Biopsy-confirmed Acute Rejection Research Articles

De-novo use of generic tacrolimus (Adoport) in renal transplant recipients: A single center experience from Türkiye

Objective: Renal transplantation is the best treatment for end-stage kidney disease, and tacrolimus has become an important immunosuppressive treatment for kidney transplant patients since it was introduced. After the first generic tacrolimus has been approved by the FDA, studies have begun to compare the effectiveness and safety of generic tacrolimus with the original tacrolimus. When using generic immunosuppressive therapies, it is also necessary to ensure that it provides adequate immunosuppression and does not cause severe toxicity. This study aims to compare clinical outcomes, including acute rejection, graft loss and adverse reactions, in patients receiving brand tacrolimus (Prograf, Astellas Pharma, U.S.) or generic tacrolimus (Adoport, Sandoz, UK) from the start of kidney transplant therapy. Study Design: Renal transplant recipients between 1 January 2015-1 March 2020 were screened retrospectively. All patients receiving de novo generic tacrolimus (n:51) and randomly selected 102 control renal transplant recipients receiving original tacrolimus were included in this study. Materials and Methods: We evaluated and recorded demographic, clinical and laboratory data including age, gender, primary kidney disease, donor type (live or dead), induction and death regimen, tacrolimus dose, tacrolimus through levels, serum creatinine, biopsy-confirmed acute rejection episodes, delayed transplant function, positive BK polyomavirus in the urine, BK polyomavirus-related nephropathy, cytomegalovirus infection in 1-year follow-up. Results: Most of the patients were male (64.1%) with a mean age of 38.3 years. There was no significant difference in demographic characteristics between the original and generic tacrolimus groups. No differences were found in terms of creatinine levels, total daily dose of tacrolimus and tacrolimus trough levels at discharge and the first year. Additionally, biopsy-confirmed acute rejection in the following year after transplantation, BKPyV positivity in urine, BKPyVAN, CMV viremia and adverse reactions related to tacrolimus were similar between the two groups. Conclusion: With this study, we aimed to contribute to the literature with our experience on the use of generic tacrolimus from our country. As a result of our study, we noted that generic tacrolimus can be safely preferred for de-novo use with close drug-level monitoring because it is an immunosuppressant agent with a narrow therapeutic index. There is a continuing need for randomized prospective-designed and multi-centric studies with a wide range of patients.

Long-Term Outcomes with Prolonged-Release Tacrolimus in Kidney Transplantation: A Retrospective Real-World Data Analysis.

BACKGROUND Long-term real-world outcomes data for kidney transplant recipients (KTRs) converting from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT) are limited. MATERIAL AND METHODS A retrospective, non-interventional review of adult KTRs treated with PRT for ≥1 month was conducted in Germany. Data were extracted from time of transplant (2008-2014) to 2018. Primary composite endpoints (graft loss, biopsy-confirmed acute rejection, graft dysfunction) and secondary endpoints (all-cause mortality, kidney function course, and tacrolimus dose/trough levels) were analyzed for sub-cohorts: de novo PRT, early conversion from IRT (within 6 months post-transplant), and late conversion (7 months to 3 years). RESULTS Analysis included 163 patients (101 de novo, 12 early converters, and 50 late converters). The overall Kaplan-Meier estimate of freedom from efficacy failure through 5 years was 0.537, (95% confidence interval (CI) 0.455-0.612) (de novo: 0.512 [0.407-0.608]; early converters: 0.500 [0.208-0.736]; late converters: 0.594 [0.443-0.717]). The overall survival rate was 0.925 (95% CI 0.872-0.957) (de novo: 0.900 [0.823-0.945]; early converters: 0.917 [0.539-0.988]; late converters: 0.977 [0.846-0.997]). During follow-up, there was a gradual reduction in tacrolimus dose and trough levels; kidney function remained stable in all cohorts. Multivariable analysis found re-transplantation, organ donor quality, best estimated glomerular filtration rate 8-12 weeks after transplant, and treatment center (between-center differences in age, sex, donor status/quality) were significantly associated with efficacy failure. CONCLUSIONS There was no difference in long-term survival profiles between KTRs who received PRT de novo vs those who converted from IRT, with 5-year survival remaining high in both groups.

Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+ T cells and CD16bright natural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+ DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+ (IFN-γ+) CD4+ and CD8+ T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+ T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+ T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

Efficacy and safety of once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in kidney transplant recipients: A meta-analysis and trial sequential analysis.

Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients. Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model. In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12 to 0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups. Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.

#3440 TOCILIZUMAB INDUCTION THERAPY IN KIDNEY TRANSPLANTATION

Abstract Background and Aims Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients (KTRs). There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in KTRs. The purpose of the present study was to compare induction therapy involving tocilizumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. Method In this prospective study, we randomly assigned patients to receive tocilizumab or conventional induction therapy such as basiliximab. Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 30% or more. The 102 high-risk patients received tocilizumab (one dose of 8 mg/kg, in 52 patients) or basiliximab (a total of 40 mg over 4 days, in 50 patients). The 113 low-risk patients received tocilizumab (one dose of 8 mg/kg, in 62 patients) or basiliximab (a total of 40 mg over 4 days, in 51 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 10-days glucocorticoid (prednisone) taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 2 years for safety and efficacy end points. Results The rate of biopsy-confirmed acute rejection was significantly lower in the tocilizumab group than in the basiliximab group at both 6 months (5.3% vs. 10.9%, P<0.01) and 12 months (7.9% vs. 12.9%, P<0.01). At 2 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with tocilizumab than with basiliximab (9.7% vs. 17.7%, P<0.05), but among high-risk patients, no significant difference was seen between tocilizumab and basiliximab (19.2% vs. 16.0%, P = 0.68). Adverse-event rates were similar among all four treatment groups. Conclusion By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with tocilizumab than with conventional therapy. The apparent superiority of tocilizumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, tocilizumab and basiliximab had similar efficacy. Further randomized and controlled studies are needed to support these results.

Efficacy of Prolonged-release Tacrolimus After Conversion From Immediate-release Tacrolimus in Kidney Transplantation: A Retrospective Analysis of Long-term Outcomes From the ADMIRAD Study.

A retrospective, noninterventional chart review study examined long-term graft survival in adult kidney transplant participants in the Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograf to Advagraf (ADMIRAD) clinical trial at 4 Belgian sites. Patients were randomized to receive once-daily PRT or twice-daily IRT for 6 mo, followed by treatment as per real-world clinical practice. Data were collected retrospectively from randomization day until December 31, 2018. Primary endpoints included efficacy failure, defined as a composite endpoint of graft loss, biopsy-confirmed acute rejection, and graft dysfunction. Secondary endpoints included overall patient survival and course of kidney function. This analysis included 78.5% of patients from ADMIRAD (n = 108 PRT; n = 64 IRT). The Kaplan-Meier survival rate without efficacy failure from randomization to year 5 was 0.741 (95% confidence interval [CI]: 0.647, 0.813) for the PRT group (n = 80), and 0.667 (95% CI: 0.536, 0.768) for the IRT group (n = 42) and remained higher for PRT throughout 10 y follow-up (P = 0.041). The Kaplan-Meier estimate of overall survival from the time of last transplant was 0.981 (95% CI: 0.928, 0.995) and 0.880 (95% CI: 0.802, 0.928) at 5 and 10 y in the PRT group. Kidney function parameters and tacrolimus trough levels remained stable over the follow-up period. Patients in the ADMIRAD study who received PRT for up to 10 y had improved long-term outcomes compared with patients receiving IRT, with a consistent effect on both graft and patient survival.

Real-world effectiveness of preemptive therapy (PET) for cytomegalovirus (CMV) disease prevention in CMV high-risk donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR).

Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET. We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring. Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts. In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted.

Perturbations of the T-cell immune repertoire in kidney transplant rejection.

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.

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

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

Management strategies and outcomes in renal transplant recipients recovering from COVID-19: A retrospective, multicentre, cohort study

SummaryBackgroundThere is an enormous knowledge gap on management strategies, clinical outcomes, and follow-up after kidney transplantation (KT) in recipients that have recovered from coronavirus disease (COVID-19).MethodsWe conducted a multi-center, retrospective analysis in 23 Indian transplant centres between June 26, 2020 to December 1, 2021 on KT recipients who recovered after COVID-19 infections. We analyzed clinical and biopsy-confirmed acute rejection (AR) incidence and used cox-proportional modeling to estimate multivariate-adjusted hazard ratios (HR) for predictors of AR. We also performed competing risk analysis. Additional outcome measures included graft loss, all-cause mortality, waiting time from a positive real-time polymerase test (RT-PCR) to KT, laboratory parameters, and quality of life in follow-up.FindingsAmong 372 KT which included 38(10·21%) ABO-incompatible, 12(3·22%) sensitized, 64(17·20%) coexisting donors with COVID-19 history and 20 (5·37%) recipients with residual radiographic abnormalities, the incidence of AR was 34 (9·1%) with 1(0·26%) death censored graft loss, and 4(1·07%) all-cause mortality over a median (interquartile range) follow-up of 241 (106–350) days. In our cox hazard proportional analysis, absence of oxygen requirement during COVID-19 compared to oxygen need [HR = 0·14(0·03–0·59); p-value = 0·0071], and use of thymoglobulin use compared to other induction strategies [HR = 0·17(0·03–0.95); p-value = 0·044] had a lower risk for AR. Degree of Human leukocyte antigen (HLA) DR mismatch had the highest risk of AR [HR = 10.2(1·74–65·83); p-value = 0·011]. With competing risk analysis, with death as a competing event, HLA DR mismatch, and oxygen requirement continued to be associated with AR. Age, gender, obesity, inflammatory markers, dialysis vintage, steroid use, sensitization and ABO-incompatibility have not been associated with a higher risk of AR. The median duration between COVID-19 real time polymerase test negativity to transplant was 88(40–145) days (overall), and ranged from 88(40–137), 65(42–120), 110(49–190), and 127(64–161) days in World Health Organization ordinal scale ≤ 3, 4, 5, and 6–7, respectively. There was no difference in quality of life, tacrolimus levels, blood counts, and mean serum creatinine assessed in patients with a past COVID-19 infection independent of severity.InterpretationOur findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19.FundingSanofi

Comparison between Tc-99m DTPA and Tc-99m MAG3 Renal Scintigraphy for Prediction of Early Adverse Outcome After Kidney Transplantation.

Renal scintigraphy (RS) with either technetium-99m diethylene-triamine-pentaacetate (Tc-99m DTPA) or technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) has both been used to evaluate early allograft function after kidney transplantation (KT). This study was done to compare the predictive performance of RS using these two radiopharmaceuticals for prediction of outcomes during first 3months of KT. This retrospective study included patients who received KT then underwent both Tc-99m DTPA and Tc-99m MAG3 RS, successively. Receiver operating characteristic (ROC) curve analysis was used to determine the predictiveness of RS parameters on early clinical adverse outcomes of either (1) graft-related death, (2) need for graft resection, (3) delayed graft function requiring temporary dialysis, or (4) a serum creatinine level of ≥ 2.0mg/dL at three months post-KT, as well as to predict biopsy-confirmed acute tubular necrosis and acute rejection. Of 187 patients included, 77 (41.2%) had at least one early adverse clinical outcome. Tc-99m MAG3 RS was more predictive than Tc-99m DTPA RS, in terms of AUCROC, in three parameters including time to peak (0.754 vs. 0.516, p-value 0.0001), 20-min to peak ratio (0.762 vs. 0.651, p-value 0.006), and 20-min to 3-min ratio (0.823 vs. 0.699, p-value 0.0005). Acute tubular necrosis was better predicted by Tc-99m MAG3 RS while both were at best only modest in predicting acute rejection. Three parameters which, when obtained from Tc-99m MAG3 RS, had superior predictiveness compared with Tc-99m DTPA RS, including time to peak, 20-min to peak ratio, and 20-min to 3-min ratio.

Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation.

To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2). In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.

Clinical and Analytical Validation of a Novel Urine-Based Test for the Detection of Allograft Rejection in Renal Transplant Patients.

In this clinical validation study, we developed and validated a urinary Q-Score generated from the quantitative test QSant, formerly known as QiSant, for the detection of biopsy-confirmed acute rejection in kidney transplants. Using a cohort of 223 distinct urine samples collected from three independent sites and from both adult and pediatric renal transplant patients, we examined the diagnostic utility of the urinary Q-Score for detection of acute rejection in renal allografts. Statistical models based upon the measurements of the six QSant biomarkers (cell-free DNA, methylated-cell-free DNA, clusterin, CXCL10, creatinine, and total protein) generated a renal transplant Q-Score that reliably differentiated stable allografts from acute rejections in both adult and pediatric renal transplant patients. The composite Q-Score was able to detect both T cell-mediated rejection and antibody-mediated rejection patients and differentiate them from stable non-rejecting patients with a receiver–operator characteristic curve area under the curve of 99.8% and an accuracy of 98.2%. Q-Scores < 32 indicated the absence of active rejection and Q-Scores ≥ 32 indicated an increased risk of active rejection. At the Q-Score cutoff of 32, the overall sensitivity was 95.8% and specificity was 99.3%. At a prevalence of 25%, positive and negative predictive values for active rejection were 98.0% and 98.6%, respectively. The Q-Score also detected subclinical rejection in patients without an elevated serum creatinine level but identified by a protocol biopsy. This study confirms that QSant is an accurate and quantitative measurement suitable for routine monitoring of renal allograft status.

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. The 7th EU Framework Programme.

Efficacy of anti-T-lymphocyte globulin-Fresenius as an induction agent in deceased-donor renal transplantation: A cohort study.

Anti-T-lymphocyte globulin (ATG) is frequently used in the induction regimen of renal transplantation, but its dose has not been standardized. In the present study, the efficacy of different ATG-Fresenius (ATG-F) doses was assessed in recipients of renal transplantation. A total of 131 adult recipients of renal transplantation who received ATG-F induction between August 2015 and July 2018 were included. The incidence of biopsy-confirmed acute rejection, graft function, as well as graft and patient survival within 12 months post-transplant, was assessed, and adverse events, including hematologic and infection-associated side effects, were compared between patients receiving a cumulative ATG-F dose of <7 or ≥7 mg/kg. The incidence of biopsy-confirmed acute rejection was similar between patients receiving cumulative doses of <7 and ≥7 mg/kg (7.5 vs. 4.7%, P=0.766). The incidence of infection within 12 months was lower in the ATG-F <7 mg/kg group compared with that in the ≥7 mg/kg group (26.9 vs. 50.0%, P=0.006), but the incidence of pneumonia did not differ between the ATG-F <7 and ≥7 mg/kg groups (10.4 vs. 20.3%, P=0.117). The incidence of urinary infection was higher in the ≥7 mg/kg group than in the <7 mg/kg group (20.4 vs. 7.46%, P=0.033), while the extent and duration of anemia and lymphopenia was similar between groups. There was no difference in graft function, delayed graft function, as well as overall and graft survival between the groups. In conclusion, a moderate reduction in the cumulative ATG-F dose was not associated with an increased risk of acute rejection, while the risk of infection was reduced. Optimization of the ATG-F dose for induction may facilitate the reduction of the risk of infection without compromising the induction efficacy in renal transplant recipients.

A urinary Common Rejection Module (uCRM) score for non-invasive kidney transplant monitoring.

A Common Rejection Module (CRM) consisting of 11 genes expressed in allograft biopsies was previously reported to serve as a biomarker for acute rejection (AR), correlate with the extent of graft injury, and predict future allograft damage. We investigated the use of this gene panel on the urine cell pellet of kidney transplant patients. Urinary cell sediments collected from patients with biopsy-confirmed acute rejection, borderline AR (bAR), BK virus nephropathy (BKVN), and stable kidney grafts with normal protocol biopsies (STA) were analyzed for expression of these 11 genes using quantitative polymerase chain reaction (qPCR). We assessed these 11 CRM genes for their abundance, autocorrelation, and individual expression levels. Expression of 10/11 genes were elevated in AR when compared to STA. Psmb9 and Cxcl10could classify AR versus STA as accurately as the 11-gene model (sensitivity = 93.6%, specificity = 97.6%). A uCRM score, based on the geometric mean of the expression levels, could distinguish AR from STA with high accuracy (AUC = 0.9886) and correlated specifically with histologic measures of tubulitis and interstitial inflammation rather than tubular atrophy, glomerulosclerosis, intimal proliferation, tubular vacuolization or acute glomerulitis. This urine gene expression-based score may enable the non-invasive and quantitative monitoring of AR.

Improvement of medication adherence with simplified once-daily immunosuppressive regimen in stable kidney transplant recipients: A prospective cohort study

Many immunosuppressive drugs are prescribed as twice-daily dosing. A simplified once-daily dosing of immunosuppressive drug regimen may improve medication adherence. We investigated medication adherence of simplified once-daily immunosuppressive regimen consisting of extended-release tacrolimus, sirolimus, and corticosteroids along with the efficacy and safety of this regimen. This study was a prospective, multicenter, controlled and cohort trial. Stable kidney transplant recipients who had received transplantation at least 3 months before the study enrollment were eligible for the study. Participants were required to fill-out the self-reported immunosuppressant therapy barrier scale (ITBS) questionnaire before and after the conversion. Other clinical laboratory parameters and adverse events were evaluated until 6 months post-conversion. A total of 160 kidney recipients comprised the intention-to-treat population. The mean total ITBS score was 19.5±4.0 at pre-conversion and 6 months after converting, the mean total ITBS score was 16.6±3.6 (p<0.001). Particularly, the ITBS scores of 4 questions related to the frequency of medication dosing were significantly different between pre-conversion and post-conversion. Only 1 patient (0.62%) was diagnosed as biopsy-confirmed acute rejection in the study period. There was no significant change in the mean estimated glomerular filtration rate after the conversion. Overall 95 patients (59.4%) had an adverse event and 28 patients (17.5%) had a serious adverse event. No graft loss and 1 death were reported. Medication adherence after the conversion to the once-daily immunosuppressive regimen was significantly improved with no additional risks of efficacy failure or adverse events.

Efficacy and safety of prolonged-release versus immediate-release tacrolimus in de novo liver transplant recipients in South Korea: a randomized open-label phase 4 study (MAPLE).

BackgroundProlonged-release tacrolimus is associated with better long-term graft and patient survival than the immediate-release formulation in liver transplant patients. However, no clinical data are available to assess the efficacy and safety of early conversion from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus in de novo liver transplant recipients in Korea.MethodsA 24-week, randomized, open-label study was conducted in 36 liver transplant recipients. All patients received immediate- release tacrolimus (0.1–0.2 mg/kg/day, divided into two doses) for 4 weeks after transplantation, at which time 50% of the patients were converted, at a ratio of 1 mg to 1 mg, to prolonged-release tacrolimus (once-daily). The primary efficacy endpoint was the incidence of biopsy-confirmed acute rejection (BCAR) from weeks 4 to 24 after transplantation (per-protocol set). Medication adherence, adverse event profiles, laboratory tests, vital signs, and physical changes were also recorded.ResultsBCAR frequency at 24 weeks was similar between the two treatment groups; two cases (mean±standard deviation, 0.14±0.53 cases) of BCAR were reported in one patient treated with prolonged-release tacrolimus (n=14), while no such cases were reported among patients treated with immediate-release tacrolimus (n=12). The tacrolimus blood concentration at weeks 12 and 24, medication adherence, and adverse event profiles were also similar between the formulations, with no unusual laboratory test results, vital signs, or physical changes reported.ConclusionsEarly conversion to a simplified, once-daily, prolonged-release tacrolimus regimen may be an effective treatment option for liver transplant recipients in Korea. Larger-scale studies are warranted to confirm non-inferiority to immediate-release tacrolimus formulation in de novo liver transplant recipients.

SAFETY AND EFFICACY OF TWO TACROLIMUS FORMULATIONS (PROGRAF® AND ADVAGRAF®) IN MALAYSIAN RENAL TRANSPLANT PATIENTS: A COMPARATIVE STUDY

Aim: A once-daily formulation of tacrolimus, Advagraf®, is increasingly being used in place of twice-daily tacrolimus, Prograf®, as a standard immunosuppressive agent for transplant patients. In this study, the clinical safety and efficacy of Advagraf® were compared with Prograf®, among multi-ethnic Malaysian renal transplanted population. Method: This retrospective study identified renal transplant patients who were converted from Prograf® to Advagraf® at the University Malaya Medical Centre (UMMC) (n=69). Clinical notes and laboratory records, including tacrolimus daily dose and trough levels, were obtained for one-year, pre-and post-conversion. Causality assessment of suspected adverse events were based on the WHO-Uppsala Monitoring Center criteria. Renal biopsy records were re-evaluated based on the updated Banff 2007 classification for biopsy-confirmed acute rejection (BPAR). Results: Following conversion to Advagraf®, the mean tacrolimus trough level and daily dose decreased significantly (p<0.01) from 6.11±2.15 to 4.91±1.25 ng/mL and 4.08±2.19 to 3.48±1.79 mg/day, respectively. There was no significant difference in serum creatinine and estimated glomerular function. HDL was significantly increased (p=0.005) while triglycerides was significantly decreased following conversion to Advagraf® (p=0.003). The incidence of BPAR was 16% (4 cases in Prograf® and 7 cases in Advagraf®). No patients died or lost their grafts during the study period. There were 34 cases of adverse events which were classified as certain (5%), probable (36%), possible (23%) and unlikely (36%) with no significant difference between groups. Conclusion: Prograf® and Advagraf® tacrolimus formulations have comparable safety and efficacy profiles among Malaysian renal transplant patients. Advagraf® may have an advantage in terms of lipid profile. Keywords: Prograf®, Renal Transplant, Advagraf®, Acute Rejection, Safety

Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia-OPTIMIZE Study.

A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs). Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2-0.3 mg/kg; target trough level, 6-10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4-6 ng/mL, weeks 4-12; 3-5 ng/mL, weeks 12-52) or standard-exposure PR-T (target: 6-10 ng/mL, weeks 4-52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded. Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, -2.82; 95% confidence interval, -7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively. Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.