Acute Rejection Events Research Articles

Donor-derived cell-free DNA is a valuable monitoring tool after single lung transplantation: Multicenter analysis

Donor-derived cell-free DNA (dd-cfDNA) is a nonspecific plasma biomarker for tissue injury which has been validated for monitoring of acute rejection (AR) after lung transplantation (LT). However, no studies to date have focused specifically on single lung transplantation (SLT). Herein we report the performance of dd-cfDNA in detecting AR in SLT from six academic centers who implemented this biomarker surveillance in their standard of practice (SOP). Dd-cfDNA test results were corrected for SLT by an algorithm in the CLIA-laboratory to permit comparison against the same 1.0% threshold used in double-lung transplant. Investigators reviewed patient SOP EMR clinical data to assign test results into cohorts based on clinical allograft health status. To avoid ambiguity in interpretation, samples drawn after a prior acute rejection or infection event or without histopathologic confirmation of acute rejection, were excluded from further analysis. Diagnostic cohorts included: Acute Rejection (AR, N=25 samples), healthy (STABLE, N=137), allograft-related Infection (INFXN, N=41), Chronic Lung Allograft Dysfunction (CLAD, N=7), and “OTHER” (N=12) types of graft injury. The study included a total of 257 dd-cfDNA results from 103 SLT patients while one patient was excluded due to active cancer. Samples were drawn a median of 233 days (IQR: 96-489) after SLT. Analysis of laterality for SLT (R vs L) and median dd-cfDNA fraction in AR and STABLE cohort was not statistically different. The median dd-cfDNA fraction was elevated with AR (1.8%) and INFXN (1.1%) vs STABLE (0.46%; p<0.0001). dd-cfDNA with CLAD was also significantly higher than STABLE cohort (p=0.0155). The Area Under Receiver Operator Characteristics (AUROC) Curve was 0.850 (95% CI: 0.72 - 0.95, p<0.0001) for AR vs STABLE cohort. Applying the dd-cfDNA threshold ≥ 1.0% for AR, yielded a Sensitivity= 77.8%, Specificity= 84.6%, Positive (PPV)= 38.31%, and Negative Predictive Value (NPV)= 96.83%. These multi-center data, incorporating real-world experiences, support the clinical validity and utility of dd-cfDNA monitoring of SLT recipients. Additional studies of the impact of biomarker surveillance on clinically meaningful outcomes should be forthcoming from robust, prospective, clinical trials already in progress.

Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies

IntroductionThis study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. MethodsA systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. ResultsThirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). ConclusionGastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.

Tacrolimus-loaded Drug Delivery Systems in Vascularized Composite Allotransplantation: Lessons and Opportunities for Local Immunosuppression.

Long-term systemic immunosuppression is needed for vascularized composite allotransplantation (VCA). The high rate of acute rejection episodes in the first posttransplant year, the development of chronic rejection, and the adverse effects that come along with this treatment, currently prevent a wider clinical application of VCA. Opportunistic infections and metabolic disturbances are among the most observed side effects in VCA recipients. To overcome these challenges, local immunosuppression using biomaterial-based drug delivery systems (DDS) have been developed. The aim of these systems is to provide high local concentrations of immunosuppressive drugs while reducing their systemic load. This review provides a summary of recently investigated local DDS with different mechanisms of action such as on-demand, ultrasound-sensitive, or continuous drug delivery. In preclinical models, ranging from rodent to porcine and nonhuman primate models, this approach has been shown to reduce systemic tacrolimus (TAC) load and adverse effects, while prolonging graft survival. Localized immunosuppression using biomaterial-based DDS represents an encouraging approach to enhance graft survival and reduce toxic side effects of immunosuppressive drugs in VCA patients. Preclinical models using TAC-releasing DDS have demonstrated high local immunosuppressive effects with a low systemic burden. However, to reduce acute rejection events in translational animal models or in the clinical reality, the use of additional low-dose systemic TAC treatment may be envisaged. Patients may benefit through efficient graft immunosuppression and survival with negligible systemic adverse effects, resulting in better compliance and quality of life.

Immune Checkpoint Inhibitors Before Liver Transplantation May Increase the Risk of Rejection: A Meta-Analysis

Abstract Background Immune checkpoint inhibitors (ICI) represent a major breakthrough in cancer immunotherapy. Several molecules have shown efficacy in HCC and are increasingly used as a bridging therapy before liver transplantation. Initial reports have raised concern about severe rejections in patients following ICI therapy. Aims This meta-analysis assesses the risk of neoadjuvant ICI therapy before liver transplantation. Methods We systematically searched MEDLINE, Web of Science and Embase for studies including all patients treated with ICI therapy before liver transplantation from a given center. A random-effects model was applied to pooled results with a priori determined subgroup analyses. Results Eight studies published during the past three years fulfilled all inclusion criteria. All studies are noncomparative case series, one prospective, and seven retrospective. Studies included 52 patients who received various PD1 inhibitors between 1 and 253 days prior to liver transplantation. Patients treated with an ICI ahead of transplantation demonstrated an overall relative risk (RR) of 2.5 [95% CI: 1.4-3.8] for an acute rejection event. Furthermore, a subgroup analysis showed that patients who received PD1 inhibitors up to 30 days (RR 7.2 [95% CI: 4.9-10.5]) or between 30 and 60 days (RR 7.2 [95% CI: 5.1-10.3]) prior to liver transplantation suffered a higher rejection risk than patients with a “washout period” beyond 60 days (RR 1.8 [95% CI: 0.6-4.9]). The ICI, age, and underlying etiology were insignificant for RR in their subgroup analysis. Conclusion PD1 inhibitors within two months of liver transplantation may significantly elevate rejection risk. This meta-analysis provides valuable insights to inform clinical decision-making. Nevertheless, future trials remain imperative to establish definitive guidelines.

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Incomplete reporting of clinically significant acute rejection episodes in the national kidney transplant registry

Administrative claims data could provide a unique opportunity to identify acute rejection (AR) events using specific antirejection medications and to validate rejected data reported to the Organ Procurement and Transplantation Network. This retrospective cohort study examined differences in registry-reported events and those identified using claims data among adult kidney transplant recipients from 2012 to 2017 using Standard Analysis Files from the US Renal Data System. Rejection rates, survival estimates, and center-level differences were assessed using each approach. Among 45 880 first-time kidney transplant recipients, we identified 3841 AR events within 12 months of transplant reported by centers in the registry; claims data yielded 2945 events. Of all events occurring within 12 months of transplant, 48.5% were reported using registry only, 32.9% were identified using claims only, and 18.6% were identified using both approaches. A 3-year death-censored graft survival probability was 90.0%, 88.4%, and 81.2% (P < .001) for ARs identified using registry only, claims data only, and both approaches, respectively. The large discordance between registry-reported and claims-based events suggests incomplete and potentially inaccurate reporting of events in the Organ Procurement Transplant Network registry. These findings have important implications for analyses that use AR data and underscore the need for improved capture of clinically meaningful events.

Microcirculatory Disease in Patients after Heart Transplantation.

Although the treatment and prognosis of patients after heart transplantation have significantly improved, late graft dysfunction remains a critical problem. Two main subtypes of late graft dysfunction are currently described: acute allograft rejection and cardiac allograft vasculopathy, and microvascular dysfunction appears to be the first stage of both. Studies revealed that coronary microcirculation dysfunction, assessed by invasive methods in the early post-transplant period, correlates with a higher risk of late graft dysfunction and death during long-term follow-up. The index of microcirculatory resistance, measured early after heart transplantation, might identify the patients at higher risk of acute cellular rejection and major adverse cardiovascular events. It may also allow optimization and enhancement of post-transplantation management. Moreover, cardiac allograft vasculopathy is an independent prognostic factor for transplant rejection and survival rate. The studies showed that the index of microcirculatory resistance correlates with anatomic changes and reflects the deteriorating physiology of the epicardial arteries. In conclusion, invasive assessment of the coronary microcirculation, including the measurement of the microcirculatory resistance index, is a promising approach to predict graft dysfunction, especially the acute allograft rejection subtype, during the first year after heart transplantation. However, further advanced studies are needed to fully grasp the importance of microcirculatory dysfunction in patients after heart transplantation.

Metformin Use and Long-term Clinical Outcomes in Kidney Transplant Recipients

Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with pre-transplant diabetes mellitus (DM) or post-transplant diabetes mellitus (PTDM) is uncertain. We investigated the clinical effects of metformin in KTRs. Retrospective cohort study. A total of 1,995 KTRs with diabetes from six tertiary referral centers in the Republic of Korea. Metformin usage was defined as the use of metformin for >90 days after kidney transplantation; 1,193 KTRs were metformin users, and 802 KTRs did not use metformin. Changing usage of metformin among those exposed for >90 days was also characterized. Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events. Survival analyses were conducted using multivariable Cox regression and competing risk analyses using Fine and Gray models. Changes in metformin use over time were modeled using a time-varying covariate. Metformin usage, mean daily dose, and HbA1c changes were considered in the landmark analysis to address time-varying confounding. Metformin use was associated with a lower risk of DCGF (adjusted hazard ratio [aHR] 0.47, 95% confidence interval [CI] 0.23-0.96, P = 0.038); there was no significant association with all-cause mortality (aHR 0.94, 95% CI 0.32-2.76, P = 0.915) or BPAR: (aHR 0.98, 95% CI 0.62-1.54, P = 0.942). In the subgroup analysis, metformin usage was associated with a reduced risk of all-cause mortality and a lower risk of DCGF for both the pre-transplantation DM and PTDM groups. Metformin usage was associated with a lower risk of BPAR in the PTDM group, although it was less effective in the pre-transplantation DM group. There was no confirmed case of metformin-associated lactic acidosis (MALA) in the present cohort. A higher dose of metformin was correlated with lower risks of DCGF and BPAR. Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited; potential limited generalizability to other populations. Metformin usage may benefit KTRs, as evidenced by its association with a reduced risk of DCGF and the absence of MALA events. Randomized controlled trials are needed to validate these observational findings.

Predictive Efficacy of the Index of Microcirculatory Resistance for Acute Allograft Rejection and Cardiac Events After Heart Transplantation: A Systematic Review and Meta-Analysis.

In patients treated by heart transplantation, the index of microcirculatory resistance (IMR) has been found to have predictive potential for subsequent acute allograft rejection (AAR) and long-time cardiac events. When consulting related literature, the studies mostly were single-center with small sample sizes. The question of whether IMR can be utilized as a predictive biomarker is becoming increasingly contentious. To confirm the predictive efficacy of IMR, researchers did a systematic review and meta-analysis. From inception to April 2022, PubMed, EMBASE, Cochrane Library, Web of Science, Ovid, ProQuest, and Scopus systematically were searched. The results were presented as pooled ratio rate (RR) with 95% confidence intervals (CI). Assessment of the quality, heterogeneity analyses, and publication bias analysis also were performed. A total of 616 patients were studied in five trials. There were significant differences in subsequent AAR (RR = 4.08; 95% CI: 2.69~6.17; P = 0.000) or long-time cardiac events (RR=2.14; 95% CI: 1.44~3.19; P = 0.000) between IMR-high and IMR-low patients in the forest plots. Patients treated with heart transplantation in the high IMR group had better predictive efficacy than the low IMR group. High IMR could predict the events of subsequent AAR and cardiac events after heart transplantation. This will help reduce the occurrence of adverse events and personalize treatment for patients.

Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial

An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid. This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed. Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; p<0·0001). No acute rejection occurred. There were no serious adverse events related to vaccination. Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed. The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.

Duration of delayed graft function and its impact on graft outcomes in deceased donor kidney transplantation

BackgroundThere is controversy regarding the impact of delayed graft function (DGF) on kidney transplant outcomes. We hypothesize that the duration of DGF, rather than DGF itself, is associated with long-term kidney graft function.MethodsWe analyzed all deceased donor kidney transplants (DDKT) done at our center between 2008 to 2020. We determined factors associated with DGF duration. DGF duration was assessed at three 14-day intervals: < 14 DGF days, 14–27 DGF days, > 28 DGF days.We studied the impact of DGF duration on survival and graft function and resource utilization, including hospital length of stay and readmissions.Results1714 DDKT recipients were included, 59.4% (n = 1018) had DGF. The median DGF duration was 10 days IQR (6,15). The majority of recipients (95%) had resolution of DGF within 28 days. Donor factors associated with DGF days were longer cold ischemia time, donor on inotropes, older age, donation after circulatory death, higher terminal creatinine, and hypertension. Recipient factors associated with increased DGF duration included male sex, length on dialysis before transplant, and higher body mass index. There were no differences in acute rejection events or interstitial fibrosis progression by 4 months when comparing DGF days. The median length of stay was 3 days. However, readmissions increased with increasing DGF duration. Death-censored graft survival was not associated with the length of DGF except when DGF lasted > 28 days.ConclusionsInferior graft survival was observed only in recipients of DDKT with DGF lasting beyond 28 days. DGF lasting < 28 days had no impact on graft survival. Duration of DGF, rather than DGF itself, is associated with graft survival.Trial RegistrationRetrospective study approved by Mayo Clinic IRB number ID: 20-011561.

Panel-Reactive Antibody Associated with Acute Rejection Episodes After Heart Transplantation: An Analysis of the UNOS Database

<h3>Purpose</h3> The presence of circulating alloantibodies can prolong transplant waiting times and may be associated with worse post-transplant outcomes. Recently, patients undergoing heart transplantation have been found to possess higher panel reactive antibody (PRA) levels, but the impact of this finding is uncertain. We aimed to determine the association between an elevated PRA and subsequent episodes of acute rejection. <h3>Methods</h3> Using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research Database, we retrospectively reviewed HTs performed from January 2004 to September 2020. Multi-organ transplants and re-transplants were excluded from analysis. Site-reported "Most recent PRA Class I" and "Most Recent PRA Class II" were used to assess PRA level, and the "Acute Rejection Episodes" variable was used to identify acute rejection, regardless of use of anti-rejection therapies. Detection methodology between centers could vary. Patients were stratified into three groups: 1) No-PRA (PRA% = 0), 2) Some-PRA (PRA% >0 and <50), and 3) High-PRA (PRA% >50). Rates of acute rejection were compared by log-rank test, with multivariate analysis adjusting for clinically relevant factors. <h3>Results</h3> A total of 41,537 patients were included in this study. Approximately 19% of patients experienced at least one acute rejection event. When stratifying based on Most Recent PRA Class I, the Some-PRA and High-PRA groups had significantly higher rates of acute rejection episodes, OR 1.22 (95% CI 1.12-1.33, p <0.001) and OR 1.79 (95% CI 1.55-2.06, p <0.001), respectively. Similar findings were obtained when using Most Recent PRA Class II, OR 1.31, (95% CI 1.19-1.45, p <0.001) and OR 1.71 (95% CI 1.47-1.99, p <0.001), respectively. When adjusting for sex and pre-operative blood transfusions, the results remained generally consistent - Class I: OR 3.9 (95% CI 1.04-17, p <0.05) and OR 3.2 (95% CI 0.13-37, p = 0.38), respectively; Class II: OR 3.79 (95% CI 0.94-17, p = 0.065) and OR 18.58 (95% CI 1.42-467, p <0.05), respectively. <h3>Conclusion</h3> Elevated PRA levels are associated with acute rejection episodes after HT, irrespective of patient sex and pre-operative blood transfusions. Further research should be conducted to verify our findings prospectively and account for possible confounders.

A Randomized Controlled Trial on Safety of Steroid Avoidance in Immunologically Low-Risk Kidney Transplant Recipients

IntroductionSteroid-based immunosuppression after transplantation increases the risk of post-transplant diabetes mellitus (PTDM), with adverse effects on patient and graft survival. In the SAILOR study, we investigated the safety and efficacy of complete steroid avoidance in immunologically low-risk kidney recipients without diabetes on the current standard-of-care maintenance regimen with tacrolimus/mycophenolate mofetil (MMF).MethodsIn this 2-year, multicenter, open-label trial, a total of 222 patients were randomized to receive either steroid avoidance protocol (tacrolimus/MMF/antithymocyte globulin [ATG] induction [n = 113]) or steroid maintenance protocol (tacrolimus/MMF/prednisolone/basiliximab-induction [n = 109]).ResultsAt 1 year, no significant differences were found between steroid avoidance and steroid maintenance arms in the incidence of PTDM, the primary end point (12.4% vs. 18.3%, respectively, P = 0.30, CI: 16.3–4.4), or in overall biopsy-proven rejections (15% vs. 13.8%, respectively, P = 0.85). At 2 years, the composite end point of freedom from acute rejection, graft loss, and death (81% vs. 85%, respectively, P = 0.4), kidney function, or adverse events was comparable between the 2 arms. Moreover, 63.9% of the patients in the steroid avoidance arm remained free from steroids at 2 years.ConclusionThe SAILOR study provides further evidence for the feasibility, safety, and efficacy of early steroid-free treatment at 2 years in immunologically low-risk kidney recipients with tacrolimus/MMF maintenance regimen.

Abstract 11935: The Index of Microcirculatory Resistance to Predict Subsequent Acute Cellular Rejection and Cardiac Events After Heart Transplantation

Introduction: Single center data suggest that the index of microcirculatory resistance (IMR) measured early after heart transplantation predicts subsequent acute cellular rejection. Hypothesis: To validate whether IMR measured early after transplantation can predict subsequent acute cellular rejection and long-term outcome in a large multicenter cohort. Methods: From 5 international heart transplantation cohorts, 237 patients who underwent IMR measurement early after transplantation were enrolled. The primary outcome was biopsy-proven acute cellular rejection of grade 2 or 3 within 1 year after transplantation. A key secondary outcome was major adverse cardiac events (MACE, the composite of death, re-transplantation, myocardial infarction, stroke, graft dysfunction, and readmission due to a cardiac cause) at 10 years. Results: IMR was measured at a median of 7 weeks (interquartile range: 3 to 10 weeks) post-transplantation. Patients with acute cellular rejection grade 2 or 3 at the time of IMR assessment were excluded. At 1 year, the incidence of acute cellular rejection was 14.0%. IMR was associated proportionally with the risk of acute cellular rejection (per increase of 1-unit IMR; adjusted hazard ratio [aHR], 1.04; 95% confidence interval [CI], 1.01-1.06; P=0.002). The incidence of acute cellular rejection in patients with IMR ≥ 18 was 23.8%, while the incidence of acute cellular rejection in those with IMR &lt; 18 was 5.5% (aHR, 4.09; 95% CI, 1.67-10.0; P=0.002). At 10 years, MACE occurred in 86 (36.3%) patients. IMR was significantly associated with the risk of MACE (per increase of 1-unit IMR; aHR, 1.03; 95% CI, 1.01-1.05; P=0.002). Conclusions: IMR measured early after heart transplantation is associated with subsequent acute cellular rejection at 1 year and clinical events at 10 years. Early IMR measurement after transplantation identifies patients at higher risk and may guide personalized post-transplantation management.

Donor-Derived Cell-Free DNA Predicts De Novo DSA after Heart Transplantation

PurposeDevelopment of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development.MethodsFrom the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05).ResultsFrom analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02).ConclusionIn the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation. Development of de novo donor-specific HLA antibodies (dnDSA) may contribute to allograft injury and dysfunction, antibody-mediated rejection (ABMR), and potential development of cardiac allograft vasculopathy (CAV). Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels have been demonstrated during acute cellular rejection (ACR) and ABMR events after heart transplant (HT). The purpose of this study is to investigate the relationship between dd-cfDNA and subsequent DSA development. From the 916 HT patients enrolled in the Surveillance Heart Care Outcome Registry (SHORE), we reviewed 2136 samples of dd-cfDNA surveillance monitoring. Patients with ACR or ABMR on biopsy were excluded from analysis. The dnDSAs included HLA Class I and/or Class II epitopes and were analyzed to development of first dnDSA or last negative test, with censoring at 365 days. There were 613 DSA samples paired with dd-cfDNA levels that were obtained within 30 days of the DSA draw, with prior negative endomyocardial biopsy. Cox proportional hazards model fitting was utilized with dd-cfDNA as a covariate (p<0.05). From analysis of 613 paired samples, 127 (20.7%) demonstrated dnDSA with an associated median dd-cfDNA of 1.20% (IQR: 0.100 - 3.10%). 71 (11.6%) were associated with dnDSA Class I and 93 (15.2%) with Class II. When dichotomized for dd-cfDNA > 0.15%, [FIGURE] the positive likelihood ratio for development of Class I and/or Class II dnDSA (+LR) was 4.47 (p=0.03). When analyzed without censoring at 365 days, using dd-cfDNA at this cutoff, the +LR was 5.68 (p=0.02). In the prospective SHORE cohort, elevated dd-cfDNA levels > 0.15% were associated with increased likelihood for the subsequent development of dnDSA within the first year after heart transplantation.

Non-Association of Infectious Exposure and Seasonality with Cardiac Graft Rejection

<h3>Purpose</h3> Graft rejection remains a significant complication following cardiac transplantation. As infection results in elevated immune system activity, we hypothesized that acute rejection events would be more common following infectious exposures and during the winter respiratory virus season. <h3>Methods</h3> Patients were included who underwent cardiac transplantation at our center in the Midwest, between January 1^st, 2014 and December 31^st, 2017. The composite endpoint consisted of antibody mediated rejection (AMR), donor specific antibodies (DSA), heart failure readmissions, and death within two years. Infectious events collected during readmissions included a primary infectious diagnosis, positive respiratory virus panel, and other diagnosed or treated infections excluding BK, CMV, and EBV. <h3>Results</h3> We analyzed 115 patients meeting inclusion criteria. The primary composite endpoint was met by 69 patients (60%). Pre-transplant PRA Class 1 was associated with the composite endpoint (HR 1.03, 95% CI 1.003-1.05, p<0.05). Overall, 85 patients (73.9%) had an infectious event. Twenty two of 69 patients (32%) meeting the composite endpoint had an infectious event within 6 months prior to the endpoint. Incidence of the composite endpoint and secondary endpoints did not vary by season (p>0.05). However, patients transplanted during winter - defined as January to March - had worse survival when compared to a composite of other seasons (2-year survival: 75% vs 88.7%, p=0.014) (Figure 1). Freedom from the composite endpoint was not associated with whether a patient had an infectious event (p>0.05). <h3>Conclusion</h3> Our study did not show any association between infectious exposure and rejection following cardiac transplantation. However, this analysis was likely underpowered to determine this association and national studies are needed.

Influence of ABCB1 gene polymorphism on concentration to dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients.

Objective:To evaluate the possible association of ABCB1 single nucleotide polymorphism (SNPs) of the ABCB1 gene with tacrolimus dosages, concentration-to-dose ratios (CDR) and adverse effects in Pakistani liver transplant recipients.Methods:This observational study was conducted at Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad and Basic Medical Sciences Institute, Karachi from September 2016 to July 2020. Eighty-one liver transplant recipients were included. Demographics, clinical data, tacrolimus trough levels and doses were monitored. Electrochemiluminescence immunoassay (ECLIA) was used to measure tacrolimus trough levels. Transplant recipients were genotyped for three ABCB1 SNPs (rs1045642, rs2032582 and rs1128503). Acute cellular rejection (ACR), sepsis and other adverse events were monitored.Results:ABCB1 rs1045642 CC genotype showed lower tacrolimus CDR as compared to CT and TT genotype in the first week of the post-transplantation period (p=0.02). There was a significant association of polymorphisms in rs1045642, rs2032582 and rs1128503 with psychosis, sepsis and ACR respectively.Conclusion:Identification of ABCB1 rs1045642 polymorphism may shorten the time to achieve optimum levels of tacrolimus during dose titration. ABCB1 polymorphism rs1045642, rs2032582 and rs1128503 may predict adverse effects in liver transplant recipients receiving tacrolimus.

Comparison of different induction dosing of CD3+ cell count based anti-thymocyte globulin for deceased donor kidney transplantation: single center experience

Background: The rabbit anti-thymocyte globulin (ATG) is the most widely used lymphocyte depleting agent in renal transplanta tion. This can be expected to have a profound immune inducing effect, but it has been not widely used in Korea due to concerns about side effects such as leukopenia, thrombocytopenia, and infection. This has made it necessary to find the minimum dosing to show adequate immunosuppressive effects. So, we compared the clinical features of CD3+ cell count based ATG use with a cumulative dose of 3 mg/kg and 4 mg/kg as an induction immunosuppressant. Methods: Fifty-one patients have received deceased donor kidney transplantation with ATG induction therapy in Bongseng Me morial Hospital from 2013 to 2020. And they were divided into two groups: patients who treated with cumulative dose 3.0 mg/kg of ATG (group A) and 4.0 mg/kg (group B). We compared patient’s survival and graft’s survival in both groups. The data were col lected regarding recipients’ panel reactive antibody, CD3+ lymphocyte count, immunosuppressant, viral infection, acute rejection, and adverse events. Results: The demographic characteristics of the two groups were comparable. The incidence of delayed graft function was sta tistically significantly lower in the cumulative dose 4 mg/kg group. There was no statistically significant difference in the graft’s survival and serum creatinine between the two groups, but it was slightly better in 4 mg/kg group. The incidence rates of acute rejection and infectious events as cytomegalovirus disease or urinary tract infection were not significantly different between the two groups. CD3+ lymphocyte count was statistically significantly decreased until 6 months after transplantation in both groups compared to before transplantation. Conclusions: We suggest that ATG induction with cumulative dose of 4 mg/kg would be safe and effective for deceased donor kidney transplantation in Korea.

DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway

Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end‐stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft‐stable cohort, patients who experienced AR‐induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft‐related inflammatory injuries. These results revealed that changes in methylation accompany AR‐induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival.

Increased early acute cellular rejection events in hepatitis C-positive heart transplantation

Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs). In this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs. A total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (<56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT- recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT- group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8-45) in the NAT+ group vs 65 (IQR: 44-84) days in the NAT-. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004). Transient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.