Immunosuppression In Liver Transplantation Research Articles

Humoral and cellular immune responses to COVID-19 mRNA vaccines in immunosuppressed liver transplant recipients

BackgroundLiver transplant recipients (LTRs) are at a high risk of severe COVID-19 owing to immunosuppression and comorbidities. LTRs are less responsive to mRNA vaccines than healthy donors (HDs) or other immunosuppressed patients. However, the disruption mechanism in humoral and cellular immune memory responses is unclear.MethodsWe longitudinally collected peripheral blood mononuclear cells and plasma samples from HDs (n = 44) and LTRs (n = 54) who received BNT162b2 or mRNA-1273 vaccines. We measured the levels of anti-receptor-binding domain (RBD) antibodies and spike-specific CD4+ and CD8+ T-cell responses.ResultsHere, we show that the induction of anti-RBD IgG was weaker in LTRs than in HDs. The use of multiple immunosuppressive drugs is associated with lower antibody titers than only calcineurin inhibitor, and limits the induction of CD4+ T-cell responses. However, spike-specific CD4+ T-cell and antibody responses improved with a third vaccination. Furthermore, mRNA vaccine-induced spike-specific CD8+ T cells are quantitatively, but not qualitatively, limited to LTRs. Both CD4+ and CD8+ T cells react to omicron sublineages, regardless of the presence in HDs or LTRs. However, there is no boosting effect of spike-specific memory CD8+ T-cell responses after a third vaccination in HDs or LTRs.ConclusionsThe third mRNA vaccination improves both humoral responses and spike-specific CD4+ T-cell responses in LTRs but provides no booster effect for spike-specific memory CD8+ T-cell responses. A third mRNA vaccination could be helpful in LTRs to prevent severe COVID-19, although further investigation is required to elicit CD8+ T-cell responses in LTRs and HDs.

Pulmonary Complications of Everolimus in Liver Transplant Patients: A 10-Year Experience.

This retrospective study aims to evaluate the safety of everolimus when used as part of the immunosuppression regimen in patients who underwent liver transplant from 2009 to 2019 at a tertiary liver transplant center. Patients were divided into two groups: those who received everolimus as part of the post-transplant regimen and those who did not. The primary safety outcome measured was the development of new pulmonary complications that had been associated with everolimus use in prior studies. Lung function was determined by pulmonary function tests if available or CT scans of the chest. Secondary outcomes measured included everolimus discontinuation rates and survival rates. During the study period, 450 patients underwent liver transplant; 35% of patients received everolimus (n=156) and 65% of patients did not receive everolimus (n=292). Primary safety outcome of pulmonary complications was seen in 3.9% of patients who received everolimus (n=6) and 6.3% of the control group patients who did not receive everolimus (n=19). The association between everolimus use and new pulmonary complications was not significant with a chi-square statistic of 1.33 (p=0.249). Overall, 51.3% of patients who received everolimus during their post-transplant course discontinued the medication (n=80). Everolimus is safe from a pulmonary toxicity standpoint in liver transplant immunosuppression regimens as there was no significant difference found in pulmonary complications between patients who received the medication and those who did not.

Outcomes of liver transplantation patients infected with COVID-19: pandemic hospital experience from Turkey

Aims: There are conflicting results for the course of the disease and mortality rates for liver transplantation patients infected with COVID-19. In this study, we aimed to present the outcomes of our liver transplant patients who were hospitalized and followed up in our tertiary hospital, which served as a pandemic hospital for COVID-19.
 Methods: Patients hospitalized with the diagnosis of COVID-19 between March 1, 2020 and March 1, 2022 in Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital and Prof. Dr. Feriha Öz Pandemic Hospital were included. In this retrospective observational study, the clinical data of the patients, the need for intensive care hospitalization, and mortality rates were recorded by hospital computer system. The relationships were analyzed with SPSS v20.0.
 Results: There were 25996 patients who were hospitalized with the diagnosis of COVID-19 and 28 of them were with the history of liver transplantation. Ages of the liver transplant patients ranged from 18 to 73, with a median age of 52. 82.1% of the patients were male and 17.9% were female. Intensive care unit hospitalization rate was 25% and mortality rate was 14.3%. The relationships according to the age groups revealed that all of the women were under the age of 50 (p=0.008) and the patients who deceased were male patients over the age of 50 (p=0.044).
 Conclusion: Mortality rates and intensive care unit requirements of chronically immunosuppressed liver transplant patients with COVID-19 infection were similar with general population. Complete immunosuppression withdrawal should not be urged in this population.

Randomized Trial of Ciclosporin with 2-h Monitoring vs. Tacrolimus with Trough Monitoring in Liver Transplantation: DELTA Study.

Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT. Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test. In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p≤0.001), with no other differences in safety and tolerability. In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

Graft-derived Cell-free DNA as a Rejection Biomarker and a Monitoring Tool for Immunosuppression in Liver Transplantation

Graft-derived Cell-free DNA as a Rejection Biomarker and a Monitoring Tool for Immunosuppression in Liver Transplantation

Clinical association between tacrolimus intra-patient variability and liver transplantation outcomes in patients with and without hepatocellular carcinoma

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084–4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272–3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC.

Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus.

Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10-15ng/mL, and corticosteroids, n=203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8ng/mL, delayed until day three, and mycophenolate mofetil 2000mg/day, n=343). Mean mGFR was similar between groups at wait-listing (85.3vs 84.1ml/min/1.73m², p=0.60), but higher in the revised treatment group at 3 (56.8vs 63.4ml/min/1.73m², p=0.004) and 12 months post-transplant (60.9vs 69.7ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p=0.01). Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death.

Recipient and Center Factors Associated With Immunosuppression Practice Beyond the First Year After Liver Transplantation and Impact on Outcomes.

Immunosuppression is a critical aspect of post-transplant management, yet practices at intermediate and late time points after liver transplantation (LT) are poorly characterized. A retrospective cohort of 11 326 adult first LT alone recipients between 2007 and 2016 was identified by linking United Network for Organ Sharing transplant data to Medicare administrative claims. The immunosuppression regimen was obtained from Medicare billing claims. Factors associated with calcineurin inhibitor (CNI) monotherapy at 1-, 3-, and 5-y post-LT were investigated using mixed-effects logistic regression. Center practice heterogeneity was evaluated. The association of immunosuppression regimen (time-updating) with patient and graft survival was studied. CNI monotherapy was used in 51.9% at 1-y post-LT and 68.6% at 5-y post-LT. Center-specific rates ranged from 20.0%-79.9% to 15.4%-95.2%, respectively. CNI monotherapy at 1- and 3-y post-LT was less likely among Black recipients ( P = 0.027 and P = 0.015 versus White, respectively). CNI plus antimetabolite was associated with improved adjusted patient (hazard ratio, 0.59; P < 0.001) and graft (hazard ratio, 0.62; P < 0.001) survival versus CNI monotherapy. The benefit of CNI plus antimetabolite on patient and graft survival increased with older age. In this first longitudinal analysis of LT immunosuppression practices among Medicare beneficiaries, a CNI plus antimetabolite approach led to improved outcomes. Significant center heterogeneity in practice was observed.

Liver transplant immunosuppression during the COVID-19 pandemic

SARS CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS Cov-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on Cov-2 SARS infection, and suggests guidelines for the management of immunosuppression.

Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives.

Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today's clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

Efficacy and safety of basiliximab as initial immunosuppression in liver transplantation: A single center study

Introduction and aimThe interleukin-2 receptor antagonist; basiliximab is used to allow delayed introduction of Calcineurin inhibitors (CNI) after liver transplantation and thus delay their renal insult. However, there is only little evidence for the safety and the efficacy of this regimen. This study aimed to evaluate the effectiveness and safety of basiliximab induction in liver transplantation. Materials and methodsThis study included 89 patients who were classified into two groups: standard triple immunosuppression (IS) regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (n = 47) and induction IS regimen of basiliximab, low dose steroids and MMF with delayed introduction of CNI (n = 42). All patients were followed after liver transplantation for at least six months or until death. ResultsThere were no significant differences in patient survival, graft dysfunction, infection rate or type, or wound healing between both groups. The acute rejection rate was equivalent in both groups. Renal dysfunction in the first six months post-transplant was less in the basiliximab group in comparison to the other group (7.1% and 19.1% respectively). ConclusionBasiliximab-induced IS protocol is a safe regimen that reduces medium-term renal dysfunction and achieves similar survival without increasing the acute rejection or infection rate in liver transplantation recipients.

Mucosal associated invariant T cells are differentially impaired in tolerant and immunosuppressed liver transplant recipients.

Mucosal associated invariant T (MAIT-) cells represent a semi-invariant T cell population responsive to microbial vitamin B metabolite and innate cytokine stimulation, executing border tissue protection and particularly contributing to human liver immunity. The impact of immunosuppressants on MAIT cell biology alone and in context with solid organ transplantation has not been thoroughly examined. Here, we demonstrate that in vitro cytokine activation of peripheral MAIT cells from healthy individuals was impaired by glucocorticoids, whereas antigen-specific stimulation was additionally sensitive to calcineurin inhibitors. In liver transplant (LTx) recipients, significant depletion of peripheral MAIT cells was observed that was largely independent of the type and dosage of immunosuppression, equally applied to tolerant patients, and was reproducible in kidney transplant recipients. However, MAIT cells from tolerant LTx patients exhibited a markedly diminished ex vivo activation signature, associated with individual regain of functional competence toward antigenic and cytokine stimulation. Still, MAIT cells from tolerant and treated liver recipients exhibited high levels of PD1, accompanied by functional impairment particularly toward bacterial stimulation that also affected polyfunctionality. Our data suggest interlinked effects of primary liver pathology and immunosuppressive treatment on overall MAIT cell fitness after transplantation and propose their monitoring in context with tolerance induction protocols.

Successful implementation of preventive measures leads to low relevance of SARS-CoV-2 in liver transplant patients: Observations from a German outpatient department.

BackgroundImmunosuppressed liver transplant (LT) patients are considered to be at high risk for any kind of infection. What the outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) means for the transplant cohort is a question that, as of now, cannot easily be answered. Data on prevalence, relevance of the novel virus, and clinical course of the infection in stable LT patients are limited.MethodsNasopharyngeal swabs were performed in our outpatient department during the shutdown between March and April 2020 in Germany.ResultsThe prevalence of SARS‐CoV‐2 was 3%. Three out of a cohort of 101 LT patients were asymptomatic for respiratory diseases. Respiratory complaints were common and not associated with SARS‐CoV‐2 infection. The overall monthly mortality rate was 0.22% and did not show alterations during the shutdown in Germany.ConclusionsIf preventive measures are applied, LT patients do not seem to be at a higher risk for SARS‐CoV‐2 infection. Telemedicine in the outpatient setting may help to maintain distance and to reduce direct patient contact. However, standard of care must be guaranteed for patients with relevant comorbidities in spite of pandemics, because complications may arise from preexisting conditions.

Diagnostic inflammatory markers of acute cholangitis in liver transplant recipients.

Acute cholangitis (AC) after liver transplantation occurs in 8-12% patients and remains a significant cause of patients' morbidity and mortality. The 2018 Tokyo guidelines use white blood cell count and C-reactive protein (CRP) as diagnostic criteria in AC. However, these and other common inflammatory markers have not been assessed in immunosuppressed liver transplant (LT) recipients with AC. The aims of this study were to compare the discriminative powers of common inflammatory markers, define the best inflammatory marker and determine the diagnostic cut-off values for the inflammatory markers in LT recipients with AC. This was a retrospective cohort study. Over 16 years 212 LT recipients who underwent endoscopic biliary decompression were identified from hospital records. Thirty LT recipients with AC and 30 LT recipients without AC were randomly drawn in a 1:1 ratio. Among inflammatory markers, CRP had the highest discriminative power for diagnosing AC. The areas under the receiver operating characteristics curves for CRP, white blood cell count, lymphocyte count and neutrophil-to-lymphocyte ratio were 95% (95% confidence interval (CI): 91-98), 59% (95% CI: 50-68), 65% (95% CI: 53-77) and 70% (95% CI: 59-80), respectively. The cut-off value of CRP for diagnosing AC was equal to or above 9.5 mg/L. CRP has the best discriminative power compared with other commonly used inflammatory markers for diagnosing AC in LT recipients. The optimal cut-off value for CRP concentration in diagnosing AC is equal to or above 9.5 mg/L.

The use of induction therapy in liver transplantation is highly variable and is associated with posttransplant outcomes.

The use of induction immunosuppression in liver transplantation (LT) remains controversial. This was a retrospective cohort study of adult, first-time liver-alone recipients (N=69349) at 114 US centers between 2005 and 2018 using data from the United Network for Organ Sharing. The comparative effectiveness of nondepleting and depleting induction (NDI and DI) was assessed. Overall, 27% of recipients received induction with 65.7% of the variance in the receipt of induction being attributed to transplant center alone. NDI and DI were associated with a lower risk of death/graft failure compared to no induction (adjusted hazard ratio 0.90 [95% confidence interval (CI): 0.86-0.95] and 0.91 [95% CI: 0.85-0.97], respectively; P<.001). In nondialysis recipients at the mean transplant estimated glomerular filtration rate (eGFR), NDI was associated with an adjusted gain in eGFR by 6months of +3.8mL/min per 1.73m2 and DI of +3.33mL/min per 1.73m2 compared to no induction (P<.001). Recipients with lower eGFR at LT had greater predicted improvement in eGFR (interaction P<.001). Only NDI was associated with a reduced risk of acute rejection in the first year post-LT (odds ratio 0.87, 95% CI: 0.8-0.94). Significant variability in induction practices exists, with center being a major determinant. The absolute incremental benefits of NDI and DI over no induction were small.

Neutrophil Gelatinase-Associated Lipocalin Is Not Associated with Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients Who Received Mycophenolate Mofetil with Delayed Introduction of Tacrolimus.

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. Here we tested this association using a different immunosuppression protocol: Mycophenolate mofetil administration beginning on Postoperative Day 1 and tacrolimus administration beginning on Postoperative Day 2 or 3. Urine samples were collected from 26 living donor liver transplant recipients before (Postoperative Day 1) and after (Postoperative Day 7 or 14) tacrolimus administration. NGAL levels were measured via enzyme-linked immunosorbent assays, as were those of three additional urinary biomarkers for kidney diseases: Monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), and human epididymis secretory protein 4 (HE4). HE4 levels after tacrolimus administration were significantly higher in patients who developed AKI (n = 6) than in those who did not (n = 20), whereas NGAL, MCP-1, and L-FABP levels did not differ significantly before or after tacrolimus administration. These findings indicate that NGAL may not be a universal biomarker of AKI in tacrolimus-treated liver transplant recipients. To reduce the likelihood of tacrolimus-induced AKI, our immunosuppression protocol is recommended.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1month and 2years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β=0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (β=0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β=-0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1month and 2years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

Su1855 – Vedolizumab is Not Associated with Increased Infection Risk in Immunosuppressed Liver Transplant Recipients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Su1855 – Vedolizumab is Not Associated with Increased Infection Risk in Immunosuppressed Liver Transplant Recipients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Graft-to-Recipient Weight Ratio Associated With Tacrolimus Metabolism Following Pediatric Living Donor Liver Transplantations.

Tacrolimus (TAC) is an important immunosuppressant in liver transplantation. Since TAC is mainly metabolized by the liver enzymes CYP3A4 and 5, liver function is crucial for its pharmacokinetics (PK). Liver function is dynamic after liver transplantation; hence the PK of TAC metabolism after pediatric liver transplantation is not well understood. We aimed to investigate the time-dependent changes in TAC metabolism and to find factors influencing TAC PK after pediatric liver transplantation. We retrospectively reviewed the characteristics of the donors and recipients in pediatric living donor liver transplantation and used the TAC concentration-dose (CD) ratio as a surrogate marker of TAC metabolism. Included were 326 patients with a median age of 13 months. After the liver transplantation, the CD ratio gradually decreased, then plateaued around day 21 to 28. A linear regression analysis demonstrated that a lower graft-to-recipient weight ratio (GRWR) and higher prothrombin time-international normalized ratio (PT-INR) were independently associated with a higher CD ratio in the early period after liver transplantation. However, association between GRWR and TAC CD ratio disappeared around 6 to 12 months after a liver transplantation possibly owing to graft regeneration. Tacrolimus metabolism improved within the first month after liver transplantation, and the small graft size was associated with lower TAC metabolism in the early period after pediatric living donor liver transplantation.

Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients.

Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce.Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily.Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period.Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.