among children. Although renal replacement therapy is available, children with ESRD are at an increased risk of mortality. Kidney transplantation is the preferred modality of treatment and surpasses renal replacement therapy in terms of survival. However, pediatric renal transplantation could prove difficult due to factors like smaller recipients and donor-recipient mismatches leading to higher complications., Materials and Methods: A retrospective single-group case series study was conducted on children with ESRD who were planned to undergo kidney transplantation from living donors between 2015 and 2021. The data was collected from two centers in the city of Sulaymaniyah., Results: The study comprised a predominantly male patient population, with a total of 39 individuals (n = 39) and 13 female patients. The donors were mostly males between 25-40 years old. The majority of participants were 15-18 years old. In majority of the patients Thymoglobulin was the immunosuppressive agent used in induction. The most common etiology for renal failure was reflux nephropathy and artery anastomosis was performed to the external iliac artery in the majority of patients. Only 9 patients had complications following the transplantation and 3 patients had an episode of acute rejection., Conclusions: Renal transplantation is the preferred treatment of renal failure in pediatric patients in the city of Sulaymaniyah. The most common etiology for pediatric renal failure was reflux nephropathy which was different from the findings of North American Pediatric Renal Trials and Collaborative Studies.

Significance Statement: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist., Background: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization., Methods: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively., Results: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted., Conclusions: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity., Clinical Trial Registration Number: NCT04294459 ., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring., Methods: This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed., Results: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II., Conclusion: Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients., (© 2023 Wiley Periodicals LLC.)

The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant., (© 2023. The Author(s).)

Introduction: Post transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid proliferations in recipients of solid organs which seem to be related to Epstein Barr Virus (EBV). The use of antilymphocyte antibodies, EBV seronegativity in the recipient,acute rejection and CMV infection have been identified as classical risk factors., Material Y Methods: We have studied in a retrospective observational study, the incidence of PTLD in a period of 22 years, its relationship with EBV, presence of classical risk factors and outcome in 21546 simple adult renal transplant recipients from cadaveric and living donors, transplanted in 21 hospitals from 1990 to 2009., Results: A total of 275 recipients developed PTLD (1,2%),195 males (70,9%), 80 females (29,1%) aged 59.2 (p25 44.7 p75 68)years. Two hundred forty-five (89.0%) were 1st transplant recipients and 269 (97,8%) from cadaveric donors. EBV in the tissue was reported in 94 out of the 155 studied recipients (60.6%) and 86.0% of the proliferations were due to B lymphocytes. PTLD median appearance after transplant were 42.months (p25, 75, 12, 77, 5). One hundred eighty-eight recipients out of 275 patients (68.3%) had any classical risk factor and the use of antilymphocyte antibodies was the most frequent. During the follow-up, 172 patients died (62,5%) and 103 (37,5%) had a complete remission. The main cause of death was PTLD progression (n = 91, 52,9%), followed by sepsis (n = 24, 13,9%). The follow-up period post-transplant of the recipients was between 3 and 22 years. The incidence was 0,14% during the first year post-trasplant and 0.98% the cumulative incidence at 10 years. Patient survival after diagnosis was 51%, 44% and 39% after 1, 2 and 5 years, respectively. Finally, overall graft survival was 48%, 39% and 33% at the same periods., Conclusion: PTLD has a low incidence in renal transplant recipients. Most of the proliferations are due to B lymphocytes and seem to have a close relationship with EBV. PTLD can develop in the absence of classical risk factors. The prognosis is poor, mainly due to PTLD progression, but the survivors can even maintain their grafts., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated., Objectives: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis., Material and Methods: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis., Results: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 ± 0.8, 2.1 ± 1.2 and 1.8 ± 1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant., Conclusions: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

We previously established a six-gene-based blood score associated with operational tolerance in kidney transplantation which was decreased in patients developing anti-HLA donor-specific antibodies (DSA). Herein, we aimed to confirm that this score is associated with immunological events and risk of rejection. We measured this using quantitative PCR (qPCR) and NanoString methods from an independent multicenter cohort of 588 kidney transplant recipients with paired blood samples and biopsies at one year after transplantation validating its association with pre-existing and de novo DSA. From 441 patients with protocol biopsy, there was a significant decrease of the score of tolerance in 45 patients with biopsy-proven subclinical rejection (SCR), a major threat associated with pejorative allograft outcomes that prompted an SCR score refinement. This refinement used only two genes, AKR1C3 and TCL1A, and four clinical parameters (previous experience of rejection, previous transplantation, sex of recipient and tacrolimus uptake). This refined SCR score was able to identify patients unlikely to develop SCR with a C-statistic of 0.864 and a negative predictive value of 98.3%. The SCR score was validated in an external laboratory, with two methods (qPCR and NanoString), and on 447 patients from an independent and multicenter cohort. Moreover, this score allowed reclassifying patients with discrepancies between the DSA presence and the histological diagnosis of antibody mediated rejection unlike kidney function. Thus, our refined SCR score could improve detection of SCR for closer and noninvasive monitoring, allowing early treatment of SCR lesions notably for patients DSA-positive and during lowering of immunosuppressive treatment., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction/aim: The Luminex assay, where beads are coated with a single HLA antigen, has been shown to detect HLA antibodies with more sensitivity and specificity as compared to microlymphocytotoxicity (CDC) assay and flow cross match (FCXM). We report the impact of low Mean Flourescence intensity (MFI) pre-transplant DSA by Luminex with negative CDC and FCXM on acute rejection, graft function, and survival., Methods: In this retrospective study between January 2015 to December 2021, 45 recipients had pre-transplant anti-HLA donor-specific antibodies (DSAs) detected by Luminex. Two control groups of 45 patients each matched for age and gender, first with non-DSA HLA antibodies and second with no antibodies by Luminex were selected to compare outcomes with DSA group., Results: In the DSA group of 45, 22 (48.8%) had class I (MFI mean 4043 ± 1909, range: 1096-7111), 20 (44.4%) class II (MFI mean 3601 ± 2310, range: 1031-9259), and 3 (6.6%) both class I (MFI mean 4746 ± 1922) and class II (MFI mean 3940 ± 2312) antibodies. Acute rejection episodes were reported in 15.6%, DSA group, 17.8% in non-DSA, and 24.4% in no antibody group (p = .538). Death censored graft survival at 1 and 5 years was 98% and 93% in DSA group, 100% and 95% in non-DSA and 93% and 85% in the no antibody group (p = .254)., Conclusions: Patients with low MFI DSA pre-transplant, with a negative CDC and FCXM under ATG induction, have similar graft outcomes at 1 and 5 years when compared to non-DSA and no antibody groups., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to retrospectively investigate the correlation of mean Class I donor-specific antibody (DSA) intensity values detected in Luminex-based techniques with the results of complement-dependent cytotoxicity crossmatch (CDC-XM) and flow cytometry crossmatch (FC-XM) results., Methods: A total of 335 patients with kidney failure and their living donors whose CDC-XM, FC-XM, and single antigen based (SAB) tests were studied between 2018 and 2020 for transplant preparation from living donor candidates were included in the study. Patients were divided into 4 groups according to their mean fluorescence intensity (MFI) values of SAB assay., Results: Anti-HLA antibodies (class I and/or class II) were detected using SAB in 91.6% patients included in the study (MFI >1000). Class I DSA was positive in 34.8% of patients with anti-HLA antibodies. When CDC-XM and FC-XM results were evaluated in the 4 groups separated according to MFI values, 3 patients with DSA MFI <1000 had negative CDC-XM and T-B-FC-XM results. Of 32 patients with DSA-MFI between 1000 and 3000, 93.75% (n = 30) had T-B-FC-XM or CDC-XM-negative results, and 6.25% (n = 2) had B-FC-XM-positive results. The CDC-XM, T, and B-FC-XM were negative in all 17 patients with DSA-MFI between 3000 and 5000. Our results showed that MFI >5834 DSA values were significantly correlated with positive T-FC-XM (P < .001), and MFI >6016 values were significantly correlated with positive CDC-XM (P = .002). In addition, MFI values >5000 were associated with both CDC-XM and FC-XM in our study., Conclusions: The MFI values >5000 correlated with both CDC-XM and FC-XM., Competing Interests: DISCLOSURE The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Antibody-mediated rejection (AMR) still persists as the major hurdle towards successful renal allograft survival. This paper aims to report on the HLA antibody landscape of renal transplant candidates in Malaysia. A total of 2,219 adult samples from 2016 to 2019 were analysed for anti-HLA antibodies using solid-phase assay. Our findings highlight the prevalence and risk factors for antibodies against HLA antigens in renal transplant settings, which could be beneficial for selecting compatible recipients from deceased organ donors. To the best of our knowledge, this study is the first to demonstrate that ethnic Malay and Chinese showed significantly higher prevalence of anti-HLA antibodies. Based on our multivariate analysis: (i) female gender was associated with higher risk for panel reactive antibodies (PRAs) against Class I, Class II, and Class I and II (p < 0.001); (ii) older patients (≥ 38 years old) were associated with higher risk of positivity against Class I, Class II and Class I and II (p < 0.001); (iii) Malays showed significant association with Class II antibodies (p = 0.035); Chinese patients presented with higher risk of PRA positivity against Class II (p < 0.001) and Class I and II (p = 0.01); Indians were significantly associated with higher risk of HLA antibody sensitization against Class I (p = 0.022), Class II (p = 0.026) and Class I and II (p = 0.05). Thus, our findings suggested that female gender, older age (≥ 38 years old) and ethnicity may serve as independent risk factors for HLA antibody sensitization in adult renal transplant candidates., (© 2023. The Author(s).)

Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 μg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR., (Copyright © 2023 Copyright: © 2023 Saudi Journal of Kidney Diseases and Transplantation.)

BACKGROUND Kidney transplantation is the most recommended treatment in chronic kidney disease. The recipient's immune system reacts to a kidney graft as to an alloantigen by producing antibodies (anti-human leukocyte antigens [HLAs]). Although immunosuppressive therapy is used to overcome this problem, the long-term survival of a kidney graft after 5 years remains low. This retrospective study from a single center in Romania of 347 renal transplant patients treated with tacrolimus, mycophenolate, and steroids aimed to evaluate the association between anti-HLA antibodies and 5-year graft survival. MATERIAL AND METHODS Anti-HLA antibodies were screened and identified using the Luminex method, while tacrolimus levels were monitored using the chemiluminescent assay. RESULTS Twenty-seven patients had pre-existing anti-HLA antibodies, while 320 patients did not. Of the 320 patients, 15% developed anti-HLA antibodies following kidney transplantation. The intrapatient minimum blood level of tacrolimus (cut-off value: 4.6 ng/mL) after transplantation was significantly associated with the risk of de novo anti-HLA antibodies (P<0.001). In patients with or without de novo anti-HLA antibodies, the 5-year allograft survival rate was 77.1% vs 90.8% (P=0.004). After Bonferroni correction, donor age (P=0.001), and donor type (P<0.0001) were statistically associated with the risk of allograft rejection. CONCLUSIONS This study showed that anti-HLA antibodies at 5 years after kidney transplantation were significantly associated with graft failure. The findings support previous studies and indicate that monitoring of anti-HLA antibodies should be considered in patients with renal transplant.

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., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Objectives: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation., Design, Setting, Participants, & Measurements: To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA-derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy., Results: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell-mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies., Conclusions: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch., (Copyright © 2022 by the American Society of Nephrology.)

Antibody-mediated rejection is a major cause of long-term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti-thymocyte globulin (ATG) is a widely used lymphocyte-depleting induction therapy. However, less is known about how ATG affects Tfh cell development and donor-specific antibody (DSA) formation. We observed an increase in circulating Tfh cells at 6 months after kidney transplant in patients who received ATG. Using an NP-OVA immunization model, we found that ATG-treated mice had a higher percentage of Tfh cells, germinal center B cells, and higher titers of antigen-specific antibodies compared to controls. ATG-treated animals had lower levels of IL-2, a known Bcl-6 repressor, but higher levels of IL-21, pSTAT3 and Bcl-6, favoring Tfh differentiation. In a mouse kidney transplant model, ATG-treated recipients showed an increase in Tfh cells, DSA and C4d staining in the allograft. Although ATG was effective in depleting T cells, it favored the expansion of Tfh cells following depletion. Concomitant use of IL-2, tacrolimus, or rapamycin with ATG was essential to control Tfh cell expansion. In summary, ATG depletion favors Tfh expansion, enhancing antibody-mediated response., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The reliability of single antigen bead (SAB) assays and their use in predicting a negative cell based cross match (CBXM) is essential in the era of expanded organ sharing. A wide range of accuracy (80-95%) in predicting negative CBXM has been reported. We hypothesized that in SAB assays an antibody against an HLA eplet that was common among a number of different HLA alleles would be distributed among all of the shared eplet positive SABs. This would reduce binding to the donor specific SAB resulting in an under-estimate of antibody strength. We tested this proposal in adsorption studies using, instead of lymphocytes, a novel reagent, single-SAB (sSAB). Properties of SAB assays were examined that provided a basis for conducting adsorption - elution experiments with the sSABs. We found that incubation of sera with sA*02:01 or sB*42:01 not only depleted reactivity to these alleles but also depleted reactivity to beads that shared the reactive eplet. Anti-eplet strength from SAB data (sum of the MFI of eplet positive SABs (MFI-s) was compared with CBXM out comes in two case studies and with 99 proficiency testing sera. In these validation studies, an MFI-s above 11,000 was associated with a positive FCXM. This approach was placed into clinical practice for listing unacceptable antigens that shared a common eplet. CDCXMs (n = 3261) and FCXMs (n = 1012) were performed on patients listed in UNOS for deceased donor kidneys. All CDCXMs were negative and all FCXMs except one were negative. We conclude that summation of eplet strength provides a highly reliable method of predicting prospective negative CBXMs resulting in substantial savings of time and effort. Based on shared eplet summation data, CMS/NYSDOH has accepted our bead based XM (BBXM) method (aka, virtual XM) performed prior to transplant as fulfilling the regulation that XM results be available before kidney transplantation., Competing Interests: Declaration of Competing Interest The author declare that he have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients who are HLA-sensitized are at high risk for early antibody-mediated rejection (AMR) and worse outcomes. Therefore, it is crucial to detect the presence of donor-specific antibodies (DSAs) using pretransplant antibody identification and crossmatch assays. An error in antibody identification can lead to disastrous clinical outcomes. We present a case of acute AMR associated with preformed HLA-DPα and HLA-DPβ DSAs that were not identified before transplantation., Case Presentation: A 27-year-old woman received a second kidney transplant from a deceased donor. Her pretransplant panel-reactive antibody level was 94%. The complement-dependent cytotoxicity crossmatch was negative for T and B cells at the time of transplantation. She experienced early acute AMR proven by a kidney biopsy. Single antigen bead testing of the patient's serum at the time of rejection as well as the pre-second transplant serum revealed strong antibodies against the DPA1*01:03 and DPB1*02:01 alleles in the second donor. These antibodies were not identified by phenotypic bead assay during the patient's time on the waiting list. The patient was treated with plasmapheresis and anti-thymocyte globulin. However, she experienced abdominal pain on day 37 post-transplantation. Surgical exploration revealed a laceration on the transplanted kidney, which was then repaired. Subsequently, infected hematoma was suspected and the transplanted kidney was removed., Conclusion: The present case highlights the clinical significance of preformed HLA-DPα and HLA-DPβ DSAs. Accuracy in determination of HLA antibodies before transplantattion is critical for transplant outcome. HLA-DP typing and single antigen bead testing are recommended for a precise antibody interpretation, especially in highly sensitized patients. Careful interpretation of antibody testing results is essential for the success of organ transplantation., (© 2022. The Author(s).)

Alloantibodies are significant biomarkers of posttransplant kidney rejection. With solid-phase assays, the presence of alloantibodies and complement-binding capacities can be tested. It has been noted that complement-binding anti-HLA (C1q) correlates well with high titers of anti-HLA antibodies (single antigen bead, SAB), but we have recently shown that lower SAB titers may be associated with complement in the complement cytotoxicity test. If so, low titers of donor-specific antibodies could be stratified for complement binding and used for better donor-recipient matching. To study this, we tested 268 patients awaiting kidney transplantation for SAB and C1q and stratified them into positive (Allo+) and negative (Allo-) cohorts. Next, all assayed specificities of SAB were matched with the corresponding C1q in order to correlate mean fluorescence intensity levels. We found a strong correlation between SAB and C1q for all HLA loci apart from HLA-DP. Moreover, there was no strict cutoff for C1q prediction on SAB mean fluorescence intensity level. In addition, an unusual laboratory phenotype was found; that is, a positive C1q result without corresponding SAB specificity. We tested this phenomenon and found positive IgM SAB. CONCLUSIONS: Simultaneous C1q and SAB testing may serve as a tool for in-depth analysis of alloantibodies before transplantation., (Copyright © 2022. Published by Elsevier Inc.)

Antithymocyte globulin (ATG) is a commonly used induction agent in kidney transplant recipients. However, the optimal dosing has not been well defined. Our protocol aims for a 5-6 mg/kg cumulative dose. It is unclear if a dose lower than 5 mg/kg is associated with more rejection. We performed a retrospective cohort study of patients who received a kidney transplant at our center between January 1, 2013 and December 31, 2016. Primary outcome was biopsy proven acute rejection (clinical and subclinical) in the first 6 months after kidney transplant. CMV viremia in high risk (D+/R-) recipients and BK viremia was compared as a secondary endpoint. Of the 543 patients, the Low Dose (LD) group (n = 56) received <5 mg/kg ATG and Regular Dose (RD) group (n = 487) received ≧5 mg/kg. Patients in RD were more sensitized (higher PRA and CPRA). LD received a dose of 4 ± 1.1 mg/kg ATG whereas RD received 5.6 ± .3 mg/kg ATG (P < .001). TCMR (Banff 1A or greater) was present in 34% of patients in LD versus 22% in RD (P = .04) (OR 2.1; 95%CI 1.12-3.81; P = .019). There was no difference in the incidence of CMV or BK viremia. ATG doses lower than 5 mg/kg may be associated with a heightened risk of rejection despite a low degree of sensitization., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Delayed graft function (DGF) is a common complication of kidney transplantation and frequently leads to the necessity of surveillance biopsies. The purpose of this study is to describe the histological findings in surveillance biopsies of deceased donor kidney transplant recipients and evaluate the risk factors for graft outcomes. This is a monocentric, retrospective study including kidney transplant recipients that underwent a graft biopsy during the DGF period between January 2006 and July 2019. 356 biopsies were performed in 335 deceased donor transplant recipients. Biopsies were analyzed according to the Banff classification. The main histological findings were: acute tubular necrosis in 150 biopsies (42.1%), acute rejection in 96 biopsies (26.9%), and borderline findings in 91 biopsies (25.5%). In the multivariate analysis, recipient age ( p = 0.028) and DGF duration ( p = 0.005) were associated with rejection, antibody-induction with anti-thymocyte globulin (ATG) was protective ( p = 0.001). The occurrence of rejection was associated with lower death-censored graft survival (log-rank; p = 0.009). Surveillance biopsies of kidney grafts experiencing DGF remain an essential tool for the care of kidney transplant recipients. The recipient's age and duration of DGF are independent risk factors for acute rejection, while antibody-induction therapy with ATG is associated with protection from its occurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castro Filho, Pompeo, Machado, Gonçalves, Bauer and Manfro.)

Antibody-mediated rejection is a common cause of early kidney allograft loss but the specifics of antibody measurement, therapies and endpoints have not been universally defined. In this retrospective study, we assessed the performance of risk stratification using systematic donor-specific antibody (DSA) monitoring. Included in the study were children who underwent kidney transplantation between January 1, 2010 and March 1, 2018 at Stanford, with at least 12-months follow-up. A total of 233 patients were included with a mean follow-up time of 45 (range, 9-108) months. Median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. Fifty-two (22%) formed C1q-binding de novo donor-specific antibodies (C1q- dn DSA). After a standardized augmented immunosuppressive protocol was implemented, C1q- dn DSA disappeared in 31 (58.5%). Graft failure occurred in 16 patients at a median of 54 (range, 5-83) months, of whom 14 formed dn DSA. The 14 patients who lost their graft due to rejection, all had persistent C1q- dn DSA. C1q-binding status improved the individual risk assessment, with persistent; C1q binding yielding the strongest independent association of graft failure (hazard ratio, 45.5; 95% confidence interval, 11.7-177.4). C1q- dn DSA is more useful than standard dn DSA as a noninvasive biomarker for identifying patients at the highest risk of graft failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sigurjonsdottir, Purington, Chaudhuri, Zhang, Fernandez-Vina, Palsson, Kambham, Charu, Piburn, Maestretti, Shah, Gallo, Concepcion and Grimm.)

The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has therapeutic potential for HLA desensitization in kidney transplantation and antibody-mediated rejection. Data from clinical trials in kidney transplantation demonstrated rapid degradation of anti-HLA donor-specific antibodies facilitating HLA-incompatible transplantation, which led to conditional approval of imlifidase by the European Medicines Agency for desensitization in kidney transplant recipients of a deceased donor with a positive cross match. Important considerations arising from the early experiences with imilfidase on kinetics of donor-specific antibodies after administration, timing of complementary therapeutic monoclonal or polyclonal IgG antibodies, and interference with cross match assays should be recognized as imlifidase emerges as a therapeutic agent for clinical transplantation., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Loon, Lamarthée, Barba, Claes, Coemans, de Loor, Emonds, Koshy, Kuypers, Proost, Senev, Sprangers, Tinel, Thaunat, Van Craenenbroeck, Schols and Naesens.)

Background: Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved., Methods: Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center., Results: Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3 + , CD4 + , CD8 + , and CD3 - CD56 + cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3 - CD56 + -independent and CD3 - CD56 + -dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3 + proliferation rate decreased with age and CD3 - CD56 + -mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3 + count < 20 mm -3 for at least 7 days and a CD4 + count > 200 mm -3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients., Conclusions: Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics., Clinical Trial Registration: Eudract No. 2009-012673-35., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Renal transplant patients are immunosuppressed and are at increased risk of opportunistic infections, including Nocardia infection. In renal transplant patients, information on the incidence and risk factors associated with nocardiosis is limited. To address the incidence and risk factors associated with nocardiosis in a large renal transplant population, we used the US Renal Data System (USRDS). Sequelae of allograft failure or rejection after infection were also examined. Demographics, clinical risk factors, Nocardia diagnosis, and allograft failure following Nocardia infection were queried in USRDS renal transplant patients using International Classification of Diseases, Ninth Revision (ICD-9) codes in billing claims and Centers for Medicare and Medicaid Services Form 2728. Generalized linear models were used to determine the risk factors associated with nocardiosis, and Cox proportional hazards models were used to examine the association of risk factors with graft failure among patients with Nocardia infection. Of 203,233 renal transplant recipients identified from 2001 to 2011, 657 (0.32%) were diagnosed with Nocardia infection. Pneumonia was the most frequent presentation (15.2%), followed by brain abscess (8.4%). Numerous factors associated with increased Nocardia infection included age >65 years (OR=2.10, 95% CI 1.71 to 2.59), history of transplant failure (OR=1.28, CI 1.02 to 1.60) or history of rejection (OR=4.83, CI 4.08 to 5.72), receipt of a deceased donor transplant (OR=1.23, CI 1.03 to 1.46), and treatment with basiliximab (OR=1.25, CI 1.00 to 1.55), cyclosporine (OR=1.30, CI 1.03 to 1.65), tacrolimus (OR=2.45, CI 2.00 to 3.00), or thymoglobulin (OR=1.89, CI 1.59 to 2.25). In patients with nocardiosis administration of antithymocyte globulin (HR=2.76), chronic obstructive pulmonary disease (HR=2.47), and presentation of Nocardia infection with brain abscess (HR=1.85) were associated with an increased risk of graft failure. This study provides new information to enhance early recognition and targeted treatment of nocardiosis in renal transplant patients., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Renal retransplant patients have decreased graft survival compared with primary renal transplant patients. Alemtuzumab induction is often used at the time of retransplant; however, the literature surrounding alemtuzumab induction in renal retransplant patients is limited. In this single-center, retrospective, observational study, we aimed to determine the 1-year incidence of infections and transplant outcomes in renal retransplant patients who received alemtuzumab induction. Thirty-four patients who received alemtuzumab met inclusion criteria and were included in the final analysis. Twenty-two (64.7%) of these patients acquired infections. Of these, 7 patients (31.8%) acquired infections that resulted in hospitalization or intravenous antibiotics. The most common infections were urinary tract infections (n = 10; 29.4%), cytomegalovirus DNAemia (n = 7; 20.6%), and BK virus (n = 6; 17.6%). The use of steroid maintenance therapy after alemtuzumab induction did not increase the number of infections compared with patients with a steroid-free interval after alemtuzumab induction. The number of patients who developed de novo donor-specific antibodies (DSA) was 11 (32.4%) with only 1 of these patients having DSA before retransplantation. The incidence of acute cellular rejection was 2.9% (n = 1). There was no graft loss, and patient survival was 97% (n = 33). There were no significant differences in infection rate or DSA development between alemtuzumab and the other induction agents, antithymocyte globulin and basiliximab, among retransplanted patients. Alemtuzumab induction in renal retransplant patients resulted in similar bacterial and viral infection rates as previously reported in the literature and did not negatively impact graft and patient survival., (Copyright © 2021. Published by Elsevier Inc.)

The index case is a 45-year old male with unknown cause for native kidney disease, who received a kidney from his wife. Antithymocyte globulin (ATG) was used for induction, and tacrolimus, mycophenolate mofetil and prednisolone were prescribed for maintenance. His baseline serum creatinine was 0.9 mg/dl. Two years after the transplant, the patient developed 3+ proteinuria on routine urinalysis with stable graft function. His 24-hour urinary protein was 2.3 grams, serum albumin was 3.0 g/dl, and the total cholesterol was 251 mg/dl. The tacrolimus C0 levels were maintained between 6 and 8 ng/ml range. Allograft biopsy revealed diffuse thickening of glomerular basement membranes, with the immunofluorescence showing 2+ granular positivity along the loops for IgG and C3. Further, tissue staining for PLA2R and THD7A were both negative. Also, no donor-specific antibodies (DSA) were detected, and serum PLA2R antibody assay was also negative. The patient was managed conservatively with losartan 50 mg and atorvastatin 20 mg, with subsequent reports of proteinuria of 1.5-2.0 grams/day. After 52 months of renal transplant, the patient presented with a serum creatinine of 2.06 mg/dl and proteinuria of 6.8 grams/day. A repeat allograft biopsy revealed thickened glomerular basement membranes with spikes on silver staining. (Figure 1a) Further, immunofluorescence studies showed 2+-3+ granular positivity for IgG, C3, with the added findings of C4d positivity on the peritubular capillaries and tissue PLA2R positivity on the basement membranes by immunohistochemistry. (Figures 1b-d) The biopsy also revealed peritubular capillaritis and acute tubular injury. Antibodies to donor Class II (HLA DR) were positive with a mean fluorescence intensity (MFI) of 6885, but serum PLA2R antibodies remained negative. Based on these findings, the patient was treated with pulse methylprednisolone, 5 sessions of plasma exchange at 40 ml/kg with 5% human albumin and fresh frozen plasma replacement, intravenous immunoglobulin (at 100 mg/kg × 5) and rituximab (two doses of 1 g 2 weeks apart). Subsequently, the serum creatinine settled to 1.6 mg/dl, and DSA reduced to < 500 MFI. Three months after discharge, the serum creatinine is 1.5 mg/dl, 24-hour urine protein is 982 mg/day and follow-up DSA remains negative., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Purpose: Induction immunosuppression has improved the long-term outcomes after lung transplant. This is the first report exploring the association of induction immunosuppression with the development of de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) in lung transplant recipients (LTR)., Methods: Sixty-seven consecutive primary LTR were followed for 3 years posttransplant. A total of 41/67 (61%) LTR-received induction immunosuppression using a single dose of rabbit Antithymocyte Globulin (rATG; 1.5 mg/kg) within 24 h of transplant. All recipients had a negative flow cytometry crossmatch on the day of transplant. Serum samples at 1, 3, 6, and 12 months posttransplant were assessed for the presence of de novo HLA DSA., Results: De novo HLA DSA were detected in 22/67 (32.8%) LTR within 1-year posttransplant. Of these, 9/41 (21.9%) occurred in the induction therapy group and 13/26 (50%) in the noninduction group. Class II DSA were detected in 3/41 (7.3%) LTR who received induction compared to 9/26 (34.6%) LTR without induction immunosuppression (p = .005). Differences in overall survival or freedom from chronic lung allograft dysfunction rates between the two groups were not statistically significant., Conclusion: Induction immunosuppression utilizing a modified regimen of single-dose rATG is associated with a significant reduction in de novo DSA production in LTR., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Leukopenia occurs frequently following kidney transplantation and is associated with adverse clinical outcomes including increased infectious risk. In this study we sought to characterize the causes and complications of leukopenia following kidney transplantation., Methods: In a cohort of adult patients (≥18 years) who underwent kidney transplant from Jan 2006-Dec 2017, we used univariable Cox proportional Hazards models to identify predictors of post-transplant leukopenia (WBC < 3500 mm 3 ). Factors associated with post-transplant leukopenia were then included in a multivariable backwards stepwise selection process to create a prediction model for the outcome of interest. Cox regression analyses were subsequently used to determine if post-transplant leukopenia was associated with complications., Results: Of 388 recipients, 152 (39%) developed posttransplant leukopenia. Factors associated with leukopenia included antithymocyte globulin as induction therapy (HR 3.32, 95% CI 2.25-4.91), valganciclovir (HR 1.84, 95% CI 1.25-2.70), tacrolimus (HR 3.05, 95% CI 1.08-8.55), prior blood transfusion (HR 1.17 per unit, 95% CI 1.09- 1.25), and donor age (HR 1.02 per year, 95% CI 1.00-1.03). Cytomegalovirus infection occurred in 26 patients with leukopenia (17.1%). Other than cytomegalovirus, leukopenia was not associated with posttransplant complications., Conclusion: Leukopenia commonly occurred posttransplant and was associated with modifiable and non-modifiable pretransplant factors.

Background: This systematic review and meta-analysis were performed to explore the association between rabbit thymoglobulin (rATG) doses and transplant-related efficacy and safety outcomes., Methods: We searched PubMed and Scopus databases from inception up to June 2020. The primary efficacy and safety endpoints in kidney transplant recipients were evaluated., Results: Data of 23 cohort studies (3457 patients) and three RCTs (154 patients) were extracted and analyzed. rATG doses of ≤4.5 m/kg was associated with lower rates of biopsy proven acute rejection, cytomegalovirus infection, BK virus infection, and malignancy with a comparable rate of delayed graft function, patients' mortality, and death-censored graft loss compared to rATG total doses of 4.5-6 mg/kg or more than 6 mg/kg. The rATG doses of 3-4.5 mg/kg was associated with better outcomes in dose-response analysis., Expert Opinion: Cumulative rATG induction doses as much as 3-4.5 mg/kg is as effective as higher doses regarding to allograft and patient outcomes while minimizing potential adverse effects in kidney transplant recipients.

Introduction: Contemporary dosing strategies for rabbit anti-thymocyte globulin (rATG) in kidney transplantation aim to reduce cumulative exposure, minimizing long-term adverse events. The use of ideal body weight-based dosing has been trialed, however concern for increased rejection post-transplant exists due to lower doses of rATG. Research Questions: The primary aim of this study was to compare rejection rates between rATG dosing protocols using actual body weight and ideal body weight and secondarily to evaluate cost savings following protocol implementation., Design: This was a retrospective study surrounding implementation of an ideal body weight-based dosing protocol for rATG. We compared 75 kidney transplant recipients in whom rATG was dosed based on actual body weight (pre-protocol group) to 64 in whom dosing was based on ideal body weight (post-protocol group), following a nine-month washout., Results: The mean cumulative rATG dose in the pre-protocol group was 6.3 mg/kg of actual body weight. When ideal body weight was used in the post-protocol group, the mean dose was 4.5 mg/kg of actual body weight. The rejection rate was 18.7% pre-protocol and 23.4% postprotocol, which did not represent a statistically significant difference (p = 0.491). The actual annual cost savings after protocol implementation exceeded $162,000, approximately $2,500 per patient., Conclusion: Results suggest ideal body weight-based dosing of rATG may reduce exposure and cost, without significantly impacting the risk of rejection in kidney transplant recipients. More studies are needed to confirm these findings.

Induction therapy with rabbit anti-thymocyte globulin (rATG) in low-risk kidney transplant recipients (KTR) remains controversial, given the associated increased risk of cytomegalovirus (CMV) infection. This natural experiment compared 12-month clinical outcomes in low-risk KTR without CMV prophylaxis (January/3/13-September/16/15) receiving no induction or a single 3 mg/kg dose of rATG. We used logistic regression to characterize delayed graft function (DGF), negative binomial to characterize length of hospital stay (LOS), and Cox regression to characterize acute rejection (AR), CMV infection, graft loss, death, and hospital readmissions. Recipients receiving 3 mg/kg rATG had an 81% lower risk of AR (aHR 0.14 0.19 0.25 , P < 0.001) but no increased rate of hospital readmissions because of infections ( 0.68 0.91 1.21 , P = 0.5). There was no association between 3 mg/kg rATG and CMV infection/disease (aHR 0.86 1.10 1.40 , P = 0.5), even when the analysis was stratified according to recipient CMV serostatus positive (aHR 0.94 1.25 1.65 , P = 0.1) and negative (aHR 0.28 0.57 1.16 , P = 0.1). There was no association between 3 mg/kg rATG and mortality (aHR 0.51 1.25 3.08 , P = 0.6), and graft loss (aHR 0.34 0.73 1.55 , P = 0.4). Among low-risk KTR receiving no CMV pharmacological prophylaxis, 3 mg/kg rATG induction was associated with a significant reduction in the incidence of AR without an increased risk of CMV infection, regardless of recipient pretransplant CMV serostatus., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Eighty primary renal allograft recipients, 61 living-related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30-47 years. They were treated with three different early immunosuppression programs (1963-1970: thymectomy, splenectomy, high oral prednisone; 1971-1979: divided-dose intravenous methylprednisolone; and 1980-1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long-term treatment often included the anti-platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40-year success. At 35 years, death-censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan-Meier estimate). Biopsy-documented early acute cellular and highly probable antibody-mediated rejections were reversed with divided-dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non-plasma-cell malignancies was identified. Twenty-seven azathioprine-treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a "low immunosuppression state of allograft acceptance (LISAA)". The lifetime achievements of these patients following a single renal allograft and low-dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To summarize the efficacy and safety of the combination of rituximab and ATG as induction therapy in highly sensitized kidney transplant recipients. Methods: Clinical data of patients who received kidney transplantation from donation after cardiac death(DCD) in Organ Transplant Center of Second Affiliated Hospital of Guangzhou Medical University from January 1st 2015 to December 31th 2016 was retrospectively analyzed. Highly sensitized patients with over 30% active panel reactive antibody (PRA>30%) received rituximab, while non-sensitized recipients as controlled group. All selected patients were observed in the renal function, urine protein, hemogram and the variation of PRA at each time point. Acute rejection, infection required hospitalization, delayed graft function(DGF), primary nonfunction (PNF), graft dysfunction, the mortality rate of patients with good allograft function and the graft survival rate were also observed. Results: 46 groups of patients were selected into highly-sensitized group and non-sensitized group. In both groups, there was no statistical difference in the renal function, urine protein and WBC (all P> 0.05). Highly sensitized recipients at day 7 and day 14 following the surgery, had a significantly lower percentage of lymphocyte counts and lymphocyte proportion compared to other groups, with statistical differences(all P< 0.05). Both groups had a similar incidence of DGF(2.2%) and no occurrence of PNF. 19.5% of highly sensitized recipients experienced acute rejection and 13% in control group. More specifically, no statistical difference was noted in the rate of infection required hospitalization(30.4% vs 22.2%), graft loss(2.2% vs 0) and the mortality rate of patients with good allograft function(4.3% vs 2.2%)(all P> 0.05). The graft survival rate was 97.8% in the highly-sensitized group, while 100% in the control group. And the rate of patient survival in these two groups was 95.7% and 97.8%, with no statistical differences(all P> 0.05). Conclusions: Immune-induction therapy that combines Rituximab with ATG can significantly inhibit lymphocyte proliferation. It is effective and safe in treating hypersensitive patients. The survival rate of human/kidney of hypersensitive patients in the short and medium term is comparable to those with low immune risk.

Introduction: There are limited data to guide optimal treatment strategies for acute cellular rejection (ACR) based on Banff grade for pediatric kidney transplant recipients. This report reviews a large pediatric transplant center's experience with ACR., Materials and Methods: A retrospective analysis of pediatric kidney transplant recipients at our center from 2007 to 2014 was performed. Primary outcomes were incidence of graft failure and graft function one year following ACR based on Banff grade and treatment received., Results: A total of 204 patients were reviewed, of which 65 received rejection treatment with either an oral steroid cycle (n = 16), intravenous steroid pulse (n = 28), or anti-thymocyte globulin (rATG, n = 21). Overall, patients received rATG for treatment of more severe rejection associated with impaired graft function and as a group experienced statistically significant improvements in eGFR over the year following treatment, though most did not regain baseline graft function., Discussion: Our data suggest that rATG is partially effective in treating ACR, but our study was underpowered to determine the effect of different treatments based on Banff grade. Since there is limited literature to guide clinical treatment of ACR in children, large transplant centers should collaborate to evaluate outcomes and establish evidence-based practice., (© 2018 Wiley Periodicals, Inc.)

Background and Objectives: Post-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder., Design, Setting, Participants, & Measurements: We reviewed the data from all patients who underwent kidney retransplantation after post-transplant lymphoproliferative disorder in all adult kidney transplantation centers in France between 1998 and 2015., Results: We identified a total of 52 patients with kidney transplants who underwent 55 retransplantations after post-transplant lymphoproliferative disorder. The delay from post-transplant lymphoproliferative disorder to retransplantation was 100±44 months (28-224); 98% of patients were Epstein-Barr virus seropositive at the time of retransplantation. Induction therapy for retransplantation was used in 48 patients ( i.e. , 17 [31%] patients received thymoglobulin, and 31 [57%] patients received IL-2 receptor antagonists). Six patients were also treated with rituximab, and 53% of the patients received an antiviral drug. The association of calcineurin inhibitors, mycophenolate mofetil, and steroids was the most common maintenance immunosuppression regimen. Nine patients were switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. One patient developed post-transplant lymphoproliferative disorder recurrence at 24 months after retransplantation, whereas post-transplant lymphoproliferative disorder did not recur in 51 patients., Conclusions: The recurrence of post-transplant lymphoproliferative disorder among patients who underwent retransplantation in France is a rare event., (Copyright © 2017 by the American Society of Nephrology.)

Objective: To compare the safety and effectiveness between antithymocyte globulin (ATG) and basiliximab in deceased donor renal transplantation within matched groups where paired recipients received graft donations from same donors. Methods: A total of 124 cases of deceased donor kidney transplantation performed at Wuhan Tongji Hospital from January 2013 to November 2015 were retrospectively analyzed. Based upon their induction therapies, the recipients receiving graft donations from same donors were divided into two groups, namely ATG group ( n =62) and basiliximab group ( n =62). Clinical data were gathered and comparisons were made between the two groups. Results: Delayed graft function (DGF) implicated less patients in the ATG group (11, 17.7%) compared with basiliximab group (21, 33.9%) ( P =0.040). Duration of DGF was also significantly shorter in the ATG group than in the basiliximab group[(14.92±6.23) vs(20.26±7.89)days, P =0.048]. The rates of DGF were 5/18 in the ATG group and 10/15 in the basiliximab group ( P =0.025), when subgrouping the patients with elevated risk factors (donor age >50 or a history of hypertension or graft cold ischemia time >24 h) for DGF. The acute rejection rates did not differ between the two groups significantly; comparable one-year graft and patient survival were observed between the ATG and basiliximab groups(all P >0.05). Conclusions: The duration of DGF and DGF rate after deceased donor renal transplantation is reduced by ATG, when compared with basiliximab. Moreover, in recipients with elevated risk factors for DGF, ATG diminishes DGF incidence significantly.