Mean Tacrolimus Levels Research Articles

Risks of Tacrolimus and Paxlovid Therapy in SARS-CoV-2 Positive Transplant Recipients: A Case Discussion and Institutional Data Review

Abstract Introduction/Objective Transplant recipients maintained on immunosuppressants like tacrolimus continue to be at high risk for morbidity due to SARS-CoV-2 infection and are strong candidates for antiviral therapies. However, co- administration of the antiviral Paxlovid (nirmatrelvir/ritonavir) poses a significant risk to these patients due to ritonavir- mediated inhibition of CYP3A, an important mediator of tacrolimus metabolism. Consequently, Paxlovid therapy in post-organ transplant patients on tacrolimus requires careful consideration. Our investigation aims to assess the continuing risk posed by this drug-drug interaction and better understand clinical circumstances linked to critically high tacrolimus levels due to Paxlovid co-administration. Methods/Case Report We conducted a large-scale retrospective analysis of tacrolimus measurements at the University of Michigan Medicine beginning in January 2020. We also performed a detailed review of patients with critically high tacrolimus levels coinciding with Paxlovid administration. Results (if a Case Study enter NA) Of 39,752 tacrolimus measurements examined, 682 correspond to 329 patients with recent positive SARS-CoV-2 nucleic acid testing, and 37 correspond to 18 patients with documented Paxlovid co- administration. Patients receiving concurrent Paxlovid and tacrolimus demonstrate 1.6- and 1.8-fold higher mean tacrolimus levels (14.1 ng/mL, p = 3e-5) compared to other SARS-CoV-2 positive (8.7 ng/mL) and negative/untested (7.9 ng/mL) patients, respectively. Among SARS-CoV-2 patients, those prescribed Paxlovid are more likely to present with supratherapeutic tacrolimus levels (OR 4.1, 95% CI 1.6 – 10.7). A detailed case review of three organ transplant recipients presenting with tacrolimus levels >60 ng/mL and creatinine levels increased by 0.45 ± 0.27 mg/dL from baseline shows Paxlovid was prescribed at outside facilities, and regular tacrolimus dose was continued. Three other patients exhibited supratherapeutic tacrolimus levels (20 – 30 ng/mL), and creatinine levels increased by 0.41 ± 0.23 mg/dL from baseline despite dose reduction or cessation before initiating Paxlovid. Conclusion Our findings highlight the importance of communication between primary and tertiary care providers and caution when prescribing Paxlovid in populations managed with tacrolimus therapy.

Böbrek nakli hastalarında de novo uzatılmış salımlı takrolimus; Güvenli mi?

Background: This study aimed to investigate whether de novo extended-release tacrolimus (ERT) therapy is safe in kidney recipients.
 Methods: The study was single-center, retrospective, and included a total of 57 patients, including 30 patients in the ERT group (Group 1) and 27 patients in the immediate-release tacrolimus (IRT) group (Group 2). Demographic and laboratory characteristics of the patients were recorded. Complications such as acute drug toxicity, acute rejection, new-onset diabetes mellitus after transplantation, and development of hypertension, opportunistic infection, and hospitalization data were recorded.
 Results: The mean age of the patients was 46.23±14.2 years in the ERT group and 47.04±14.6 years in the IRT group. There were 21 (70%) males in group 1, while 20 (74%) patients in group 2 had a male gender (P=0.73). The rate of improved serum creatinine values in the first week postoperatively was similar in both groups. While the mean tacrolimus levels on postoperative day 1 were significantly lower in the group- 1 (P

Mapping children by ALT 4-5 years after liver transplant: Potential individual and population applications.

Although clinicians repeatedly measure ALT to assess allograft health in children with liver transplants, they generally make decisions based on single values or qualitative trends without quantitative aggregation or synthesis. We therefore aimed to derive and test a holistic ALT metric for the 5th post-transplant year (Yr 4-5) that may better guide clinical decision-making and/or population comparisons. We derived the "adjusted mean Yr 4-5 ALT" for children transplanted in 2005-2016 by averaging the median ALT from each month. Patients in quartiles (Q1-4) defined by the adjusted mean Yr 4-5 ALT were compared by clinical variables, Yr 5-8 outcomes, and tacrolimus standard deviation (MLVI). For 97 children [49 male; 77 deceased donors; median (IQR) age at LT 2.5 (0.8-11.7) years], the 25th, 50th, and 75th percentile thresholds for adjusted mean Yr 4-5 ALT were 19, 28, and 47 U/L, respectively. Age, donor type, LT indication, rejection history, and mean tacrolimus levels did not differ between quartiles (Q). Children in Q4 had more Yr 4-5 acute rejection episodes (p < .01), higher Yr 4-5 MLVI (p < .01), and more Yr 5-8 for-cause liver biopsies (p < .01) than those in Q1 + Q2. Children in Q3 also had higher Yr 4-5 MLVI than Q1 + Q2 (p = .047). Rates of chronic rejection and therapeutic liver-related procedures were higher in Q4 but the difference did not reach significance. An integrated ALT metric calculated utilizing all available ALT values correlates with MLVI and future for-cause biopsies. Further study of this novel ALT metric as a predictor of clinical outcomes and descriptor of populations is warranted.

Experience of outpatient follow-up of heart transplant recipients at Shumakov center

Heart transplantation (HT) is considered the optimal therapy for end-stage heart failure. In recent years, the number of operations performed has been growing, which has led to a rise in the number of heart transplant recipients requiring outpatient follow-up.Objective: to evaluate the effectiveness of the model of dual personalized follow-up of heart transplant recipients in the consultative and diagnostic department of Shumakov National Medical Research Center of Transplantology and Artificial Organs.Materials and methods. The study included 1,436 patients under outpatient follow-up from January 2008 to December 2022. Recipient data, results of laboratory and instrumental examination methods, nature and frequency of complications at different follow-up periods were analyzed.Results: At the time of discharge from the hospital, 98.7% of patients had received triple-drug immunosuppressive therapy; 6 months later, methylprednisolone was discontinued in 72.2% of recipients. Mean tacrolimus level during the 1-year follow-up was 8.7 ± 2.7 ng/mL; in the period from 1 to 5 years of followup, the mean was 5.1 ± 2.4 ng/mL. At year 1 after transplantation, 23 (1.7%) recipients had been converted to everolimus; by the end of year 5 of follow-up, the number had increased to 8.6%. The most frequently detected complications during outpatient follow-up were: hypertension (48.65%), post-transplant diabetes mellitus (7.24%), nephropathy (35.97%), and malignant neoplasms (4.2%). Recipient survival, excluding in-hospital mortality, was 96.5%; and 88.0% at year 1 and 5 of follow-up, respectively.Conclusion: The dual personalized approach model for outpatient follow-up and treatment of heart transplant recipients will improve recipient survival and quality of life in the long-term post-HT period.

P681 Effectiveness and safety of oral Tacrolimus salvage therapy for acute severe ulcerative colitis: a retrospective study

Abstract Background Calcineurin inhibitors are a therapeutic option in patients with acute severe ulcerative colitis (ASUC) failing to respond to intravenous steroids. There are limited data regarding the real world effectiveness of tacrolimus in this setting. We describe our experience with tacrolimus in a tertiary IBD center. Methods This retrospective study includes patients who were hospitalized at our center with ASUC between 2018-2022 and received tacrolimus salvage therapy. We collected demographic, clinical, and laboratory data. The primary endpoint of this study was clinical response to tacrolimus therapy leading to patient discharge. Secondary endpoints were safety of therapy and long-term effectiveness. Results Sixteen patients received tacrolimus therapy; 15 patients with UC and 1 patient with indeterminate colitis. The median age was 36 (interquartile range (IQR) 29-51), median disease duration 9 years (IQR 4.5-12), 10 (69%) were females, 11 (69%) had pan-colitis; 12 (75%) had previous biologic exposure. The median CRP was 44.46 mg/L (IQR 20.1-155), median albumin 3.2 g/dL (IQR 2.9-3.7). 15 patients (94%) responded to tacrolimus and were discharged, 1 patient failed to respond and underwent colectomy. Mean tacrolimus level during induction was 12.48 ng/ml (± 4.5). Following discharge, 1 patient had an exacerbation secondary to poor adherence and underwent colectomy within 2 months. 12 patients were transitioned to biologic therapy (7 vedolizumab, 3 ustekinumab, 2 adalimumab, 1 golimumab) and 1 patient to azathioprine. All 13 patients avoided colectomy with a median follow-up of 5.5 months (IQR 3-12). One patient was lost to follow up. Regarding safety, 10 patients had mild electrolyte disturbance requiring oral supplementation. No other adverse events were observed and no patient discontinued therapy due to adverse events. Conclusion Oral tacrolimus salvage therapy shows effectiveness and acceptable safety profile in patients with ASUC. The oral nature of this therapy provides an attractive therapeutic option in this setting.

BK virus nephropathy in renal transplantation and the effect of intravenous immunoglobulin: A prospective longitudinal single-center study in South Asia

Aims and Objectives: The aim was to assess the prevalence and treatment of BK virus nephropathy (BKVN) in patients who underwent renal transplantation at a single center in South India with a 1-year follow-up analysis. To assess the efficacy of treatment with intravenous immunoglobulin (IvIg) in cases of proven BKVN. Materials and Methods: Three hundred and seventy-one patients underwent renal transplantation from 2018 to 2020. All were screened for BKVN with quantitative serum polymerase chain reaction (PCR) every 3 months for 1 year after transplant. Patients with positive tests underwent renal allograft biopsy. In all patients, antimetabolite was stopped, tacrolimus dose was reduced, and leflunomide was started. All patients with biopsy-proven BKVN were administered IvIg 2 grams/kg over 5 days and had a 1-year follow-up. Results: Fourteen patients had BK viremia; 12 had biopsy-proven BKVN. All were male with a mean age of mean age: 45.3 years ± 14.8 standard deviation (SD). Induction: basiliximab (7) and antithymocyte globulin (ATG) (7). Maintenance immunosuppression: tacrolimus, enteric-coated mycophenolate mofetil, and prednisolone. The median presentation time was 12 months. Mean graft function: baseline S. Creatinine of 1.32 mg/dL changed to 2.01 mg/dL at diagnosis. The mean presenting BKV PCR (copies/ml) was 44912 ± 56285 SD. No significant differences were observed in time of presentation, severity, mean tacrolimus level, and graft failure between patients receiving basiliximab or ATG. There were two relapses; two grafts failed. Class I BKVN had a better prognosis. Graft survival at 1 year was 85.71%. Conclusions: This is the first South Asian follow-up study of BKVN in kidney transplant recipients treated with IvIg. BKVN was documented in the first 15 months after transplant. There was no increased prevalence of BKVN in patients with ATG. Histopathological class has prognostic relevance with Class I having a better prognosis. Multipronged treatment, including IvIg, leads to 1-year graft survival of 85.71%. Long-term outcomes need follow-up.

242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.

Comparison of Tacrolimus Serum Levels During First Month After Lung Transplant in Patients with and without Gastroparesis

<h3>Purpose</h3> Gastroparesis is suspected to alter the absorption of immunosuppressive medications in solid organ transplant recipients. Limited data exists in lung transplant recipients (LTRs), who typically have high rate of post-transplant gastroparesis. The objective of this study was to compare the post-transplant route of tacrolimus administration and variation in serum tacrolimus levels in LTRs with and without gastroparesis. <h3>Methods</h3> All recipients who underwent lung transplant in 2019 were included. Objective gastric emptying data was documented. Daily tacrolimus dose, route of administration and serum levels for 30 days post-transplant were evaluated and compared. <h3>Results</h3> There were 123 LTRs in 2019, of which 31 (25%) developed gastroparesis. After matching, baseline characteristics were similar amongst the 2 groups, however, gastroparesis patients were younger (54 ±14 vs 59 ±14 years, p<0.05). Majority (118) of patients started with sublingual tacrolimus postoperatively, of which 82 (69%) were switched to the oral route. Patients with gastroparesis had longer duration of sublingual administration compared to patients with normal gastric emptying (median days 14 vs 7, p<0.05) . Median time to reach 10mg/dl serum level was 9 days in gastroparesis patients vs 7 days in non-gastroparesis group. Overall, there was no significant difference in mean serum tacrolimus levels amongst the 2 groups over 30 days (<b>Figure 1</b>). <h3>Conclusion</h3> Gastroparesis is common after lung transplant and may require longer sublingual administration of tacrolimus. Ultimately, however, gastroparesis patients can be switched safely from sublingual to oral tacrolimus as there is no significant difference in the postoperative trend of serum tacrolimus levels, even when accounting for change in route of tacrolimus administration.

Long-Term Outcome After Tacrolimus-Related Neurotoxicity in Pediatric Living Donor Liver Transplantation

Tacrolimus-related neurotoxicity is a serious complication. Posterior reversible encephalopathy syndrome, which is severe neurotoxicity after pediatric living donor liver transplantation (LDLT), is a medication-induced complication related to calcineurin inhibitors. The purpose of this study was to evaluate the long-term outcome of tacrolimus-related neurotoxicity after pediatric LDLT. Pediatric patients who underwent LDLT between 2007 and 2020 at our institution and developed neurologic symptoms with tacrolimus were included in the study. Tacrolimus-related encephalopathy was defined as encephalopathy that resolved after tacrolimus was discontinued. All patients received tacrolimus and a steroid for immunosuppression starting just after LDLT. During the study period, 128 patients underwent LDLT. All patients received tacrolimus and a steroid. Six patients (5%) developed tacrolimus-related encephalopathy. The median age at transplant was 1.6 years. The original diseases were biliary atresia (n=5) and progressive familial intrahepatic cholangiopathy type 2 (n=1). Patients developed encephalopathy at a median of 9 days after LDLT. All patients recovered with conversion to cyclosporine. Posterior reversible encephalopathy syndrome was confirmed by magnetic resonance imaging in 3 patients. The mean tacrolimus level at encephalopathy was 11 ng/dL (range, 5.6-14.6 ng/dL). White blood cell count elevation was observed in all patients. One patient died of pancreatitis. Surviving patients (n=5) were followed for a median of 9 years. All patients resumed tacrolimus a median of 8 months from onset. No neurologic complications were observed after resuming tacrolimus. We observed tacrolimus-induced encephalopathy in 5% of patients after pediatric LDLT. Patients can resume tacrolimus safely without further neurologic symptoms.

Evaluation of rejection, infection, and malignancy outcomes in elderly liver transplant recipients receiving a similar level of immunosuppression compared to a younger group

Elderly liver transplant (LTx) recipients at a lower risk of acute rejection compared to younger recipients due to immunosenescence. As such, they may benefit from reduced immunosuppression (IS) to minimize infectious and malignant complications. We aimed to evaluate outcomes in LTx recipients ≥60 years compared to a younger group of LTx recipients aged 18–59 years maintained on a similar level of IS. This was a single-center retrospective evaluation of adult LTx recipients from 2013 to 2018 who received methylprednisolone induction and were maintained on tacrolimus, mycophenolate mofetil (MMF), and a prednisone taper. A total of 143 LTx recipients were evaluated. Mean age in the older group was 65 ± 3.8 compared to 49 ± 10.4 years in the younger group (p < 0.0001). Mean tacrolimus levels and the duration of MMF and steroids were comparable. Both groups had a similar incidence of first rejection within 1 year (19.2% in the elderly group vs. 23.1% in the younger group, p = 0.57). There were no statistical difference in terms of infection, malignancy, or patient survival. In conclusion, our data suggests that elderly LTx recipients, when treated with a similar level of IS, had similar 1 year incidence of rejection, infection, malignancy, and patient survival as younger LTx recipients.

Acute Kidney Injury before Day 90 Predicts for Both Early and Late Mortality after FluBu4

Acute kidney injury (AKI) is a frequent complication after hematopoietic stem cell transplantation (HSCT). Prior studies have shown a negative impact on survival when AKI develops early after HSCT, but have primarily included patients receiving regimens associated with a high degree of toxicity, in particular total body irradiation based-regimens. Fludarabine/ i.v. busulfan (FluBu4) is a myeloablative regimen with reduced extra-hematologic toxicity. We sought to examine the impact of AKI on survival in patients receiving FluBu4.We retrospectively analyzed 91 consecutive adult patients who underwent allogeneic stem cell transplant and conditioning with FluBu4 between January 2003 and December 2016. The FluBu4 regimen consisted of daily fludarabine 40 mg/m2 and i.v. busulfan (AUC of 4800 mmol-min per dose) over 4 days. All patients received GVHD prophylaxis with tacrolimus and methotrexate. We observed a high incidence of AKI (defined as creatinine clearance below 60 ml/min) within 90 days of HSCT (n=62, 68%). The mean of the lowest measured creatinine clearance was 39.4 ml/min (± 14.2) in the AKI group and 81.7 ml/min (± 16.26) in the non-AKI group (p<0.0001). Baseline characteristics including disease risk index (DRI) and hematopoietic cell transplant-comorbidity index (HCT-CI) were similar between the two groups. However, patients in the AKI group were older (48.5 versus 29 years, p<0.0001). The mean tacrolimus concentration in the first 90 days after HSCT was similar between the two groups (9.2 versus 9.1 ng/mL, p=0.87).In our cohort, we found that the median time to neutrophil (16 versus 15 days, p=0.5) and platelet (16 versus 16 days, p=0.16) engraftment was similar between the AKI and non-AKI group. Patients that experienced AKI within the first 90 days of HSCT had significantly worse overall survival (OS) (26.3 months versus median not reached, p=0.04) and progression-free survival (PFS) (19.6 months versus median not reached, p=0.02). When patients who died within the first 90 days were excluded and survival was measured from Day 90, AKI still predicted for poor OS (46.8 months versus not reached, p=0.03) and PFS (43.2 months versus not reached, p=0.02). The incidence of grade III-IV acute graft-versus-host disease was similar between the two groups. However, patients who developed AKI had a significantly higher cumulative incidence of relapse (21 (34%) versus 4 (14%), p=0.03) making this the major driver of reduced OS and PFS. In an age-adjusted multivariate analysis, AKI was associated with significant decreases in both OS (p=0.047) and PFS (p=0.033).We next analyzed the impact of early AKI on the development of chronic kidney disease (CKD) at one year. In all patients surviving more than one year, we found that 13 (34%) of 38 patients in the AKI group and 1 (4.5%) of 22 patients in the non-AKI group developed CKD (p=0.02). OS measured from 1 year post transplant was significantly shorter in patients with CKD (39.3 months versus median not reached, p=0.002).This is the first study evaluating the impact of AKI on outcomes in patients undergoing HSCT with FluBu4. We observed a high incidence of AKI during the first 90 days that predicted for worse OS and PFS. We hypothesize that the significantly higher relapse rate observed in the AKI group is due to increased tacrolimus exposure and diminished graft-versus-leukemia effect. Although mean tacrolimus levels were comparable between groups, these measurements are likely not an accurate estimation of cumulative tacrolimus exposure. Finally, early AKI also leads to a significant increase in CKD at one year, which in our cohort is associated with late mortality after HSCT. DisclosuresPatel:Celgene: Consultancy, Honoraria.

P1762THE EFFECT OF IMMUNOSUPPRESSIVE THERAPY ON THE CLINICAL FOLLOW-UP OF BK VIRUS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims BK virus nephropathy occurs in up to 10% of kidney transplant recipients and can result in graft loss. The reactivation of BK virus is largely asymptomatic, and routine surveillance especially in the first 12-24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and antiviral treatment in the early stages may be effective in stopping BK virus replication. This study is designed to investigate the effect of management in immunosuppressive therapy on BK virus titers and graft functions in our kidney transplant group. Method A total of 370 kidney transplant recipients between the ages of 18-69 years and receiving a triple immunosuppressive therapy (Tacrolimus+Mycophenoloic Acid+Prednisolone) were included in the study. Demographic characteristics, BK virus titers, serum creatinine and immunosuppressive drug (Tacrolimus, Everolimus) levels were measured at regular intervals in the first 24 months. Among these patients 43 of them were found to have BK virus positivity. At the time of the detection of BK virus positivity, patients were divided into three groups regarding the change in the immunosuppressive protocols: Group I: Tacrolimus + Everolimus + Prednisolone, Group II: Everolimus + Prednisolone, Group III: Tacrolimus + Prednisolone. BK virus titers and graft functions of all three groups were compared with each other. SPSS 15 for Windows was used for statistical analysis. Results The mean age of the patients was 45.3 years, and the mean duration of transplantation was 16.3 months at the time of the BK virus positivity. During the follow-up, mean Tacrolimus levels were found to be in their highest value (14.1 ng/mL) in the posttransplant three months while BK virus titer reached the highest value (1.1x106 copies/ml) in the posttransplant seven to nine months. Increased creatinine values two months after BK virus positivity were strongly correlated (p = 0.02, p = 0.008, p = 0.05, p = 0.002 at 6th, 9th, 12th and 24th months, respectively). A significant decrease in BK virus titers was observed in all three groups due to reductions in immunosuppressive treatment protocol (p = 0.005, p = 0.003, p = 0.028, in groups I, II, III respectively). Conclusion Our study favors the benefits of the prospective screening for BK virus to identify early viral replication, permit intervention, and prevent progression to nephropathy or allograft loss. The best studied treatment for BK viremia and nephropathy is careful reduction of immunosuppression

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

The Authors' Reply: Tacrolimus Trough Concentrations After Liver Transplantation: Back to the Future.

The authors thank Dr Rodríguez-Perálvarez for initiating this valuable discussion on our article. We strongly agree with the authors that minimizations strategies are required to reduce the side effects associated with calcineurin inhibitors (CNI) exposure, and our results should not be interpreted as an encouragement to increase immunosuppression (IS) during the early posttransplant period. We deliberately referred to the first 15 days of CNI exposure (not minimization) as a poor tool in predicting long-term adverse events, at least in our population. We concluded that “the effect of early CNI exposure is possibly limited to early posttransplant outcomes and that other factors developing over time have possibly a greater impact on long-term events.”1 Indeed, and as an example, we as well as others have clearly shown the impact of additional variables, such as Framingham score or cumulative doses of CNI overtime on long-term outcomes.2,3 We understand the concerns of the authors regarding the subgroup analysis of patients immunosuppressed with tacrolimus (TAC); indeed, these types of analyses should always be interpreted with caution. We therefore additionally conducted a Bayesian model to further estimate the distribution of IS levels considering a confidence interval (CI) between 0.8 and 1.4 as clinically relevant. The area under the curve obtained of 0.81 highlights that, in our cohort, the first 15 days of CNI levels had no impact on long-term survival or graft loss with an 80% probability. Though we also agree with the authors that mean TAC levels may better reflect peaks of TAC, we also believe that predicting the lifetime events of a transplant patient by 1 TAC peak during the first 15 days is likely an overestimation of the potential toxicities of CNI. Furthermore, it is known that CNI levels during the first 15 days post–liver transplantation are extremely variable as shown in Figure S1 (SDC, https://links.lww.com/TP/B854) of the article.1 In that sense, using median levels of CNI, probably more consistent with their real exposition, is a better approach for understanding the real impact of early IS. Moreover, similar results were achieved regardless of the statistical approach used (mean versus median levels, sensitivity analysis). As highlighted by Rodríguez-Perálvarez, there may be competing risks for particular outcomes such as cardiovascular events; thus, we additionally performed a competing risk analysis for cardiovascular events taking into consideration mortality without finding any association between early IS exposition and cardiovascular events (hazard ratio = 1.229, CI 95% = 0.630-2.398, P = 0.489; hazard ratio = 0.944, CI 95% = 0.478-1.864, P = 0.867, comparing high versus low and optimal IS, respectively, see Figure 1).Figure 1.: Competing risk regression for cardiovascular disease: the cumulative incidence of cardiovascular events comparing high vs low and optimal immunosuppression was not significantly different taking into consideration mortality as competing risk factor.Finally, we would like to highlight the current difficulties in defining optimal IS or minimization strategies given the lack of adequate tools that provide accurate measurement of the net status of IS in a given patient.4,5 Such tools have long been considered the holy grail in immunology and organ transplantation.

Evaluation of Tacrolimus Levels and Risk of Graft-Versus-Host Disease, Relapse and Non-Relapse Mortality after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Following haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy), the range of target tacrolimus blood levels is wide (5-15 ng/ml). This fact, combined with pharmacogenomic variation and effects of drug interactions, leads to significant variability in tacrolimus serum concentrations. In the setting of matched related or unrelated donor transplantation using conventional graft-versus-host disease (GVHD) prophylaxis, several published studies have correlated higher post-transplant tacrolimus levels with a lower risk of GVHD. Therefore, we hypothesized that early post-transplant tacrolimus levels following haplo-HCT might impact the incidence of GVHD and other post-transplant endpoints and that more precise tacrolimus level targeting may improve post-transplant outcomes. To this end, we analyzed the relationship between mean weekly tacrolimus levels and acute and chronic GVHD, relapse, non-relapse mortality (NRM) and survival in 158 consecutive patients with hematologic malignancies receiving haplo-HCT using PTCy, tacrolimus and mycophenolate for GVHD prophylaxis between 2013-2018. Transplanted patients had a median age of 51 years (range, 19-75) and comorbidity index was ≥3 in 97 (61%). Peripheral blood was the graft source in 142 (90%), and regimen intensity was myeloablative in 90 (57%). Mean weekly tacrolimus levels were calculated each week for the first 4 weeks starting on day +7 and ending day +35 post-transplant, as well as aggregate mean tacrolimus level for 2- and 4-week intervals. Table 1 depicts a summary of the univariate analysis of weekly mean tacrolimus levels and various clinical endpoints (hazard ratios are depicted for each 1 ng/ml increment in mean tacrolimus levels). In this analysis, there were no significant associations between higher mean weekly tacrolimus levels and acute GVHD, chronic GVHD, relapse, NRM, or survival. Using tertiles, mean tacrolimus levels during weeks 1-4 were divided into <10.9 ng/ml, 10.9-13 ng/ml, and ≥13 ng/ml subgroups. In univariate analysis, there were no significant differences between mean weekly tacrolimus level subgroups and cumulative incidence of acute GVHD, chronic GVHD, relapse or NRM (Figure 1). In conclusion, following haplo-HCT with PTCy, there were no significant associations found between serum tacrolimus concentrations and the incidence of GVHD or other post-transplant outcomes. Given the lack of an obvious detrimental effect of lower tacrolimus levels, combined with the known toxicities associated with tacrolimus use (i.e. renal, neurologic, cardiovascular, diabetes mellitus), we speculate that lower target tacrolimus serum concentrations may be preferable following PTCy-based haplo-HCT.

Incidence of New-Onset Diabetes and PostTransplant Metabolic Syndrome after Liver Transplantation - A Prospective Study from South India.

Background and Aims:Liver transplantation has become an effective therapy for patients with end-stage liver disease. The risk of new-onset diabetes after transplantation (NODAT) and posttransplant metabolic syndrome (PTMS) is high among patients after liver transplantation. These are thought to be associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Our study aimed to document the incidence of NODAT and PTMS and analyze pre and posttransplant predictive factors for their development in patients undergoing a liver transplant.Methods:This was a prospective comparative study on 51 patients who underwent live donor liver transplantation. They were evaluated at baseline, 3 and 6 months after transplantation with fasting glucose, lipids, serum insulin levels, C-peptide, and HbA1C. They were followed up at 5 years to document any cardiovascular events or rejection.Results:The incidence of preoperative diabetes mellitus (DM) in the study group was 25/51 (49%). The incidence of NODAT was 38.5% (10/26 patients) and PTMS 29% (10/35), respectively. Age (47.7 ± 5.4 vs 41.5 ± 12.7 years), HOMA2 - IR (2.3 ± 1.8 vs 2.1 ± 1.6), serum insulin (16.1 ± 12.0 vs 17.9 ± 14.5), and C-peptide (4.6 ± 0.5 vs 4.8 ± 0.7) were similar at baseline in the NODAT group compared to those who did not develop it. Mean tacrolimus levels were higher in PTMS group (6.8 ± 2.9 vs 5.0. ± 2.0 P value = 0.042). By the end of 5 years, 7 patients expired; 6 due to rejection and one due to cardiovascular disease. Moreover, 2 of these patients had preexisting DM and 2 had NODAT.Conclusions:None of the baseline metabolic factors in patients undergoing liver transplant were predictive of the development of NODAT or PTMS. Mean tacrolimus levels were significantly higher in the PTMS group. A 5-year follow-up showed no excess risk of cardiovascular events or rejection in those with preexisting DM or in those who developed NODAT.

Clinical Efficacy and Safety of Tacrolimus in Pakistani Living Donor Liver Transplant Recipients.

To evaluate the association between tacrolimus trough levels and dosage in Pakistani patients undergoing live donor liver transplantation (LDLT), and the efficacy and adverse effects at different tacrolimus trough levels and dosages. An observational study. Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad and Basic Medical Sciences Institute, Karachi, from September 2016 to October 2018. Sixty liver transplant recipients were included. Demographics, clinical data, tacrolimus trough levels and doses were monitored as per routine protocol. Electrochemiluminescence immunoassay (ECLIA) was used to measure tacrolimus trough levels. Acute cellular rejection (ACR), sepsis and other adverse events were monitored at different tacrolimus trough levels in early post-transplantation period. Mean age of transplant recipients was 49.1 ± 10.6 years. Mean tacrolimus trough levels were 6.1 ± 2.2 ng/ml and mean dose was 0.94 ± 0.3 mg. Sepsis (27%) psychosis (20%), seizures (10%), and renal insufficiency (13%) were the most common adverse effects. Acute cellular rejection (ACR) was observed in 15% patients. Patients with sepsis had significantly high mean tacrolimus levels of 7.7 ± 2.5 ng/ml versus 5.5 ± 1.9 ng/ml (p=0.001). Mean tacrolimus trough levels in patients with ACR were significantly lower (4.05 ± 1.6 ng/ml vs. 6.43 ± 2.2ng/ml, p=0.003). None of the patients with a single tacrolimus trough level >10 ng/ml experienced ACR. A tacrolimus trough level between 5 to 7.5 ng/ml appears to be safe in Pakistani liver transplant recipients significantly minimising the risk of ACR and other adverse events.

Factors Affecting eGFR Slope of Renal Transplant Patients During the First 2 Years

PurposeIn healthy individuals, glomerular filtration rate decreases by 1 mL/min/y after a peak level of 125.0 mL/min has been reached in adulthood. Any reduction greater than this is a progressive slope (slope more negative than −1 mL/min/y, stable [−1 to +1]), or an improvable slope if it shows more of an increase, that is, greater than +1.0 mL/min/y). The aim of the study was to determine the factors affecting estimated glomerular filtration rate (eGFR) slope during the first 2 years of renal transplant in patients with negative pretransplant panel-reactive antibody. Materials and MethodsThe characteristics of 59 renal transplant patients, such as age, sex, etiology, and 2 years of laboratory data, were collected retrospectively. For each patient, the eGFR decline rate (slope) (mL/min−1/1.73 m2−1/y−1) was determined by linear regression analysis using all calculated eGFR values over the study period. FindingsOf 59 patients, 7 (11.8%) had a progressive slope, 22 (37.2%) had a stable slope, and 30 (50.8%) had an improvable slope. The first-year mean tacrolimus level was lower in patients with progressive slope than in the patients with stable slope and improvable slope (P < .022). The determinants of eGFR slope in multiple regression analysis were post-transplant hypertension (β = −0.393; P = .002) and the first-year mean tacrolimus level (β = 0.320; P = .01), whereas age, serum albumin, and 2-year mean tacrolimus level did not reach the level of significance. ConclusionKeeping tacrolimus levels high in the first year to prevent eGFR declining is important.

Pediatric Heart Transplantation: Transitioning to Adult Care (TRANSIT): Feasibility of a Pilot Randomized Controlled Trial

Background:Young-adult heart transplant recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine the feasibility of and to test a transition intervention for young adults who underwent heart transplantation as children and then transferred to adult care. Methods:Participants were randomized to the transition intervention (4 months long, focused on heart-transplant knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models. Results:Transfer to adult care was successful and feasible (ie, excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between-group or within-group differences in percentage of tacrolimus bioassays within target range (> 50%). Average overall adherence to treatment was similarly good in both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups. Conclusions:The feasibility of the study was demonstrated. Our transition intervention did not improve outcomes.

Adherence Behavior in Subjects on Hemodialysis Is Not a Clear Predictor of Posttransplantation Adherence

IntroductionNonadherence is common in both hemodialysis (HD) and kidney transplant recipients and is a major risk factor for poor clinical outcomes. This retrospective study explored whether nonadherent HD patients become nonadherent transplant recipients.MethodsData were collected for 88 patients from the electronic patient system at a subregional renal unit about adherence to HD regimens in the 6 months before transplantation, and for 1 year posttransplantation following return transfer to the posttransplantation clinic from the transplanting center. Pretransplantation definitions of nonadherence included whether the patients: on average, shortened their dialysis prescription by >10 minutes; shortened it by >15 minutes; missed 2 or more HD sessions; and had mean serum phosphate levels >1.8mmol/l. Posttransplantation definitions of nonadherence included mean tacrolimus levels outside 5 to 10 ng/ml; and missed 1 or more posttransplantation clinic appointments.ResultsNonadherence ranged from 25% to 42% pretransplantation and from 15.9% to 22.7% posttransplantation, depending on how it was operationalized. There was little relationship between pretransplantation data and posttransplantation adherence, with the exception of a significant relationship between pretransplantation phosphate and posttransplantation clinic attendance. Patients who had missed 1 or more transplant clinic appointments had higher mean pretransplantation phosphate levels. Nonadherent patients with high phosphate levels pretransplantation and missed clinic appointments posttransplantation were significantly younger.ConclusionOur findings provide little support for the likelihood of a strong direct relationship between pre and posttransplantation behaviors. The findings require confirmation and further research to assess whether interventions in relation to pretransplantation adherence may enhance adherence posttransplantation and improve outcomes.