Everolimus Use in Lung Transplant Recipients

BackgroundMost lung transplantation centers prefer triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. However, to prevent complications and comorbidities caused by tacrolimus, replacing the drug with everolimus has been considered.MethodsThis is a retrospective observational study investigating everolimus switch for different reasons. The population was divided into 3 groups: chronic lung allograft dysfunction (CLAD), kidney impairment, and malignant neoplasm groups. We investigated whether we achieved the goal of the switch and the frequency of rejection, cytomegalovirus and fungal infections, and everolimus adverse effects.ResultsNineteen patients received everolimus therapy, and 5 of these were for CLAD, 7 for tacrolimus nephrotoxicity, and 7 for explant/de novo malignant neoplasm. The patients were followed up for a mean (SD) of 30 (16.7) months under the therapy. The number of acute cellular rejection, cytomegalovirus infection, and aspergillosis infection cases before switch were 7, 13, and 2, respectively, and 7, 2, and 3 after that. The mean values of creatinine and estimated glomerular filtration rate of the whole population after the switch improved with no statistical significance, whereas it was significant in tacrolimus nephrotoxicity group. Three patients in the CLAD group remained stable after switching, whereas 2 progressed. Only 1 of the 7 patients with malignant neoplasms had a recurrence during 31.1 (16.5) months of median follow-up. Eleven cases of everolimus adverse effects occurred in 9 patients (47.3%), with 2 (10.5%) withdrawal events. Kidney impairment (P = .02) and age (P = .05) stood out as significant risk factors for drug adverse effects.ConclusionsAfter lung transplant, everolimus can be a safe alternative for immunosuppression with acceptable adverse effects.     

In Vitro Study Evaluating the Effect of Different Immunosuppressive Agents on Human Polyomavirus BK Replication

BackgroundHuman polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection.MethodsHuman renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study.ResultsThe highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27).ConclusionsOur experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.     

Everolimus-Based Immunosuppression in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Liver Transplantation: A Case Series

BackgroundLiver transplantation offers the most effective treatment in patients with hepatocellular carcinoma (HCC). However, transplant patients outside the Milan criteria have a high risk of tumor recurrence, which has been linked to standard immunosuppression regimens. Everolimus is a mammalian target of rapamycin inhibitor that has been used for immunosuppression, but its effect on recurrence and survival in HCC patients with a high risk of tumor recurrence has not been examined. We compared long-term survival and cumulative recurrence in high-risk patients receiving everolimus-based immunosuppression after liver transplantation for HCC with an historic control group.MethodsThe everolimus group comprised 21 patients receiving a liver transplant at our center from February 2005 to December 2010. The control group comprised 31 patients receiving a liver transplant from May 1994 to January 2005. All patients received cyclosporine or tacrolimus as initial post-transplant immunosuppression. Patients in the everolimus group switched to everolimus 2 weeks later.ResultsThere were no differences between the two groups in number of rejection episodes or of infectious or surgical complications. Five-year survival was 60.2% in the everolimus group and 32.3% in the control group (P = .05). Five-year cumulative recurrence rate was 61.3% in the control group and 41.3% in the everolimus group. Treatment with everolimus was identified as an independent predictor of longer survival (hazard ratio = 0.34; P = .02).ConclusionsPatients receiving liver transplantation for HCC with a high risk of tumor recurrence may well benefit from everolimus-based immunosuppression, with no added risks of rejection or other post-transplant complications.     

Randomized controlled trial assessing the impact of everolimus and low‐exposure tacrolimus on graft outcomes in kidney transplant recipients

This was a single‐center, randomized controlled trial assessing the impact of a 3‐month (10‐16 weeks) conversion to everolimus with low‐exposure tacrolimus, as compared to remaining on full exposure tacrolimus with mycophenolate (NCT 02096107). Adult kidney transplant recipients with a functioning graft were eligible for participation. Goal troughs in the intervention arm were 2‐5 ng/mL for tacrolimus and 3‐8 ng/mL for everolimus, with tacrolimus maintained at 5‐12 ng/mL in the control arm; 60 were randomized (30 in each arm) and were well matched at baseline; mean age was 51 years and 57% were African‐American. At 12‐months, fibrosis scores (27.8% tacrolimus/mycophenolate vs 22.9% tacrolimus/everolimus, P = .391), acute rejection rates (7% tacrolimus/mycophenolate vs 3% tacrolimus/everolimus, P = .554), and graft function (mean eGFR tacrolimus/mycophenolate 56 ± 15 vs tacrolimus/everolimus 59 ± 14 mL/min/1.73 m², P = .465) were similar between arms. The everolimus arm had significantly lower rates of CMV infection, severe BK infection, and improved BK viral clearance kinetics, as compared to the MPA arm. In this population, including a significant number of African‐Americans, an immunosuppression regimen of everolimus with low‐exposure tacrolimus provided similar efficacy to tacrolimus and mycophenolate, with significantly lower rates of BK and CMV.     

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

SIMCER was a 6‐mo, multicenter, open‐label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low‐exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus‐based therapy (n = 95), both with basiliximab induction and enteric‐coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. ?13.3 mL/min per 1.73 m² for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m² for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy‐proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus‐treated patients (17.8%) and three tacrolimus‐treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI‐based immunosuppression but more frequent BPAR.     

Everolimus Associated With Low-Dose Calcineurin Inhibitors,an Option in Kidney Transplant Recipients of Very Old Donors

BackgroundDespite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010.MethodsAssociated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group.ResultsThere were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36–49 mL/min and 51–55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively.ConclusionsInduction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.     

Early Conversion From Calcineurin Inhibitor‐ to Everolimus‐Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.73² versus ?1.5(1.5) mL/min/1.73² (p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novo donor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.     

Comparison of the Prolonged- and Immediate-Release Tacrolimus Capsule Formulation: The Patient's View and Medication Satisfaction of Patients After Pediatric Heart Transplantation

BackgroundMedication adherence is essential for long-term success after pediatric organ transplantation. Causes of reduced adherence should be detected early to improve the consequent medication intake. We describe the influence of switching from tacrolimus twice daily (tacrolimus-BID) to tacrolimus once daily (tacrolimus-QD) on medication satisfaction and medication adherence in patients after pediatric heart transplantation.MethodsA retrospective analysis was conducted regarding patient satisfaction and adherence to the immunosuppressant tacrolimus after pediatric heart transplantation, before and after conversion from tacrolimus-BID to tacrolimus-QD, using questionnaires.ResultsThirty-eight patients were enrolled (tacrolimus-BID: n = 35, mean age 15.7 ± 5.2 years; tacrolimus-QD: n = 38, mean age 16.2 ± 5.6 years). The amount of unadministered medication in the last 3 months did not differ between the 2 pharmaceutical forms. However, 17% (n = 6) reported unstable tacrolimus trough levels when taking tacrolimus-BID, vs 8% (n = 3) under tacrolimus-QD (P = .453). However, there was no statistically significant difference in the stability of the last 6 trough levels of each patient (P = .074). A total of 57% (n = 20) of patients had subjective side effects before conversion, compared to only 29% (n = 11) after conversion (P = .013). Regarding the intensity of the side effects, 6 patients reported strong/very strong side effects when taking tacrolimus-BID vs 1 patient when taking tacrolimus-QD (P = .250). In addition, the overall satisfaction with the immunosuppressant was higher under tacrolimus-QD (92% vs 83%; P = .508). However, this improvement was statistically not significant and may not be clinically relevant.ConclusionsThe amount of forgotten medication was not reduced after conversion from tacrolimus-BID to tacrolimus-QD. However, subjective side effects as well as patient satisfaction improved under tacrolimus-QD.     

A Randomized Controlled Trial of Envarsus Versus Immediate Release Tacrolimus in Kidney Transplant Recipients With Delayed Graft Function

BackgroundThe incidence of delayed graft function (DGF) among kidney transplant recipients (KTRs) in the United States continues to increase. The effect of immediate-release tacrolimus (tacrolimus) compared with extended-release tacrolimus (Envarsus) among recipients with DGF is unknown.MethodsThis was a single-center open-label randomized control trial among KTRs with DGF (ClinicalTrials. gov, NCT03864926). KTRs were randomized either to continue on tacrolimus or switch to Envarsus at a 1:1 ratio. Duration of DGF (study period), number of dialysis treatments, and need for adjustment of calcineurin inhibitor (CNI) doses during the study period were outcomes of interest.ResultsA total of 100 KTRs were enrolled, 50 in the Envarsus arm and 50 in the tacrolimus arm; of those, 49 in the Envarsus arm and 48 in the tacrolimus arm were included for analysis. There were no differences in the baseline characteristics, all P > .5, except donors in the Envarsus arm had higher body mass index (mean body mass index 32.9 ± 11.3 vs 29.4 ± 7.6 kg/m² [P = .007]) compared with the tacrolimus arm. The median duration of DGF (5 days vs 4 days, P = .71) and the number of dialysis treatments (2 vs 2, P = .83) were similar between the groups. However, the median number of CNI dose adjustments during the study period in the Envarsus group was significantly lower (3 vs 4, P = .002).ConclusionsEnvarsus patients had less fluctuation in the CNI level, requiring fewer CNI dose adjustments. However, there were no differences in the DGF recovery duration or number of dialysis treatments.     

The Immunobiogram,a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients

BackgroundDiagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome.MethodsWe conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression.ResultsClinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001–0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001–0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001–0.499; p = 0.026).ConclusionsOur results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.     

Alemtuzumab Induction and Antibody-Mediated Rejection in Kidney Transplantation

BackgroundInduction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit-antithymocyte globulin (r-ATG).MethodsThis was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy.ResultsAmong the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P = .008) and similar incidence of ACR (4.4% vs 10%; P = .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 ± 0.8 mg/dL vs 1.79 ± 1.8 mg/dL; P = .66) as well as graft (91.1 ± 3.5% vs 94.5 ± 3.8%; P = .48) and patient (93.8 ± 3.0% vs 96.4 ± 3.5%; P = .92) survivals were similar for the alemtuzumab versus the r-ATG groups.ConclusionOur study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients.     

Immunosuppressive Medication Adherence in Patients With Hepatocellular Cancer Who Have Undergo Liver Transplantation: A Case Control Study

BackgroundWe aimed to compare the adherence to immunosuppressive medication use in patients who underwent liver transplantation (LT) due to hepatocellular carcinoma (HCC) and non-HCC reasons.MethodsThe study population was determined as 242 patients with HCC and 1290 patients with non-HCC who had LT performed in our institute between March 2002 and November 2021; all these patients were contacted by phone in March 2022. The sample size was calculated using the MedCalc software program, and the number of patients required in each group was determined as 111 patients. Furthermore, we used the sample.int function, a random integer generator in the R (version 4.1.2) software program. Whereas demographic and clinical parameters were determined as independent variables, the immunosuppressive medication adherence scale (IMAS) score was determined as a dependent variable. Patients were evaluated by the IMAS. This 11-item IMAS scale evaluates the lowest compliance score as 11 and the highest as 55.ResultsOut of a total number of 221 patients, 161 (72%) were men and 60 (27.1%) were women, with a median age of 58 years (IQR: 14); one patient in the non-HCC group was excluded due to lack of data. Among the HCC and non-HCC groups, significant differences were found in terms of the variables of age (P = .003), IMAS score (P < .001), sex (P = .001), working status (P = .004), chronic diseases (P = .008), tacrolimus alone (P < .001), tacrolimus plus everolimus (P < .001), and often medication changes (P < .001). A statistically significant correlation was found between the IMAS score and whether the patients had HCC (P < .001) and frequently changing immunosuppressive drugs (P = .023).ConclusionThis study showed that patients with frequent drug changes or non-HCC etiology had better adherence to immunosuppressive drug use.     

Hemoderivative Transfusion in Liver Transplantation: Comparison Between Recipients of Grafts From Brain Death Donors and Recipients of Uncontrolled Donors After Circulatory Death

IntroductionIntraoperative bleeding during liver transplantation has been correlated with a higher risk of morbidity and mortality and decrease in patient and graft survival.Materials and MethodsBetween January 2006 and December 2016 we performed 783 orthotopic liver transplants. After applying exclusion criteria, we found liver grafts from donors after circulatory death (DCD, group A) were used in 69 patients and liver grafts from donors after brain death (group B) were used in 265 patients.ResultsNo difference was found in terms of sex, body mass index, Model for End-Stage Liver Disease score, indication for transplantation, intensive care unit stay, and Child-Pugh score. The mean transfusion of hemoderivates was as follows: red blood cell 9 (0-28) units in group A vs 6 (0-20) units in group B (P = .004) and fresh frozen plasma 10 (0-29) units in group A vs 9.5 (0-23) in group B (P = .000). The only 2 factors related to massive blood transfusion (>6 units of red blood cell) were uncontrolled DCD condition (odds ratio = 2.38; 95% confidence interval, 1.32-4.31; P = .004), and higher Model for End-Stage Liver Disease score (odds ratio = 2.63; 95% confidence interval, 1.53-4.55; P = .001). Survival at 1, 3, and 5 years was 81.3%, 70.2%, and 68.9% in group A vs 89%, 83.7%, and 78% in group B (P = .070).ConclusionThe use of liver grafts from DCDs is associated with increased necessity of transfusion of hemoderivates in comparison with the use of liver grafts from donors after brain death.     

Frequencies and Association of CYP3A5 Polymorphism With Tacrolimus Concentration Among Renal Transplant Recipients in Vietnam

BackgroundThis study aims to investigate the frequencies and association of CYP3A5 polymorphism with tacrolimus concentration among renal transplant recipients in Vietnam. Methods. Sixty-eight kidney transplant recipients were included in this study from the department of nephrology and dialysis, Military Hospital 103. Blood samples were collected for monitoring of tacrolimus levels and determination of CYP3A5 genetic polymorphism.ResultsA total of 68 patients studied. The CYP3A5*3*3, CYP3A5*1*3, and CYP3A5*1*1 genotypes were detected in 48 (70.6%), 16 (23.5%), and 4 (5.9%), respectively. Tacrolimus concentrations were much lower in CYP3A5 expressors than in CYP3A5 nonexpressors on the first day, month 1, 3, 6, and 12 (5.98 ± 1.05 vs 6.57 ± 1.03, P = .03; 5.79 ± 1.13 vs 6.82 ± 1.05, P < .001; 4.76 ± 1.48 vs 6.73 ± 1.09, P < .001; 4.29 ± 1.64 vs 6.46 ± 1.23, P < .001; 4.20 ± 1.36 vs 6.04 ± 1.26, P < .001), respectively. Notably, the concentration/dose ratio in the CYP3A5 expressors was lower than in CYP3A5 nonexpressors at time points of follow up (P < .001). However, there were no significant differences in the age, sex, HLA mismatch, type of donors, acute rejection, and creatinine levels at time points between group of CYP3A5 expressors and those of CYP3A5 nonexpressors.ConclusionIn conclusion, this research indicated the significant association of CYP3A5 genetic polymorphism with daily dose and tacrolimus concentrations in renal transplant recipients. This study provided a closer step to individualize the dose of tacrolimus in renal transplant patients in Vietnam.     

Renal Cyp3a5-Expressing Genotype Decreases Tacrolimus-to-Dose Ratio in Small Cohort of Renal Transplant Recipients—Preliminary Report

BackgroundPrevious reports have established that patient CYP3A5 allelic variability may be the most important genetic contributor to interindividual variation in tacrolimus exposure in renal transplant recipients. However, CYP3A5 protein is expressed in the allogenic kidney. The aim of this study was to investigate the role of the renal CYP3A5 genotype in tacrolimus concentration-to-dose ratio within 3 years posttransplant.MethodsA retrospective cohort study of 90 renal transplant recipients and their donors evaluated the effect of the CYP3A5 single-nucleotide polymorphism (rs776746) on tacrolimus exposure. The area under the curve for tacrolimus concentration-to-dose ratio within 3-year follow-up was calculated and compared in kidneys carrying at least 1 CYP3A5*1 allele and those carrying the CYP3A5*3/*3 genotype.ResultsA significant effect of CYP3A5 expression on tacrolimus exposure was observed in both donors (mean ± SD: 23.8 ± 7.9 vs 32.6 ± 7.4 ng/mL/mg, respectively; P < .001) and recipients (mean ± SD: 27.1 ± 8.0 vs 32.2 ± 7.9 ng/mL/mg, respectively; P = .034) and was lower when CYP3A5 enzyme occurred. Thus, new groups were formed: the group in which at least 1 of the pairs, donor or recipient, had a CYP3A5 expressing allele (n = 23) had lower exposure to tacrolimus compared with nonexpressors (n = 67; mean ± SD: 26.2 ± 7.6 vs 33.2 ± 7.4 ng/mL/mg, respectively; P < .001).ConclusionIntrarenal metabolism of tacrolimus may affect both local and systemic drug exposure. Nonexpressors receiving kidneys with the CYP3A5*1 allele may benefit from higher tacrolimus doses to hasten achievement of target drug concentrations.     

Impact of Immunosuppressive Strategies on Post–Kidney Transplantation Thrombocytopenia

BackgroundThrombocytopenia after kidney transplantation is a common complication, partly induced by immunosuppressive therapies. Peritransplant thrombocytopenia may cause serious hemorrhages. We assessed the incidence of early posttransplantation thrombocytopenia (defined as a platelet count of <150,000 mm³ or <150 G/L) in de novo kidney transplant recipients (KTRs) across 4 immunosuppressive regimens.MethodsThis was a single-center observational study that included all consecutive KTRs who received either Thymoglobulin (THY) or Grafalon (GRA) and maintenance therapy of either mycophenolate-mofetil (MMF) or everolimus (EVR), associated with tacrolimus/corticosteroids.ResultsBetween July 27, 2016, and September 7, 2018, 237 KTRs were included; 64.6% experienced thrombocytopenia within the first week. Thrombocytopenia was significantly more frequent (P = .004) among GRA-treated patients (73.4%) compared to THY-treated patients (61.3%). These patients also had lower nadir platelet count (120 ± 52 vs 142 ± 48 G/L; P = .002) and lower platelet count at discharge (227 ± 94 vs 243 ± 92 G/L; P = .25). More of the GRA-EVR group had thrombocytopenia (81.0% vs 61.4% in THY-MMF, 60.9% in THY-EVR, and 69.8% in GRA-MMF; P = .081) and a worse nadir platelet count (109 ± 41 in GRA-EVR vs 141 ± 47G/L in THY-MMF, 145 ± 52 G/L in THY-EVR, and 125 ± 56 G/L in GRA-MMF; P = .011) but GRA was the only risk factor for thrombocytopenia in multivariate analyses (P = .002). Rates of hemorrhage, red blood cell transfusions, reoperations needed within the first week, delayed graft function, acute rejection, graft loss, and death did not differ between the groups after a mean follow-up of 25 ± 8 months.ConclusionsGRA associated with EVR led to more frequent and severe thrombocytopenia, although we found no significant clinical consequences.     

The use of LCP-Tacrolimus (Envarsus XR) in simultaneous pancreas and kidney (SPK) transplant recipients

BackgroundExtended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK).MethodsThis is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 1001standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively.ResultsThere was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07).ConclusionsSignificantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.     

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients

BackgroundBelatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant.Materials and methodsThis retrospective analysis of a prospectively collected database included all adult kidney transplants patients at SUNY Upstate Medical Hospital from 1 January 2014 to 30 December 2022. Early conversion was defined as all conversions done at <6 months after kidney transplantation, and late conversion to belatacept was defined as conversion at >6 months after kidney transplantation.ResultsOut of 61 patients included in this study, 33 patients (54%) were in the early conversion group, and 28 patients (46%) were in the late conversion group. The mean eGFR in the early conversion group was 26.73 ± 16.26 ml/min/1.73 m2 before conversion to belatacept, which improved to 45.3 ± 21.01 ml/min/1.73 m2 at one-year post-conversion (p = 0.0006). Furthermore, eGFR changes in the late conversion group were insignificant, with 46.30 ± 15.65 ml/min/1.73 m2 before conversion to belatacept, and 44.76 ± 22.91 ml/min/1.73 m2 after one year of follow-up (p = 0.72). All four biopsy-proven allograft rejections in the early conversion group were acute T-cell-mediated rejections (ATMR). In the late conversion group, out of three biopsy-proven rejections, one was chronic antibody-mediated rejection (CAMR), one was ATMR, and one was mixed ATMR/CAMR. All four patients with ATMR rejection received mycophenolic acid (MPA) as part of their immunosuppressive regimen, and none received tacrolimus. The one-year post-conversion allograft survival rate in early and late conversion groups was 100%. However, the one-year post-conversion patient survival rate was 90.9% in the early conversion group and 100% in the late conversion group (P = 0.11).ConclusionsEarly post-transplant conversion to belatacept can improve the eGFR more meaningful when compared to late conversion. Patients who receive belatacept and MPA rather than tacrolimus may have increased rates of T-cell-mediated rejection.     

Differences in the Incidence and Clinical Evolution of Early Neurotoxicity After Liver Transplantation Based on Tacrolimus Formulation Used in the Immunosuppressive Induction Protocol

IntroductionPosttransplant early calcineurin inhibitor (CNI)-induced neurotoxicity (ECIIN) was related to high CNI levels, among other factors. Minimizing exposure could modify its incidence or clinical evolution.ObjectiveTo compare the incidence, predisposing factors, and clinical evolution of ECIIN after immunosuppressive induction with low-dose tacrolimus-MR (Advagraf) or conventional dose tacrolimus (Prograf).Patients and MethodsWe matched 71 patients treated with an immunosuppression induction schedule with basiliximab and low doses of Advagraf (cases group) 1:1 by recipient age and indication for liver transplantation (OLT) with patients treated with a conventional tacrolimus regimen (control group). Baseline characteristics, liver and kidney function, operative technical characteristics, kidney function, and C₀ tacrolimus levels at several time points after liver OLT were analyzed.ResultsThere were 31 cases of ECIIN (21%), 14 in the cases group (20%) and 17 in the control group (24%; P < .001). The incidence of ECIIN was higher in alcoholic liver disease (odds ratio [OR], 8.2; 95% CI, 2.3–28.6; P < .001) and past history of encephalopathy (OR, 2.6; 95% CI, 1.16–5.9; P < .02). Among cases, the incidence of ECIIN was higher when encephalopathy signs were present at time of transplantation (36% vs 12%; P < .001). Control of ECIIN required a switch to cyclosporine therapy in all those in the cases group, whereas this was only needed for 9 cases in the control group (47%; P < .001).ConclusionIn this study, although the incidence rate of neurotoxicity induced by Advagraf was lower than the induced by Prograf, it did not respond to routine treatment and required a significantly higher rate of switch to cyclosporine for its control.     

Surgery for type A aortic dissection in patients with cerebral malperfusion: Results from the International Registry of Acute Aortic Dissection

BackgroundThe strategy for intervention remains controversial for patients presenting with type A aortic dissection (TAAAD) and cerebral malperfusion with neurologic deficit.MethodsSurgically managed patients with TAAAD enrolled in the International Registry of Acute Aortic Dissection were evaluated to determine the incidence and prognosis of patients with cerebral malperfusion.ResultsA total of 2402 patients underwent surgical repair of TAAAD. Of these, 362 (15.1%) presented with cerebral malperfusion (CM) and neurologic deficits, and 2040 (84.9%) patients had no neurologic deficits at presentation. Patients with CM were more less likely to present with chest pain (66% vs 86.5%; P < .001) and back pain (35.9% vs 44.4%; P = .008). Patients with CM were more likely to present with syncope (48.4% vs 10.1%; P < .001), peripheral malperfusion (52.7% vs 38.0%; P < .001), and shock (16.2% vs 4.1%; P < .001). There was no difference in the incidence of Marfan syndrome (2.8% vs 3.0%; P = .870) or history of known aortic aneurysm (11.7% vs 13.9%; P = .296). Patients with CM were more likely to have a DeBakey I (63.8% vs 47.1%; P < .001) and a pericardial effusion (53.8% vs 40.6; P < .001) on presentation. There was no difference in total arch replacement (21.3% for CM vs 19.5% for no CM; P = .473). Patients with CM had an increased incidence of postoperative cerebrovascular accident (17.5% vs 7.2%; P < .001) and acute kidney injury (28.3% vs 18.1%; P < .001). In-hospital mortality was greater in patients with CM (25.7% vs 12.0%; P < .001).ConclusionsFifteen percent of patients with TAAAD presented with CM and neurologic deficits. Despite the fact that this subset of the population was older and more likely to present with peripheral malperfusion, cardiac tamponade, and in shock, in-hospital survival was noted in nearly 75% of the patients. Surgeons may continue to offer lifesaving surgery for TAAAD to this critically ill cohort of patients with acceptable morbidity and mortality.