Tacrolimus Trough Blood Levels Research Articles

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series

BackgroundAmong the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug–drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear.Case presentationWe experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold.ConclusionsThese cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

Tacrolimus monitoring in hair samples of kidney transplant recipients.

Calcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients. Single-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations. In total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible. Measuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.

Visual evoked potentials as a method for the prospective assessment of tacrolimus neurotoxicity in patients after kidney transplantation

IntroductionNeurotoxicity, including optic nerve injury, is one of the most common adverse effects of tacrolimus, the principal calcineurin inhibitor used after kidney transplantation (KTx). The electrophysiologic measurements of both pattern visual evoked potentials (PVEP) and flash visual evoked potentials (FVEP) are valuable when drug-induced optic neuropathy is suspected.ObjectivesTo determine whether VEP measurement is a sensitive and repeatable method for monitoring tacrolimus neurotoxicity.Material and methodsThis prospective study focused on 35 patients (20 M, 15F, 69 eyes, mean age 43 ± 11 years) who were at a median of 3.0 (IQR, 2.2–3.7) months after KTx at the time of the initial VEP evaluation and were treated with tacrolimus since KTx. The follow-up VEP examination was done after a median of 24 (22–27) months (both VEP measurements followed the ISCEV standards). The P100 wave latency and amplitude for the 1° and 15’ PVEP simulations, and the P2 wave latency and amplitude for the FVEP were analyzed.ResultsFor the 1° checks, the P100 wave latency and amplitude values were significantly worse in the follow-up examination compared to the early post-transplant time-point. Independent associations between FVEP parameters and the tacrolimus blood trough level were observed in the follow-up examination but not at the early post-transplant period. The P2 wave latency correlated with the tacrolimus trough level only in patients treated with the twice-daily, but not the once-daily, tacrolimus formulation. The brain derived neurotrophic factor (BDNF) level correlated with the P100 (15’) latency (R = 0.499; p = 0.005) and the P2 latency (R = 0.409; p = 0.025) only in patients treated with the once-daily, but not the twice-daily, tacrolimus formulation.ConclusionThe observations in this study may support the rationale for the use of VEP measurements as non-invasive monitoring of subclinical tacrolimus neurotoxicity.

Calcineurin Inhibitor–Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function

Although effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown. This retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L). Despite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P=.24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P=.79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r=-0.26, P=.03); a correlation that was not observed during the remainder of the year (r=-0.09, P=.52). In LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.

Cell-Free DNA to Monitor Immunosuppression Adequacy in Lung Transplantation

<h3>Purpose</h3> Tacrolimus is a primary immunosuppressive drug used in lung transplantation (LTx). Unfortunately, significant variability in drug level monitoring and dosing makes it challenging to determine immunosuppression adequacy. Furthermore, the relationship between drug levels and allograft injury remain poorly defined. This study examines the relationship between tacrolimus blood and donor-derived cell-free DNA (ddcfDNA), a biomarker of allograft injury. <h3>Methods</h3> 96 LTx from a multicenter cohort were included. Periodic tacrolimus blood levels (n= 4,204) were obtained. Serial plasma samples (n=2,122) were assayed for %ddcfDNA by shotgun sequencing. %ddcfDNA was log-transformed to adjust for skewness. Tacrolimus trough levels were dichotomized to "therapeutic" and "non-therapeutic" based on clinically desirable trough ranges. Tacrolimus trough and %ddcfDNA trends were analyzed. Separate analysis was performed in patients with and without ACR (> Grade 1 per ISHLT criteria). <h3>Results</h3> Over a 24-month follow up period, %ddcfDNA showed an inverse relationship to tacrolimus tough levels (Figure 1a); patients showed higher %ddcfDNA with non-therapeutic tacrolimus trough levels than with therapeutic levels (p<0.0001) (Figure 1b). 27% of patients experienced at least one episode of ACR. During the study follow-up, their %ddcfDNA levels were higher (p=0.049) and their percentage of non-therapeutic trough levels was higher (p=0.006) compared to patients with no ACR. However, even when tacrolimus trough levels were therapeutic, patients with ACR showed higher %ddcfDNA levels compared to patients without ACR (p=0.020). <h3>Conclusion</h3> %ddcfDNA levels vary inversely with tacrolimus blood trough levels in LTx. Even in patients with therapeutic trough levels, those with ACR demonstrate higher %ddcfDNA levels. Further studies should examine whether sensitive biomarkers such as ddcfDNA can be used to augment immunosuppression monitoring in LTx rather than trough levels alone.

Long-Term Tacrolimus Blood Trough Level and Patient Survival in Adult Liver Transplantation.

Tacrolimus is the most widely used immunosuppressant in liver transplant (LT) patients. However, the ideal long-term target level for these patients is unknown. This retrospective study aimed to investigate the impact of tacrolimus blood concentration five years after LT on long-term patient survival outcomes in adult LT recipients. Patients who underwent LT between January 2004 and July 2014 at a tertiary medical center were included in this study (n = 189). The mean tacrolimus blood concentrations of each patient during the fifth year after LT were recorded and the overall survival rate was determined. A multivariate analysis of factors associated with long-term survival was conducted using a Cox’s model. The median follow-up period was 9.63 years, and 144 patients (76.2%) underwent live donor LT. Sixteen patients died within 5 years of LT. In the Cox’s model, patients with a mean tacrolimus blood trough level of 4.6–10.2 ng/mL had significantly better long-term survival than those with a mean tacrolimus blood trough level outside this range (estimated hazard ratio = 4.76; 95% confidence interval: 1.34–16.9, p = 0.016). Therefore, a tacrolimus level no lower than 4.6 ng/mL would be recommended in adult LT patients.

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study

PurposeTacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet.MethodsIn this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients).ResultsThe median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4–49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5–51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed.ConclusionsFlucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.

Adipose-derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long-term graft tolerance in vascularized composite allotransplantation.

The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as a reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus, and cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4-Ig) with adipose-derived stromal cells (ASCs) to allow VCA survival without long-term systemic immunosuppression. Full-mismatched rat hind-limb-transplant recipients received tacrolimus (0.5mg/kg) for 14days and were assigned to 4 groups: controls (CTRL) received no conditioning; ASC-group received CTLA4-Ig (10mg/kg body weight i.p. postoperative day [POD] 2, 4, 7) and donor ASCs (1×106 iv, POD 2, 4, 7, 15, 28); the ASC-cyclophosphamide (CYP)-group received CTLA4-Ig, ASC plus cyclophosphamide (50mg/kg ip, POD 3); the ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500µL ip, POD 1, 5). Banff grade III or 120days were endpoints. ASCs suppressed alloresponse in vitro. Median rejection-free VCA survival was 28days in CTRL (n=7), 34 in ASC (n=6), and 27.5 in ASC-CYP (n=4). In contrast, ASC-ALS achieved significantly longer, rejection-free VCA survival in 6/7 animals (86%), with persistent mixed donor-cell chimerism, and elevated systemic and allograft skin Tregs , with no signs of acute cellular rejection. Taken together, a regimen comprised of short-course tacrolimus, repeated CTLA4-Ig and ASC administration, combined with ALS, promotes long-term VCA survival without chronic immunosuppression.

Characteristics of BK polymavirus infection in kidney transplant recipients

To analyze the characteristics of BK polymavirus (BKV) infection and the optimal time window for intervention in kidney transplant recipients (KTRs). We retrospectively analyzed the clinical data and treatment regimens in 226 KTRs in our center between January, 2013 and January, 2018. Among the recipients, 157 had a urine BKV load ≥1.0×104 copy/mL after transplantation, and 69 had a urine BKV load below 1.0×104 copy/mL (control group). Among the 157 KTRs, 60 (38.2%) recipients were positive for urine BKV, 66 (42.0%) had BKV viruria, and 31(19.7%) had BKV viremia. The incidence of positive urine occult blood was significantly higher in BKV-positive recipients than in the control group (P &lt; 0.05). The change of urine BKV load was linearly related to that of Tacrolimus trough blood level (r2=0.351, P &lt; 0.05). In urine BKV positive group, the average estimated glomerular filtration rate (eGFR) was below the baseline level (60 mL·min-1·1.73 m-2) upon diagnosis of BKV infection reactivation, and recovered the normal level after intervention. In patients with BKV viruria and viremia, the average eGFR failed to return to the baseline level in spite of improvement of the renal function after intervention. Positive urine occult blood after transplantation may be associated with BKV infection reactivation in some of the KTRs. BKV infection is sensitive to changes of plasma concentration of immunosuppressive agents. Early intervention of BKV replication in KTRs with appropriate dose reduction for immunosuppression can help to control virus replication and stabilize the allograft function.

Safety and Effectiveness of Conversion From Cyclosporine to Once-Daily Prolonged-Release Tacrolimus in Stable Kidney Transplant Patients: A Multicenter Observational Study in Japan

This study investigated the safety and effectiveness of conversion from cyclosporine- to prolonged-release tacrolimus (PR-T)-based immunosuppression in kidney transplant recipients (KTRs) in Japanese routine clinical practice. Materials and methodsThis was a prospective observational study of stable KTRs who were converted from cyclosporine to PR-T according to local clinical practice. Clinical data were collected up to 12 months postconversion. Study outcomes included conversion dosing ratios, PR-T dose and trough levels, change in estimated glomerular filtration rate between conversion and month 12, graft/patient survival, and rejection rate (Kaplan–Meier). Outcomes of ongoing preconversion hypertrichosis, gingival hypertrophy, and cyclosporine-related renal toxicity were detailed. Data for adverse drug reactions were collected. ResultsOverall, 266 patients (mean ± SD age 51.9 ± 13.5 years) were included. The mean ± SD conversion ratio (PR-T:cyclosporine, mg:mg) was 0.029 ± 0.017. After an initial decrease between conversion and month 3, mean ± SD PR-T daily dose remained stable up to month 12 (2.4 ± 1.5 mg at months 3 and 12), as did tacrolimus trough blood levels (3.5 ± 1.8 vs 3.6 ± 1.7 ng/mL, respectively). Estimated glomerular filtration rate was stable over 12 months (mean ± SD change from conversion to month 12 was 0.3 ± 7.8 mL/min/1.73m2). Month 12 Kaplan–Meier patient and graft survival rates were 99.6% and 95.5%, respectively. Eight patients reported 9 rejection episodes. PR-T demonstrated potential to improve cyclosporine-related renal toxicity, hypertrichosis, and gingival hypertrophy. Postconversion, 46 adverse drug reactions were reported in 39 patients (14.7%); there was 1 death. ConclusionsConversion from cyclosporine to PR-T in Japanese stable KTRs was effective and tolerable over 12 months, with low rates of rejection reported.

CYP3A5*3 Genetic Polymorphism and Tacrolimus Concentration in Myanmar Renal Transplant Patients

BackgroundGenetic polymorphism is an important factor that influences tacrolimus concentrations and has the potential to predict the optimal dosage of tacrolimus in personalized medicine. Tacrolimus, a drug of narrow therapeutic index, is used in renal transplant recipients as an immunosuppressant agent. It is a substrate of cytochrome P450 3A (CYP3A) and has highly variable pharmacokinetic parameters. ObjectiveThe aim of this study was to identify the proportion of CYP3A5 gene polymorphism in Myanmar kidney transplant recipients and to determine the impact of CYP3A5 gene polymorphisms on tacrolimus level in CYP3A5 expressors and nonexpressors. MethodsThis study included 41 adult Myanmar post–renal transplant patients. Tacrolimus trough blood levels were determined and CYP3A5 genotype analysis was conducted by using polymerase chain reaction amplification of target followed by detection by restriction fragment length polymorphism analysis.Results. The CYP3A5 nonexpressors and expressors were detected in 25 (60.97%) and 16 (39.02%) of the 41 renal transplant recipients, respectively. The tacrolimus concentration/dose ratio in the CYP3A5 expressor group was lower than in the CYP3A5 nonexpressor group (1.49 ± 0.69 vs 3.49 ± 3.08 [P = .003] at 1 month; and 1.54 ± 0.9 vs 7.88 ± 8.25 [P = .0001] at 3 months). ConclusionsThe findings of the present study revealed that more than one half of the study population were carrying the mutant allele CYP3A5*3(A6986G). CYP3A5 genetic polymorphism is one of the important factors in determining daily requirements for tacrolimus and in adjusting tacrolimus trough concentrations.

Bariatric surgery in solid organ transplant patients: Long-term follow-up results of outcome, safety, and effect on immunosuppression.

The surgical risk of transplanted patients is high, and the modified gastrointestinal anatomy after bariatric surgery (BS) may lead to pharmacokinetic alterations in the absorption of immunosuppressive drugs. Data on outcomes of BS and the safety and feasibility of maintaining immunosuppression and graft safety among solid organ transplanted patients are scarce. In the current study, weight loss, improvement in comorbidities, and changes in dosage and trough levels of immunosuppression drugs before and after BS were analyzed for all transplanted patients who underwent laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass (LRYGB) in our institution between November 2011 and January 2017. Thirty-four patients (13 females, 21 males, average age 53years) were included in the study. A successful weight loss (>50% excess weight loss in 28 of them [82%]) was recorded at the last follow-up. Comorbidities improved significantly. Immunosuppressive stability increased from 39% to 47% among all patients. The tacrolimus blood trough levels declined slightly, but remained within therapeutic range. These data suggest that LSG and LRYGB ensure good immunosuppressive maintenance together with significant weight loss and improvement in comorbidities without serious graft rejection or dysfunction. The surgical risk is higher than in the regular BS population.

Tacrolimus Blood Level Fluctuation Predisposes to Coexisting BK Virus Nephropathy and Acute Allograft Rejection

BK virus nephropathy (BKVN) and allograft rejection are two distinct disease entities which occur at opposite ends of the immune spectrum. However, they coexist in renal transplant recipients. Predisposing factors for this coexistence remain elusive. We identified nine biopsy-proven BKVN patients with coexisting acute rejection, and 21 patients with BKVN alone. We retrospectively analyzed the dosage and blood concentrations of immunosuppressants during the 3-month period prior to the renal biopsy between the two patient groups. Compared to the BKVN alone group, renal function was noticeably worse in the coexistence group (p = 0.030). Regarding the dose and average drug level of immunosuppressants, there was no difference between the two groups. Interestingly, the coefficient of variance of tacrolimus trough blood level was noticeably higher during the 3-month period prior to the renal biopsy in the coexistence group (p = 0.010). Our novel findings suggest that a higher variability of tacrolimus trough level may be associated with the coexistence of BKVN and acute rejection. Since the prognosis is poor and the treatment is challenging in patients with coexisting BKVN and acute rejection, transplant clinicians should strive to avoid fluctuations in immunosuppressant drug levels in patients with either one of these two disease entities.

Betel Nut Chewing Is Associated With Reduced Tacrolimus Concentration in Taiwanese Liver Transplant Recipients

PurposeStudies have shown that arecoline, the major alkaloid component of betel nuts, alters the activity of enzymes in the cytochrome P450 (CYP-450) family. Tacrolimus, an immunosuppressant that protects against organ rejection in transplant recipients, not only is mainly metabolized by CYP3A enzymes but also has a narrow therapeutic range. We aimed to investigate whether dose-adjusted blood trough levels of tacrolimus differed over time between betel nut-chewing and non–betel nut-chewing liver transplant recipients. MethodsIn this retrospective case-control study, 14 active betel nut-using liver recipients were matched at a 1:2 ratio to 28 non-betel nut-using liver recipients by sex, age, graft source, duration of follow-up after liver transplantation, and estimated glomerular filtration rate. Differences in liver function index, renal function index, and dose-adjusted blood trough levels of tacrolimus over an 18-month period were compared between the 2 groups by using the Generalized Estimating Equation approach. ResultsDose-adjusted blood trough levels of tacrolimus tended to be significantly (P = .04) lower in betel nut chewers (mean = 0.81, medium = 0.7, 95% confidence interval [CI] = 0.73 to 0.90) than in nonchewers (mean = 1.12, medium = 0.88, 95% CI = 1.03 to 1.22) during the 18-month study period. However, there was no significant difference in renal and liver function index between the 2 groups. ConclusionLiver transplant recipients receiving tacrolimus tend to have lower blood trough levels of the drug over time if they chew betel nuts.

Neurotoxic Side Effects of Calcineurin Inhibitors in Patients After Liver Transplantation: Preliminary Results of a Quantitative MRI Study of the Brain

Background: Calcineurin inhibitors (CNI) are the most often used immunosuppressive drugs for the prevention of graft rejection after liver transplantation (LT). Long-term CNI treatment, however, is associated with cardiovascular disease and renal dysfunction. Considering the high frequency of neurotoxic side effects during the first weeks after treatment onset, long-term effects upon brain tissue structure and brain function must be expected. Aiming to estimate the long-term influence of CNI on cerebral microstructure and function after LT we carried out this quantitative MR study. Methods: Ninety patients (mean age: 58 ± 8) with a history of at least 3 years after liver transplantation were studied. They were divided into three groups according to their medication of the last two years: 23 patients without CNI, 36 patients with reduced dose of CNI (stable tacrolimus blood trough levels below 5 μg/l or stable cyclosporine A blood trough levels below 50 μg/l) and 31 patients with standard dose of CNI. Four patients were excluded due to incomplete examinations or artefacts. Thirty-two healthy gender- and age-adjusted volunteers served as reference group. All subjects underwent neuropsychological testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and MR examinations at 3 T (Verio, Siemens, Erlangen). The MR protocol included a T1 weighted GRE with 2 flip angles, a T2 weighted TSE with three echoes, a T2* weighted GRE with triple TE. Quantitative T1, relative proton density (PD, in ratio to water phantom), T2 and T2* maps were obtained on-the-fly on the MR system with an extended image reconstruction provided by the manufacturer, using monoexponential fitting to the signal intensity decay curves of the T1 GRE, T2 TSE and T2 GRE sequences, respectively, for region of interest (ROI) measurements, which were made in 18 ROIs located in cerebellum, brainstem, and cerebral gray and white matter. One-way ANOVA with Bonferroni corrected post hoc tests (α = 0.05) were used to compare the qMRI data and Kruskal–Wallis test to compare the RBANS scores between groups. Results: RBANS scores revealed that patients receiving CNI owned a significantly worse visuospatial/constructional ability, and patients with low dose CNI an overall impaired cognitive function compared to controls. qMRI revealed significant microstructural changes, especially in frontal white matter, with higher PD and T2 (CNI free) and higher T2* (CNI free and low dose), indicating increased free water (PD and T2) and reduced metabolism (T2*) within brain tissue of these patients compared to controls. Interestingly, little change has been found in patients with standard CNI dose, indicating probably different phenotypes between patients, by considering that the CNI dose was applied depending on patients’ tolerability to CNI medication. Conclusion: These preliminary results showed that long term medication with CNI affects tissue microstructure in human brain and the brain function after liver transplantation (Figure 1). The authors have none to declare.

Tacrolimus Given As an Alternative to Cyclosporin after Allogeneic HSCT in Case of Renal Impairment: A Prospective Pilot Study

▪IntroductionTacrolimus is a widely used calcineurin inhibitor in solid organ transplantation and in allogeneic HCST for prophylaxis and treatment of GvHD. Recently, several transplantation centers showed advantageous effects for patients with tacrolimus in comparison with cyclosporin A (CsA) regarding renal function after renal and heart transplantation. Based on these observations, we have conducted a prospective study in wich CsA is switched for tacrolimus (Prograf or Advagraf ER) in case of renal impairment due to CsA after allogeneicHSCT.Patients, MethodWe enrolled 31 consecutive patients between March 2012 and March 2016 from two centers in France (Lyon and Nancy) with renal impairment due to CsA (serum creatinine > 90 µMol/L), the conversion dose was established on an mg:mg basis 1 :100 from CsA total daily dose to a total daily dose of tacrolimus. In this cohort, 27 patients received oral formulation Advagraf and 4 received Prograf initially i.v. and then converted to oral form. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L.We evaluated the tacrolimus blood trough level changes after conversion, serum creatinine, potassium, one time a week from one week after switching to discontinuation. Before the switch, 22 patients (70%) had CsA for GvHD prophylaxis and 9 patients (30%) for acute GvHD treatment in association with prednisone.ResultsAll patients had hematological malignancies, the median age was 54 years (range, 17-67). Twelve patients (39%) had a matched related donor, 19 patients (61%) had a HLA-10/10 matched unrelated donor .The stem cell source was bone marrow for 11 patients (35.5%), PBSC for 18 patients (58%) and cord blood for 2 patients (6.5%). Fifteen patients (48%) received a myeloablative regimen and 16 patients (52%) a reduced intensity regimen. ATG was administrated in 28 patients and 10 patients received 12Gy TBI. The status at transplantation was CR1 for 13 patients (42%), CR2 or more for 10 patients (32%), partial response for 5 patients (16%) and 3 patients (10%) had a refractory leukemia.The median follow-up after transplantation was 35.6 months (range, 1-51,7). The median time of switch for tacrolimus was 40 days (range, 3-1286) and the median of serum creatinine in wich the switch was realized was 110 mol/L (range, 94-262). Concerning creatinine level, the median of serum creatinine was 105 µmol/L (range, 51-262) with CsA and 84 µmol/L (range, 50-129) with tacrolimus (p<0.01) (Figure 1). Moreover the median of potassium level was 4.2 mmol/L (range,3.2-5.2 ) with CsA and 4.0 (range,3-5.1 ) with tacrolimus (p<0.001 ) (Figure 2). Before the switch, the median of serum creatinine was 94µMol/L (range, 51-213),106µMol/L (range, 57-262) and 110 µMol/L (range, 75-180) at D+30, D+45 and D+60 respectively after transplantation for patients with CsA and the median residual value of CsA was 250 µg/l (range, 162-629) at D+30. The median dose of CsA was 200mg (range, 25-600) and the median dose of tacrolimus was 2.4mg (range, 0.5-5). The median of serum creatinine was 88µMol/L (range, 59-130), 84µMol/L (range,54-129) and 84µMol/L (range, 54-129) at D+5, D+15 and D+30 after the switch for tacrolimus and the median residual value of tacrolimus was 8.7µg/l (range,2.7-15) at D+20 after the switch (Figure 3).The cumulative incidence of grade II-IV aGvHD was 53% (95%CI, 25-64) at +90 days. Seventeen patients (58%) developed aGvHD grade ≥ II and 7 patients (22%) developed chronic GvHD with NIH score 2-3 after discontinuation of GvHD prophylaxis. The cumulative incidence of cGvHD was 26.5% (95%CI, 7.75-45) at 1 year, 32.14%(95% CI, 11.6-52) after 2 years and 32.14% (95% CI, 11.6-52) after 3 years. In this cohort, 27 patients (87%) are alive and 26 patients (84%) are in complete response at this time. Four patients died two from relapse, one from cerebral bleeding and one from severe pneumonia (fungal and Pneumocystis carinii infection).ConclusionThe conversion from CsA to Tacrolimus was followed by a clinically significant improvement in kidney function with stable tacrolimus blood trough levels. Based on these observations, we suggested that the use of tacrolimus in case of renal impairment due to CsA is safe in allogeneic HSCT patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresMichallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.

Therapeutic Drug Monitoring of Tacrolimus in Saudi Kidney Transplant Patients

Background: Tacrolimus is immunosuppressive agent used for the prevention of rejection in kidney transplant patients, has narrow therapeutic range, and variable pharmacokinetics. Objectives: To identify the optimum Tacrolimus blood trough level for Saudi kidney transplant patients (SKTP). Method: The research population consisted of 100 SKTP at the Armed Forces Hospital in the Southern Region (AFHSR) treated with Tacrolimus and followed-up for a period of 24 months (2012 till 2014). Results: A significant relationship between Tacrolimus trough level and incidence of kidney rejection was remarkably found only after 180 days post-transplantation. During this period, Tacrolimus mean trough level (ng/ml) was 7.4 ± 0.2 in SKTP with no rejection, 5.3 ± 0.7 for those with acute rejection, and 3.8 ± 0.4 for those with chronic rejection. Furthermore, the coefficient of variation (CV%) which reflects fluctuation in Tacrolimus trough level, was obviously high in SKTP with acute rejection in all post-kidney-transplant periods. Conclusion: After 6 month post- kidney transplantation in SKTP, Tacrolimus trough level (

Increased phosphorylation of the renal Na+-Cl- cotransporter in male kidney transplant recipient patients with hypertension: a prospective cohort.

Evidence in rodents suggests that tacrolimus-induced posttransplant hypertension is due to upregulation of the thiazide-sensitive Na+-Cl- cotransporter NCC. Here, we analyzed whether a similar mechanism is involved in posttransplant hypertension in humans. From January 2013 to June 2014, all adult kidney transplant recipients receiving a kidney allograft were enrolled in a prospective cohort study. All patients received tacrolimus as part of the immunosuppressive therapy. Six months after surgery, we assessed general clinical and laboratory variables, tacrolimus trough blood levels, and ambulatory 24-h blood pressure monitoring. Urinary exosomes were extracted to perform Western blot analysis using total and phospho-NCC antibodies. A total of 52 patients, including 17 women and 35 men, were followed. At 6 mo after transplantation, of the 35 men, 17 developed hypertension and 18 remained normotensive, while high blood pressure was observed in only 3 of 17 women. The hypertensive patients were significantly older than the normotensive group; however, there were no significant differences in body weight, history of acute rejection, renal function, and tacrolimus trough levels. In urinary exosomes, hypertensive patients showed higher NCC expression (1.7±0.19) than normotensive (1±0.13) (P=0.0096). Also, NCC phosphorylation levels were significantly higher in the hypertensive patients (1.57±0.16 vs. 1±0.07; P=0.0049). Our data show that there is a positive correlation between NCC expression/phosphorylation in urinary exosomes and the development of hypertension in posttransplant male patients treated with tacrolimus. Our results are consistent with the hypothesis that NCC activation plays a major role in tacrolimus-induced hypertension.

The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation.

We investigated the effects of pregnancy and delivery on renal function in transplant recipients and the relationship between doses of immunosuppressants and blood drug levels during pregnancy in 75 women with 88 deliveries. Significant serum creatinine elevation (> 0.5 mg/dL) was found in eight deliveries. In the remaining 80 cases, serum creatinine was reduced by an average of 0.14 mg/dL and returned to pre-pregnant levels after delivery. Tacrolimus was used in 28 deliveries and cyclosporine in others. Tacrolimus blood trough level declined from 5.8 ± 2.8 ng/mL 12 months before delivery to 4.2 ± 1.8 ng/mL at second trimester; therefore, drug dose was increased from 4.1 ± 1.9 mg/d at first trimester to 5.5 ± 2.5 mg/d at delivery. Similarly, cyclosporine levels were 125.1 ± 65.1 ng/mL 12 months before delivery and 75.4 ± 35.0 ng/mL at second trimester resulting in dose elevation from 183.0 ± 71.8 mg/d at first trimester to 225.4 ± 85.1 mg/d at delivery. Renal function in female kidney transplant recipients improved slightly during pregnancy and returned to pre-pregnant level after delivery. The dose elevation of calcineurin inhibitor by approximately 20-25% should be considered during gestational period to maintain optimal blood drug level.

The Therapeutic Efficacy of Local Delivery of a Combination of Tacrolimus and Mycophenolic Acid Along With Lower Doses of Systemic Immunotherapy in Prolongation of The Composite Tissue Allograft Survival With a Minimum Systemic Toxicity.

Wide spread use of vascularized composite tissue allo-transplantation (VCA) is limited by the side effects of the life-long systemic immunosuppression. Alternative therapies to avoid both the acute rejection and the complications of the life-long systemic immunosuppression are needed. VCA provides a unique opportunity for the local delivery of the drugs directly to the graft. Therefore, the goal of our study is to investigate the therapeutic efficacy of the local delivery of a combination of tacrolimus and mycophenolic acid along with lower doses of systemic immunotherapy in the prolongation of the survival of the composite tissue allograft with a minimum systemic toxicity. Brown Norway -to- Lewis rat orthotopic hind limb transplants were performed and received 0.1mg/kg/day of tacrolimus intraperitoneally. Topical application of no treatment (Control), tacrolimus 0.1% ointment, mycophenolic acid 1% lipoderm, and a combination of the two topical formulations were initiated at day 0 to overlap with the systemic therapy. Treatment was continued until grade III rejection. Tail vein sampling was performed at days 4, 7, 14, and at sacrifice. Whole blood trough levels of tacrolimus, and plasma trough concentrations of mycophenolic acid was analyzed by HPLC-MS, and HPLC. Tissue biopsies (Skin, muscle, and lymphatic nodes) were collected at end point for tissue drug levels, as well as for storage in formalin and OCT for histopathology and IHC. Systemic toxicity was evaluated using 24hr urinary creatinine excretion. Best outcomes were obtained in group (n=6) treated with a combination of the two topical formulations in a conjunction with low dose of systemic immunotherapy (Allograft Survival > 100 days). Drugs levels were low or undetectable in blood and/or plasma, whereas tissue levels were significantly higher than blood levels (P<0.05). 24 hr urinary creatinine excretion were in the normal range. Histological evaluation was correlated with the clinical sign of rejection. We concluded that local delivery of a combination of tacrolimus, and mycophenolic acid along with lower doses of systemic immunotherapy was successful in prolongation of the composite tissue allograft survival with a minimum systemic toxicity.