Tacrolimus-based Therapy Research Articles

Evanescing renal allograft cortical necrosis from living donor renal transplantation: A lesson learned over two decades

BackgroundRenal graft cortical necrosis (GCN) is a catastrophic cause of graft failure. We evaluated the incidence, causes, management, and outcome of GCN across two decades from our center. MethodsThis is a retrospective analysis of transplant patients who had biopsy-proven GCN transplanted between 2000 and 2020. The clinical details, immunological workup, induction, maintenance regimen, causes of cortical necrosis, and the outcomes were compared between the first period 2000–2012, and the second period 2013–2020, when Flow cytometric and Luminex based crossmatch were included in the workup plan. ResultsAmong 2333 live ABO-compatible renal transplants, 37 (0.015%) patients (36 patients between 2000 and 2012 and 1 between 2013 and 2020) developed GCN (60% had diffuse and 40% patchy GCN) at a median of 8 days after transplantation.Twenty-six (60%) received ATG, 4 received plasmapheresis and ATG (10.8%) as antirejection therapy. The cyclosporine-based regimen was associated with a higher risk of GCN (RR 2.54; 95% CI 1.26 to 5.12, p = 0.009), whereas tacrolimus-based therapy had a lower risk (RR 0.39; 95% CI 0.19 to 0.79, p = 0.009). The introduction of flow cytometry and DSA assay has significantly decreased the incidence of acute rejection and GCN. Only one patient had GCN during the 2013–2020 period because of graft's mucormycosis. Twenty-five (67.56%) patients had no recovery, and 12 (32.43%) had partial recovery of graft function. ConclusionGCN is mainly associated with rejection, and cyclosporin-based maintenance regimen had a higher incidence. The remarkable decrease in GCN after 2012 onwards could be attributed to the use of Flowcytometry, Luminex-based DSA assays, and tacrolimus-based regimens.

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BackgroundTacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens.Material/MethodsEmbase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival.ResultsSixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0–9.6%) or Prograf (0–7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm.ConclusionsGraft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.

Increased Levels of sCD30 Have No Impact on the Incidence of Early ABMR and Long-Term Outcome in Intermediate-Risk Renal Transplant Patients With Preformed DSA.

Background: It is still incompletely understood why some patients with preformed donor-specific anti-HLA antibodies (DSA) have reduced kidney allograft survival secondary to antibody-mediated rejection (ABMR), whereas many DSA-positive patients have favorable long-term outcomes. Elevated levels of soluble CD30 (sCD30) have emerged as a promising biomarker indicating deleterious T-cell help in conjunction with DSA in immunologically high-risk patients. We hypothesized that this would also be true in intermediate-risk patients.Methods: We retrospectively analyzed pre-transplant sera from 287 CDC-crossmatch negative patients treated with basiliximab induction and tacrolimus-based maintenance therapy for the presence of DSA and sCD30. The incidence of ABMR according to the Banff 2019 classification and death-censored allograft survival were determined.Results: During a median follow-up of 7.4 years, allograft survival was significantly lower in DSA-positive as compared to DSA-negative patients (p < 0.001). In DSA-positive patients, most pronounced in those with strong DSA (MFI > 5,000), increased levels of sCD30 were associated with accelerated graft loss compared to patients with low sCD30 (3-year allograft survival 75 vs. 95%). Long-term survival, however, was comparable in DSA-positive patients irrespective of sCD30 status. Likewise, the incidence of early ABMR and lesion score characteristics were comparable between sCD30-positive and sCD30-negative patients with DSA. Finally, increased sCD30 levels were not predictive for early persistence of DSA.Conclusion: Preformed DSA are associated with an increased risk for ABMR and long-term graft loss independent of sCD30 levels in intermediate-risk kidney transplant patients.

S1140 Practical Consideration for Drug Monitoring of Tacrolimus in Liver Transplant Recipients With SARS-CoV-2 Infection

Introduction: Previous studies have shown that infection-related cytokine increase of interleukins can cause suppression of cytochrome P450.. SARS-CoV-2 infection has been associated with increased cytokine levels which may suggest suppression of CYP3A4 enzymes and downstream interaction with CYP-mediated drug metabolism including calcineurin inhibitors. Tacrolimus is a calcineurin inhibitor metabolized via CYP3A4. This potential effect of CYP3A4 inhibition on immunosuppression management with tacrolimus in liver transplant recipients with SARS-CoV-2 infection has yet to be evaluated. Methods: We retrospectively evaluated data between June 1, 2020 through December 31, 2020. All patients had confirmed SARS-CoV-2 and among those on tacrolimus-based therapy, serial tacrolimus trough levels were collected during the hospitalization were analyzed. Results: 18 OLT recipients were hospitalized with SARS-CoV-2.14 patients had tacrolimus trough levels throughout hospitalization, 12 of which were on stable immunosuppression therapy. 9 (64.3%) patients had elevated liver enzymes at time of admission. All patients experienced a decrease in baseline albumin levels and 7 out of 10 had an elevated ferritin level within 72 hours from admission.13 (92.8%) patients on tacrolimus had an increase from their baseline levels after testing positive, with an average increase of 105.6% (SD, 81%.7). 9 patients (64.3%) had at least a 50% increase from baseline trough levels. Among these patients, tacrolimus dose was subsequently reduced by an average of 45%. Steroid use did show a positive correlation (Pearson coefficient=0.57, P=0.03) with a rise above baseline tacrolimus trough. Conclusion: We found that most patients on tacrolimus had a supratherapeutic trough goals. There was an average two-fold increase in tacrolimus trough levels compared to baseline, with 64% (n=9) of patients experiencing at least a 50% increase. As expected, these supratherapeutic levels in trough levels in the setting of SARS-CoV-2 infection led to considerable change in immunosuppressive therapy with an approximately 50% reduction in daily tacrolimus dosing. These observations may suggest that SARS-CoV-2 infection in liver transplant recipients should be taken into special consideration when managing immunosuppression. This is the first study to describe these findings. Our study provides compelling evidence to closely monitor tacrolimus levels during acute infection and adjust dosing accordingly.Figure 1.: Pathophysiologic Mechanisms of Liver Injury in COVID-19Table 1.: Characteristics of Patients with Cirrhosis and Clinically Significant Portal Hypertension (CSPH) Based on SARS-CoV-2 Infection. Abbreviations: IQR, interquartile range; BMI, body mass index; CAD, coronary artery disease; BMI, body mass index; MELD-Na, Model for End-stage Liver Disease; CTP, Child Turcotte Pugh; HgbA1C, hemoglobin A1c; COPD, chronic obstructive pulmonary disease

Tacrolimus-Based Immunosuppressive Therapy Influences Sex Hormone Profile in Renal-Transplant Recipients—A Research Study

Simple SummaryAlthough renal-transplant-recipients can lead much more comfortable life in comparison to patients on dialysis, they need to face other problems. One of them is lifetime immunosuppressive therapy on daily basis. Immunosuppressive regimen contains usually three different drugs and although each one of them is crucial to keep graft in good condition and to suppress immune response against the transplanted organ, they influence, among the other, reproductive system. In current paper we have observed that immunosuppressive therapy based on tacrolimus significantly affected the hormonal balance of sex hormones in both men and women. It is of great importance, as nowadays infertility is rising problem even in health people, therefore more attention should be paid to choose the best suitable immunosuppressive regiment for recipient in reproductive age.It is estimated that approximately 20% of couples suffer from infertility worldwide and within renal-transplant recipients, this problem is 10 times more common. An intake of immunosuppressants may lead to hormonal imbalance. The aim of the study was to investigate the influence of tacrolimus-based therapy on the hormonal status of grafted patients. Blood samples were obtained from patients from the Department of Nephrology, Transplantology, and Internal Medicine of Independent Public Clinical Hospital No. 2, Pomeranian Medical University. All 121 patients had stable graft function for over 6 months. The blood plasma concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, estradiol, cortisol were assessed by the electrochemiluminescence method. We observed decreased levels of prolactin (11.9 ng/mL) and cortisol (87.4 μg/mL) in patients under tacrolimus-based therapy. Tacrolimus-based therapy was also associated with increased testosterone and follicle-stimulating hormone in males, 4.04 ng/mL and 6.9 mLU/mL, respectively, and decreased testosterone levels in females, 0.121 ng/mL. We also assessed that immunosuppressive therapy based on tacrolimus is less nephrotoxic in comparison to other regimens. Concluding, tacrolimus-based therapy may influence the hormonal status of transplant recipients in the current study. Results presented here are believed to be helpful for clinicians and patients, especially within the aspect of willingness for biological offspring.

MO981OUTCOMES OF INTERLEUKIN-2 RECEPTOR ANTAGONIST INDUCTION THERAPY IN STANDARD-RISK RENAL TRANSPLANT RECIPIENTS MAINTAINED ON TACROLIMUS - A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on the risk of delayed graft function, cytomegalovirus (CMV) infection, and malignancy. Method We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis. We divided the studies included in this meta-analysis into two groups: Group A (included studies that used same dose of tacrolimus in both arms of each study) and Group B (included studies that compared patients who received induction therapy and low dose tacrolimus versus those who received no induction therapy and high dose of tacrolimus). Standard-risk renal transplant was defined as HLA mismatch &amp;lt;5 and PRA&amp;lt;50%. Results In group A, 11 studies were included (n=2886). IL2-RA induction therapy was not associated with significant differences in comparison to no induction therapy in terms of acute rejection rates (Risk Ratio=1.03, 95% Confidence Interval [CI] range: 0.84 - 1.26, I squared=0%, P=0.79), graft survival (Risk Ratio=1.15, 95% CI range: 0.82 to 1.62), delayed graft function (Risk Ratio=1.01, 95% CI range: 0.82 to 1.24), CMV infection (Risk Ratio =1.37, 95% CI range: 0.53 to 3.51) or malignancy (Risk Ratio=1.29, 95% CI range: 0.61 to 2.75). In group B, two studies were included (n=669). There was no difference between both arms in terms of acute rejection rates (Risk Ratio=0.62, with 95% CI range: 0.33 to 1.14) or graft survival (Risk Ratio=1, 95% CI range: 0.57 to 1.74) or delayed graft function (Risk Ratio=0.88, 95% CI range: 0.45 to 1.71). Conclusion IL2-RA induction therapy does not improve outcomes in patients maintained on tacrolimus-based immunotherapy in standard risk population. our results strengthen the argument for individualized medical therapy and the potential tailoring the immunosuppression regimes according to the actual patients, needs.

THERAPEUTIC DOSAGE RANGES AND CHRONIC ADVERSE EFFECTS OF TACROLIMUS IN THAI KIDNEY TRANSPLANT PATIENTS

Objective: This study proposed to study the therapeutic dosage ranges and to determine the prevalence of and the risk factors for the adverse effectsof Thai tacrolimus-based therapy kidney transplant patients.Methods: The fifty-nine kidney transplant patients who had kidney transplantation between January 2016 and May 2018 and were non-diabetic,non-hypertension, and normal kidney parameters before kidney transplantation were enrolled and followed up for 6 months. Data on graft rejectionepisodes and three significant adverse effects of tacrolimus, nephrotoxicity, hypertension (HTN), and post-transplant diabetes mellitus (PTDM) ateach time point were recorded and analyzed.Results: The range and mean (±standard deviation) of tacrolimus troughs level for the 204 points were 3.9–10.2 ng/ml and 6.4±1.8 ng/ml, respectively.About 73% of patients had HTN, 61% were on antihypertensive drugs, and 32% had PTDM. Seven patients (12%) proved to have allograft rejectionby kidney biopsy. Only four patients did not have any three adverse effects. Similarly, laboratory parameters (SCr, BUN, and blood pressure) wereidentical during each period. All patients received prednisolone and mycophenolate mofetil as part of the comedication immunosuppressive regimen.Conclusion: There was no significant difference between tacrolimus chronic adverse effects and therapeutic tacrolimus trough concentrations in Thaikidney transplant patients. Further investigations concerning pharmacokinetics and pharmacodynamics will be needed to improve the efficacy andsafety of tacrolimus.

Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Influence of everolimus-based treatment on circulating regulatory T cells after liver transplantation: Comparative study with tacrolimus-based therapy

Liver transplantation remains the only treatment for terminal liver diseases. However, immunosuppressive drugs required for allograft acceptance are toxic and may be responsible for severe side effects. Modulating the immune system to induce tolerance is a promising approach to reduce immunosuppressive regimen. More particularly, promoting natural CD4+ CD25+ FoxP3+ Tregs could be crucial in achieving tolerance. Contrary to calcineurin inhibitors, reports indicate that mTOR inhibitors may have a positive impact on Tregs.Here we present the first randomized prospective clinical study where Tregs levels from liver transplanted patients receiving either tacrolimus or everolimus were monitored for 6 months, starting from the day of transplantation. A total of 30 patients from four centers were monitored. Blood samples were obtained at day 0, day 14, one month, three months and six months post-transplantation. Flow-cytometry immunophenotyping of Tregs (CD4+ CD25+ CD127− FoxP3+) and functional assays with Tregs were performed to assess their immunosuppressive capacity. Levels of Tregs were significantly reduced after one month of standard tacrolimus-based immunosuppressive regimen (p<0.05). Four months after conversion, levels of Tregs from patients treated with everolimus was significantly higher than patients under tacrolimus (p<0.02). Functional assays demonstrated that Tregs conserved their capacity to suppress the proliferation of activated PBMC.

Differentially expressed urinary exo-miRs and clinical outcomes in kidney recipients on short-term tacrolimus therapy: a pilot study.

Aim: To analyze the expression of urinary exosome-derived miRNAs (exo-miRs) in kidney recipients on tacrolimus-based therapy. Patients & methods: Clinical and drug monitoring data were recorded from 23 kidney recipients. Expression of 93 exo-miRs was measured by quantitativePCR array and mRNA targets were explored. Results: 16exo-miRswere differentially expressed, including marked upregulation of miR-155-5p, and downregulation of miR-223-3p and miR-1228-3p. Expression of miR-155-5p and miR-223-3p correlated with tacrolimus dose (p<0.05), miR-223-3p with serum creatinine (p<0.05), and miR-223-3p and miR-1228-3p with blood leukocytes (p<0.05). 12miRNAs have predicted targets involved in cell proliferation, apoptosis, stress response, PIK3/AKT/mTOR and TGF-βsignaling pathways. Conclusion: Differentially expressed urinary exo-miRs may be useful markers to monitor tacrolimus therapy and graft function in kidney transplantation.

Differential expression of genes related to calcineurin and mTOR signaling and regulatory miRNAs in peripheral blood from kidney recipients under tacrolimus-based therapy.

BackgroundGenetic and epigenetics factors have been implicated in drug response, graft function and rejection in solid organ transplantation. Differential expression of genes involved in calcineurin and mTOR signaling pathway and regulatory miRNAs was analyzed in the peripheral blood of kidney recipient cohort (n=36) under tacrolimus-based therapy.MethodsPPP3CA, PPP3CB, MTOR, FKBP1A, FKBP1B and FKBP5 mRNA expression and polymorphisms in PPP3CA and MTOR were analyzed by qPCR. Expression of miRNAs targeting PPP3CA (miR-30a, miR-145), PPP3CB (miR-10b), MTOR (miR-99a, miR-100), and FKBP1A (miR-103a) was measured by qPCR array.ResultsPPP3CA and MTOR mRNA levels were reduced in the first three months of treatment compared to pre-transplant (P<0.05). PPP3CB, FKBP1A, FKBP1B, and FKBP5 expression was not changed. In the 3rd month of treatment, the expression of miR-99a, which targets MTOR, increased compared to pre-transplant (P<0.05). PPP3CA c.249G>A (GG genotype) and MTOR c.2997C>T (TT genotype) were associated with reduced expression of PPP3CA mRNA and MTOR, respectively. FKBP1B mRNA levels were higher in patients with acute rejection (P=0.026).ConclusionsThe expression of PPP3CA, MTOR and miR-99a in the peripheral blood of renal recipients is influenced by tacrolimus-based therapy and by PPP3CA and MTOR variants. These molecules can be potential biomarkers for pharmacotherapy monitoring.

Incidence of end‐stage renal disease after heart transplantation and effect of its treatment on survival

AimsMany heart transplant recipients will develop end‐stage renal disease in the post‐operative course. The aim of this study was to identify the long‐term incidence of end‐stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival.Methods and resultsA retrospective, single‐centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end‐stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re‐transplantations. During a median follow‐up of 8.6 years, 121 (19.7%) patients developed end‐stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end‐stage renal disease (examined as a time‐dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus‐based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end‐stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end‐stage renal disease development.ConclusionsEnd‐stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end‐stage renal disease.

Assessment of knowledge and practice of Sudanese renal transplant recipients about tacrolimus usage: A cross-sectional study

BACKGROUND: Tacrolimus is an immunosuppressive drug used for the prevention of rejection in kidney transplant recipients (KTRs). There are many factors that can affect tacrolimus blood levels, include nonadherence, blood sampling time, food effect, and co-medication. This study aimed to assess Sudanese KTRs knowledge and practice about tacrolimus use. MATERIALS AND METHODS: This was a descriptive cross-sectional hospital-based study. The study population was Sudanese KTRs under tacrolimus-based therapy attending the renal transplant outpatient clinic in Khartoum renal dialysis and transplantation center from April to July 2018. A total of 190 KTRs were interviewed. The collected data were manually scored, coded, and then analyzed using SPSS. RESULTS: Regarding overall knowledge, approximately 46% of enrolled KTRs have a low level of knowledge about tacrolimus therapy, and there is a significant association between KTRs knowledge and their level of education. There is a variation between the knowledge about tacrolimus monitoring and KTRs' practice. The primary source of information for the KTRs was doctors, and more than half of them never forget to take the tacrolimus. Only 32.1% of KTRs have nonadherence problems. The association between KTRs knowledge and their level of education and the transplantation period was statistically significant. Regarding tacrolimus side effects, 50% of KTRs said they have been informed or read about the drug side effects. CONCLUSION: Knowledge of the Sudanese KTRs enrolled in this study was inadequate, and the behavior of them when suffering from a new complaint was relatively good. Great efforts are needed to improve their knowledge, to maintain graft function, and to prevent graft loss.

CYP3A5*3 and CYP2C8*3 variants influence exposure and clinical outcomes of tacrolimus-based therapy.

Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n=178) or mycophenolate sodium (n=97). The variants in CYP2C8, CYP2J2, CYP3A4, CYP3A5, POR, ABCB1, ABCC2, ABCG2, SLCO1B1 and SLCO2B1 were analyzed. Main results:CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p<0.05). The living donor and CYP2C8*3 variant were associated with reduced risk for delayed graft function (OR=0.07; 95% CI=0.03-0.18 and OR=0.45; 95% CI=0.20-0.99, respectively, p<0.05). Conclusion: The CYP3A5*3 variant is associated with increased early exposure to TAC. Living donor and CYP2C8*3 variant seem to be protective factors for delayed graft function in kidney recipients.

The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients.We aim to investigate the effects of cytochrome P450 (CYP)3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6months after heart transplantion to evaluate acute rejection degrees. All participants were then followed upannually until May 2018.The designed primary endpoint was all-cause mortality. In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6months after heart transplantion. The median follow-up period was 94.7months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

A Higher Need for Permanent Pacing after Orthotopic Heart Transplantation Due to Increased Donor Age

Purpose Extreme shortage in donors in the Netherlands has led to increasingly aging donors in heart transplantations (HT). The aim of the study was to evaluate the relationship between donor age and the need for a permanent pacemaker (PPM) implantation after HT. Methods All HTs in our centre between 1984 and august 2018 were retrospectively analysed. Retransplantation within 30 days (n=2) and patients who died within 30 days after HT (n=53) were excluded from the study. In this study 664 HTs were included. Based on the donor age, the HTs were divided into three groups: Group I ( 50 years, n=96). Primary outcome was the implantation of a PPM post-HT, either early (≤ 90 days) or late (> 90 days). Results The biatrial technique was performed in 659 HTs and only 5 using the bicaval technique. Before 2000 (the moment of immunosuppressive regime switch from cyclosporine- to tacrolimus-based therapy), the median donor age was 26 [IQR 20-35] and after 2000 42 [IQR 25-51] (P 90 days (median 7.6 years [IQR 3.4-13.4]) post-HT. The early PPM rate was 1.5% before 2000 vs 11% late PPM rate, while after 2000 the rates were 10.6% and 5.9% respectively. Indications for PPM implantation were sinus node dysfunction in 52.1% and atrioventricular block in 47.9%. Total PPM rates were 10% (Group I), 18% (Group II) and 25% (Group III) (P Conclusion The need for an early PPM is statistically higher in HTs with a donor age > 50 years. However, the long-term survival was non-inferior in patients with a PPM.

Novel strategy of sirolimus plus thymalfasin and huaier granule on tumor recurrence of hepatocellular carcinoma beyond the UCSF criteria following liver transplantation: A single center experience

Although liver transplantation (LT) lengthens the survival time of patients with hepatocellular carcinoma (HCC), LT patients exhibit a high recurrence rate; particularly those that had advanced HCC associated with the tumor biological characteristics and long-term application of immunosuppressants. A consensus on optimal prophylaxis and treatment for recurrent HCC following LT does not currently exist. The present study retrospectively analyzed data from 36 non-University of California at San Francisco criteria-eligible patients with advanced HCC who underwent LT, and then treated them with sirolimus (SRL)-based therapy with thymalfasin and huaier granules (SRL+, n=18), or with tacrolimus-based therapy (controls; n=18). The SRL+ group had significantly longer recurrence times (P=0.008) and survival times (P<0.0001) (OS, 1-year: 100%, 3-year: 94.4%, 5-year: 77.8%; DFS, 1-year: 88.9%, 3-year: 55.6%, 5-year: 50.0%). Furthermore, compared with pre-LT values and the control group, the SRL+ group had significantly lower serum α-fetoprotein (AFP) levels (both P<0.0001) and percentage of Forkhead box P3 (FoxP3)+ Treg lymphocytes (P<0.001) during the first year. In the SRL+ group, FoxP3+/cluster of differentiation (CD)8+ Treg lymphocyte percentages decreased significantly following LT (P<0.001); however, CD8+/CD3+ T-cells significantly increased (P<0.001). Levels of serum AFP and FoxP3+ Treg cells increased when tumors relapsed, and decreased to near-normal when relapse foci were cured or stabilized. SRL+ therapy may decrease AFP and Treg levels, while increasing CD8+ T cells, indicating an associated mechanism among them. In conclusion, SRL+ therapy appears to be safe and effective in preventing HCC recurrence following LT with no significant adverse events, and warrants further investigation.

MTOR Inhibition and Clinical Transplantation: Liver.

The evidence base concerning use of mammalian target of rapamycin (mTOR) inhibitor therapy after liver transplantation is evolving rapidly, clarifying their benefits and disadvantages in different clinical scenarios. The H2304 trial showed that starting everolimus at 1 month posttransplant, with reduced tacrolimus, achieves a sustained improvement in renal function versus standard tacrolimus-based therapy, with at least equivalent immunosuppressive efficacy. Randomized studies evaluating early discontinuation of calcineurin inhibitor (CNI) therapy after introduction of an mTOR inhibitor consistently demonstrated a substantial improvement in renal function versus standard CNI therapy. However, concomitant mycophenolic acid is advisable to avoid an increase in mild biopsy-proven acute rejection, and induction with an interleukin-2 receptor antagonist may also be helpful. High-quality robust data regarding prevention of posttransplant malignancies under mTOR inhibitors is lacking in liver transplantation, although there are some indications of benefit. In maintenance patients, robust data are limited regarding mTOR inhibitor initiation in response to deteriorating renal function or other indications but late conversion (>1 year) appears ineffective. Rates of mTOR inhibitor discontinuation due to adverse events are high, affecting at least a quarter of patients. In conclusion, the evidence base for use of mTOR inhibitors early posttransplant to support CNI reduction now convincingly demonstrates a renal advantage, but adequate adjunctive immunosuppression is essential to preserve efficacy.

Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) - results of a randomized controlled clinical trial.

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short‐term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long‐term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus‐based and 197 to tacrolimus‐based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline‐adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy‐proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus‐based therapy, sirolimus‐based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.

Correlation between T cell subsets and acute graft rejection in tacrolimus-based therapy kidney transplant patients

Correlation between T cell subsets and acute graft rejection in tacrolimus-based therapy kidney transplant patients