Tac Therapy Research Articles

Tacrolimus Therapy Among Steroid-Resistant Nephrotic Syndrome Children: A Preliminary Study in West Java, Indonesia

Objective: To explore the outcomes of Tac therapy for Steroid-Resistant Nephrotic Syndrome (SRNS) and its implication in reducing the number of CKD events.Methods: An open, prospective, cohort study was conducted at a tertiary hospital in Bandung, West Java, Indonesia. Children (age 1–18 years old) with steroid and cyclophosphamide resistant nephrotic syndrome were enrolled in this study. Blood pressure, urinary protein, serum ureum, and creatinine levels were measured every month, Tac and soluble urokinase plasminogen activator receptor (supaR) levels were assessed at the 0, third, and sixth months.Results: Ten of fifteen subjects enrolled in this study got better within 3–6 months with a trend of decreasing suPAR level and proteinuria, as well as stable blood pressure and serum creatinine and ureum level. During treatment, no side effects of the subjects were found with the Tac level maintain safely.Conclusion: Tac is an effective and safe agent in treating SRNS, especially for those do not respond well to an alkylating agent.

Tacrolimus impairs airway mucociliary clearance of rats

ObjectivesTacrolimus (TAC) is the most widely used immunosuppressive agent after lung transplantation. Considering that the ciliary beat frequency (CBF) mainly depends on the cytoplasmic calcium concentration and that TAC can affect this due to its binding with the intracellular immunophilin FKBP12, we hypothesized that TAC could also impair the airway mucociliary clearance of rats. MethodsSixty rats were divided into two groups (n = 30 each): Control = water; TAC = tacrolimus. After 7, 15 or 30 days of treatment, ten animals from each group were euthanized and the following parameters were studied: mucus transportability, CBF, mucociliary transport velocity (MCTV), and neutral and acid mucus production. ResultsThere was a significant decrease in CBF (Control vs TAC: 7 days, p = 0.008; 15 days, p = 0.007; 30 days, p = 0.001) and MCTV (Control vs TAC: 7 days, p = 0.004; 15 days, p < 0.001; 30 days, p < 0.001) in all immunosuppressed animals. TAC therapy also caused an increase in acid mucus production at all treatment times (Control vs TAC: 7 days, p = 0.001; 15 days, p = 0.043; 30 days, p = 0.001). ConclusionsTAC impairs airway mucociliary clearance of rats.

Safety Profile of the Concomitant Use of Atorvastatin and Cyclosporine in Renal Transplant Recipients.

Cyclosporine (CyA) and atorvastatin (AT) are often administered concomitantly to treat dyslipidemia in renal transplant recipients. However, CyA greatly increases the plasma concentration of AT; therefore, concomitant use might increase the frequency of statin-induced adverse effects. The aim of this study was to investigate whether concomitant use of CyA and AT increases intolerance of the latter agent in Japanese renal transplantation recipients. We performed a retrospective cohort analysis of renal transplant recipients aged 18 years and older who had concomitantly received AT and CyA, or tacrolimus (Tac) therapy. We defined statin intolerance as a decrease in dose or discontinuation of AT due to adverse effects. We evaluated the incidence of statin intolerance in concomitant therapy with CyA for 100 days after the initial administration of AT in comparison with Tac. A total of 144 renal transplant recipients who received AT and CyA, or Tac between January 2013 and December 2019 were included. There was no statistical difference in the incidence of statin intolerance in both the CyA (1.8%; 1/57 patients) and Tac (3.4%; 3/87 patients) groups. Concomitant use of CyA and AT might not increase the incidence of statin intolerance in Japanese renal transplant recipients.

Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation.

Background.The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).Methods.One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively.Results.In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8).Conclusions.This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.

Relationship between mucosal healing by tacrolimus and relapse of refractory ulcerative colitis: a retrospective study

BackgroundTacrolimus (TAC) is a powerful remission-inducing drug for refractory ulcerative colitis (UC). However, it is unclear whether mucosal healing (MH) influences relapse after completion of TAC.We investigated whether MH is related to relapse after TAC.Patients: Among 109 patients treated with TAC, 86 patients achieved clinical remission and 55 of them underwent colonoscopy at the end of TAC. These 55 patients were investigated.MethodsPatients with MH at the end of TAC were classified into the MH group (n = 41), while patients without MH were classified into the non-MH group (n = 14). These groups were compared with respect to 1) clinical characteristics before treatment, 2) clinical characteristics on completion of treatment, and 3) the relapse rate and adverse events rates. This is a retrospective study conducted at a single institution.Results1) There was a significant difference in baseline age between the two groups before TAC therapy, but there were no significant differences in other clinical characteristics. The NMH group was younger (MH group: 48.1 (23–79) years, NMH group: 36.3 (18–58) years, P = 0.007). Endoscopic scores showed significant differences between the 2 groups at the end of TAC. There were also significant differences in the steroid-free rate after 24 weeks (MH group: 85.3%, NMH group 50%, P = 0.012). There was no significant difference in the relapse rate between the 2 groups at 100 days after remission, but a significant difference was noted at 300 days (17% vs. 43%), 500 days (17% vs. 75%), and 1000 days (17% vs. 81%) (all P < 0.05).ConclusionsTAC is effective for refractory ulcerative colitis. However, even if clinical remission is achieved, relapse is frequent when colonoscopy shows that MH has not been achieved. It is important to evaluate the mucosal response by colonoscopy on completion of TAC.

Fast Tac Metabolizers at Risk ⁻ It is Time for a C/D Ratio Calculation.

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL × 1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis.

Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study

PurposeTacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TACblood), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TACPBMC) is considered as an efficient surrogate marker of TAC efficacy. However, it is still not applicable in daily practice. New TDM methods are therefore needed, especially during the early postoperative period. TAC is metabolized in the liver and eliminated through biliary excretion. We therefore hypothesised that TAC concentration measured in excreted bile (TACbileC) could be a relevant surrogate marker of its efficacy. MethodsThe Therapeutic Drug Monitoring of Tacrolimus Biliary Concentrations for Liver-Transplanted Patients (STABILE) study is a prospective monocentric trial. During the 7 first days after TAC therapy initiation, TACbileC was measured. The correlation between TACbileC and TACPBMC as well as between TACblood and TACPBMC was assessed. The correlations between TACbileC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated. FindingsBetween May 2016 and April 2017, 41 patients were analyzed. TACbileC was significantly correlated with TACPBMC (r = 0.25, P = 0.007). However, a better correlation was found between TACPBMC and TACblood (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TACbileC was significantly correlated with liver graft function, such as factor V (r = 0.40, P = 0.009) or bilirubin level (r = 0.21, P = 0.01), and significantly lower in patients presenting with neurologic toxic effects (P < 0.001). Receiver operating characteristic curve analysis found that a TACbileC level lower than 0.20 ng/mL on day 2 after TAC therapy initiation was a good predictive marker of occurrence of neurotoxic effects (AUC = 0.81). ImplicationsTACbileC is not a better surrogate maker of TAC activity than TACblood. However, TACbileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259.

Tacrolimus - Pharmacokinetic Considerations for Clinicians.

The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation.

Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.5h after Tac dosing at approximately 1week, 6weeks and 1year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 (IL2), interferon gamma (IFNG), colony stimulating factor 2 (CSF2)] and cytochrome P450 3A5 (CYP3A5) genotyping were determined by real-time polymerase chain reaction. The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5h postdose (C1.5 ) >15μg l-1 were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10%, while lower Tac C1.5 resulted in more variable responses (RGE 2.5-68.7%). Patients with ongoing subclinical acute rejection (n = 5) demonstrated limited cytokine inhibition (RGE 39.7-72.6%), while patients with polyoma virus viraemia (n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia. The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viraemia.

Comparison of quality of life (QOL) for patients with breast Cancer receiving adjuvant tac (docetaxel, doxorubicin, Cyclophosphamide) and fac (5-fluorouracil, doxorubicin, Cyclophosphamide) therapy

Comparison of quality of life (QOL) for patients with breast Cancer receiving adjuvant tac (docetaxel, doxorubicin, Cyclophosphamide) and fac (5-fluorouracil, doxorubicin, Cyclophosphamide) therapy

Are Tacrolimus Pharmacokinetics Affected by Nephrotic Stage?

Although tacrolimus therapy is not the first-line therapy for childhood nephrotic syndrome, it is often used instead of cyclosporine to ameliorate the side effects. The pharmacokinetics (PK) of tacrolimus (Tac) can be influenced by many conditions, and it has a high plasma protein binding. The Tac PK during relapse and remission of childhood nephrotic syndrome has not been well described. We performed 14 PK profiles (with measurements before intake and 0.5, 1, 2, 4, and 12 hours postintake) in 7 children with steroid-resistant nephrotic syndrome at week 1 (all nephrotic) and week 16 after Tac therapy (all in remission). These data were compared with historical PK data of 161 PK profiles in 87 pediatric renal transplant recipients with measurements before intake and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postintake. Tac levels were measured using the Abbott Tacro II assay. We used descriptive statistics to generate percentiles and compared these with those of patients with steroid-resistant nephrotic syndrome. The median age of patients with nephrotic syndrome was 3.2 years (range 2.5, 17.2), male gender 71.4%, significantly younger than the control group. Median Tac dose was similar during both PK profiles (0.11 mg·kg·d at week 1 versus 0.13 mg·kg·d at week 16, P = 0.81). There were no statistically significant differences in median dose-normalized area-under-the-time-concentration profiles, peak concentration, time to reach peak concentration, and Tac trough levels. Individual dose-normalized Tac levels for each time point during the PK profile were also not different (P = 0.81). We conclude that Tac PK profiles are unaltered during relapse of nephrotic syndrome.

Effect of the anti-Warburg agent BPM 31510 on TAC therapy synergy and survival in a xenograft model of triple-negative breast cancer (TNBC).

1096 Background: High glycolytic metabolism in breast cancer is known to support tumor progression and metastasis, and a unique glycolysis signature has been identified in ER- and triple-negative (...

Cryptosporidium infection after renal transplantation in an endemic area.

Cryptosporidium is one of the common causes of infective diarrhea in post-transplant patients in endemic areas. However, data are limited on Cryptosporidium infection in recipients of solid organ transplantation. The aim of this study was to determine the incidence, disease manifestation, management, and outcome of Cryptosporidium infection in living-donor renal transplant recipients (RTR). We performed a detailed retrospective review of the data on all RTR who had diarrheal illness requiring evaluation and hospitalization, and Cryptosporidium infection. During the study period, 119/1235 (8.98%) RTR developed diarrhea, and Cryptosporidium was found in 34/119 (28.5%). Nine of 680 (1.3%) patients were on a cyclosporine (CSA)-based regimen, and 25/643 (3.8%) patients were on a tacrolimus (Tac)-based regimen. The relative risk of developing Cryptosporidium infection was lower on the CSA-based regimen, compared with the Tac-based regimen (odds ratio [OR]: 0.35, 95% confidence interval [CI]: 0.17-0.72, P=0.003). Twelve of the 34 patients had acute graft dysfunction, mainly caused by combined Tac toxicity and dehydration. Mean serum creatinine and trough Tac level were 2.04±0.65mg/dL and 8.24±1.19ng/dL, respectively. Nitazoxanide alone was used in 13 patients, and nitazoxanide in combination with fluoroquinolone in 21 patients, with duration of treatment ranging from 16 to 60days. Tac was changed to CSA in 8/11 patients. The clearance of cysts and response to nitazoxanide alone were significantly lower, compared with combination therapy (61.53% vs. 95.23%, P=0.01, 38.46 vs. 85.71%, P=0.004, respectively). The OR for cyst clearance and response was also significantly lower with nitazoxanide alone, in comparison with combination therapy (OR: 0.65, 95% CI: 0.34-0.92, P=0.01, OR: 0.45, 95% CI: 0.21-0.81, respectively). Four (16%) of 24 patients with response had relapse. Patients with Tac and mycophenolate mofetil combination therapy had a significantly high risk of Cryptosporidium infection. Cryptosporidial infection may require prolonged nitazoxanide therapy, either alone or in combination, with or without reduction in immunosuppression.

Similar MPA Exposure on Modified Release and Regular Tacrolimus

Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration-time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg·h·L(-1), respectively, which was not statistically significant using repeated measures (P = 0.1327, R(2) = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR.

Multi-center analytical evaluation of a novel automated tacrolimus immunoassay

BackgroundTacrolimus (TAC) is a post-transplantation immunosuppressant drug used in patients for whom careful monitoring of TAC concentration is essential. A new semi-automated immunoassay for TAC measurement, the Elecsys Tacrolimus assay, is available and has been assessed in a multi-center evaluation. MethodsResidual whole blood samples from patients undergoing TAC therapy after organ transplant were used in assay evaluation at five clinical laboratories in Europe. Experiments included imprecision according to CLSI EP5-A2 (within-run and intermediate), functional sensitivity, linearity according to CLSI EP6-A, and recovery from external quality assessment scheme (EQAS) samples. The assay was compared to LC–MS/MS used routinely at each investigational site, and to the Abbott Architect immunoassay. ResultsLinearity from 0.5 to 40μg/L was observed and functional sensitivity of 0.3μg/L (CV≤20%) was determined. Within-run imprecision was ≤5.1% on cobas e 602 (5.1% at 1.5μg/L) and ≤8.9% (8.9% at 0.8μg/L) on cobas e 411. The intermediate imprecision for TAC concentrations ≥6.8μg/L was ≤6.5%. At lower therapeutic concentrations (to 1.5μg/L) it was consistently ≤10%. Deming regression analysis of method comparison to LC–MS/MS yielded slopes of 1.07 (95%CI: 1.05/1.10) for heart transplant samples, 1.13 (95%CI: 1.09/1.16) for kidney, and 1.05 (95%CI: 1.02/1.08) for lung transplant samples. ConclusionsThe Elecsys Tacrolimus assay has good linearity, functional sensitivity and intermediate imprecision and is comparable to LC–MS/MS methods. The over-all performance of ECLIA demonstrates a modern generation TAC assay that meets the demands of monitoring drug concentrations in current immunosuppressive regimens.

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: A seven‐yr experience

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

Reduced residual gene expression of nuclear factor of activated T cells‐regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation

Pharmacokinetic monitoring of calcineurin inhibitors (CNIs) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic (PD) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells (NFAT)-regulated genes in liver transplant (LT) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression (RGE) of NFAT-regulated genes and evaluated the association between the RGE of NFAT-regulated genes and the incidence of cytomegalovirus (CMV) infection. In 20 LT recipients, 10 patients on cyclosporine (CsA) and 10 patients on tacrolimus (Tac) therapy, who presented with CMV infection, the RGEs of interleukin-2, interferon-γ (IFNγ), and granulocyte-monocyte colony-stimulating factor were measured and compared with the RGEs of these cytokines in 40 healthy dose-matched LT controls. CsA-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (30 ± 17 vs. 44 ± 20, P = 0.067). For IFNγ, the level of significance was reached (26 ± 17 vs. 43 ± 17, P = 0.0125). Daily CsA dosage, CsA baseline (C0 ) and 2 h (C2 ) concentrations were comparable (CsA dosage 169 mg/day vs. 165 mg/day; CsA C0 94 μg/L vs. 85 μg/L; CsA C2 389 μg/L vs. 381 μg/L). In addition, Tac-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (68 ± 25 vs. 84 ± 22, P = 0.0769). Analogous to CsA-treated CMV patients, the level of significance was reached for IFNγ (61 ± 24 vs. 88 ± 29, P = 0.0154). Daily Tac dosage and Tac 1.5 h concentrations (C1.5 ) were comparable in both groups (Tac dosage 4 mg/day vs. 4 mg/day; Tac C1.5 8 μg/L vs. 10 μg/L), whereas Tac C0 concentrations were significantly higher in controls (Tac C0 4 μg/L vs. 6 μg/L, P = 0.0276). Measuring the RGE of NFAT-regulated genes is appropriate to assess the risk of infections in LT recipients. Measuring the RGE of IFNγ is particularly suitable to assess the risk of CMV infection. PD monitoring of CNIs in LT recipients is an approach to individualize immunosuppression, which may help to reduce infectious complications.

Preliminary study of interaction of clarithromycin with tacrolimus in cats.

ABSTRACTTacrolimus (Tac) is a core immunosuppressive drug in human organ transplantation. In feline kidney transplantation, however, the cost of Tac therapy is a significant obstacle. Clarithromycin (CLM) increases the blood trough level of Tac, effectively reducing the Tac dosage in human transplant patients. The interaction between CLM and Tac in cats has not been reported. In this study, the effect of multiple CLM dosing on the pharmacokinetics of Tac in three healthy cats was investigated. The treatments included Tac at 0.3 mg/kg and Tac at 0.3 mg/kg + multiple-dose CLM at 10 mg/kg. Co-administration of CLM and Tac resulted in significant increases in the oral bioavailability of Tac. These preliminary findings suggest that administration of multiple doses of CLM may decrease the required Tac dosage in Tac-based immunosuppressive therapy used as an alternative to the classic cyclosporine-based protocol for feline renal transplantation.

PP73 FROM CHILDHOOD TO ADOLESCENCE: THE COELIAC DISEASE EXPERIENCE FROM THE POINT OF VIEW OF THOSE WHO ARE GROWING UP AND THOSE WHO ARE TAKING CARE OF THEM

Stool calprotectin is useful in monitoring rejection in small bowel transplantation. We report about our initial experience in Children’s Hospital “Bambino Gesu” in Rome on monitoring gut rejection by using stool calprotectin together with intestinal biopsies. Case 1: a 12 year-old boy underwent at the age of 8 SBTx for short gut syndrome; he experienced one ACR, recovered on steroid bolus and he did well for 6 months. Sirolimus was started for initial renal damage, but it had to be discontinued for severe thrombotic micro-angiopathy. A second severe ACR occurred 1 year after transplant and again medical therapy was effective in recovery. After 3 years of well being, with no previous evidence of rejection at histology, he was admitted in Rome for acute diarrhea following Rotavirus infection. Hystology revealed ACR, initially treated by steroid without any effects so repeated steroid bolus, infliximab and mesenchymal cell infusion were administered, but severe exfoliative rejection led to re-transplant, performed in Rome on TAC, steroid, MMF and basiliximab; at + 3 months, CMV enteritis occurred, successfully treated by ganciclovir. Before and after re-Tx, stool calprotectin levels were strict monitoring: normal levels ( 1000 mcg/g) if severe ACR, while in CMV infection levels were always below 800 mcg/g. Case 2: C.S. is now a 10 yr-old boy affected by CIPO who underwent SBTx at the age of 7 for recurrence of severe dehydration and hemorrhagic events; surgical procedure was uneventful, on basiliximab, TAC and steroid therapy. Six months after transplant he experienced ACR and severe CMV enteritis, with complete recovery. The follow-up was continued in Rome, where he underwent protocol biopsies without any evidence of rejection so far. Stool calprotectin levels were always within normal ranges (<250 mcg/g), according to histology. In our experience stool calprotectin levels appear to correlate to gut inflammation, and high levels seem to be more associated to rejection. This could be a useful tool to suspect graft dysfunction.