Tacrolimus Trough Blood Levels Research Articles

De Novo Anti-HLA Sensitization in Pediatric Kidney Transplant Recipients.

Introduction: Anti-HLA de novo sensitization may have a poor impact on graft survival as it is usually related to the presence of acute or chronic Humoral Rejection, both events being a known cause of graft loss. Anti-HLA antibodies screening may allow us to identify a subgroup of patients on special risk of immunological adverse events. Methods: The results of a periodic anti-HLA antibody (HLA Ab) screening (Luminex® technique), performed from January 2010 since January 2013, in a cohort of 38 pediatric (1-18 years old) kidney transplant receptors of a single center are analyzed. The mean post-transplant follow-up time is 79.2 (27.3-165.1) months. Patients with an anti-HLA positive screening have been studied with Single Antigen (SAg) technique. The HLA Ab prevalence and specificities and their relationship with: donor type, previous kidney grafts, time since transplant, graft rejection, HLA mismatches, immunosuppressive (IS) medication and Tacrolimus trough blood levels, are studied. The relationship between HLA sensitization and graft outcome by Glomerular Filtration Rate (GFR) and Proteinuria/creatinuria ratio measurements at last follow-up are also analyzed. Results: An anti-HLA sensitization prevalence of 34.2% (13/38 receptors) is found in our studied population. Single Antigen technique concluded that in 10 receptors the HLA antibodies found were Donor Specific Antibodies (DSA) against the actual graft while in 3 cases they were DSA against a previous donor. At 15.9 (2.4-27) months of follow-up after the diagnosis of sensitization no impact on graft survival or GFR is found on these 10 receptors, but a significant presence of proteinuria and Hypertension is observed. HLA sensitization is more frequent on receptors with long term transplant (p 0.016) and on those with low Tacrolimus trough blood levels (p 0.024). Double IS therapy is more frequent in HLA sensitized receptors than triple IS therapy, but no statistical significance on the analysis isfound (p 0.062). Conclusions: HLA sensitization is present in one third of our pediatric kidney transplant receptors and is related to anticalcineurin minimization strategies. At short term follow-up no graft losses are found but proteinuria and hypertension are more prevalent on these receptors, probably being a first marker of subjacent renal damage.

Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure

Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.

Magnesium excretion and hypomagnesemia in pediatric renal transplant recipients

Background: We investigated magnesium excretion and rate of hypomagnesemia in pediatric renal transplant recipients. Method: The medical records of 114 pediatric renal transplant recipients were retrospectively evaluated. After exclusion of 23 patients, 91 patients were included in the study. We recorded serum magnesium levels at the time of measurement of urine magnesium wasting. Results: Mean serum magnesium levels were 1.73 ± 0.22 mg/dL and 38 of the patients (41%) had hypomagnesemia. There was a negative correlation between serum magnesium levels and estimated glomerular filtration rate and serum tacrolimus trough level (r = −0.215, p = 0.040 and r = −0.409, p = 0.000, respectively). Also, there was a statistically significant positive correlation between serum magnesium levels and transplantation duration (r = 0.249, p = 0.017). Mean fractional magnesium excretion was 5.9 ± 3.7% and 59 patients (65%) had high magnesium excretion. There was a significant negative correlation between fractional magnesium excretion and estimated glomerular filtration rate (r = −0.432, p = 0.001). There was a significant positive correlation between fractional magnesium excretion and serum creatinine (r = 0.379 p = 0.003). Conclusion: Patients with higher tacrolimus trough blood levels, lower glomerular filtration rate and at early posttransplant period had risk of hypomagnesemia.

Reduced Variability of Tacrolimus Trough Level in Once-Daily Tacrolimus-Based Taiwanese Kidney Transplant Recipients With High-Expressive Genotype of Cytochrome P450 3A5

BackgroundOur previous study results indicated that conversion from twice-daily Prograf to once-daily Advagraf associated with lower variability of tacrolimus blood trough level. Some factors, such as frequency of interaction by food exposure, expression of cytochrome P450 3A5 genetic polymorphism, and other interactions of unknown factors, could be the reasons for the change of variability. We aimed to clarify the impact of cytochrome P450 3A5 genetic polymorphism on the variability of tacrolimus blood trough level in Taiwanese kidney transplant recipients. MethodsWe collected blood samples from kidney transplant recipients to prepare DNA and then performed single-nucleotide polymorphism genotyping by using the restriction fragment length polymorphism. ResultsWe found that 79 (52.7%) of 150 kidney transplant recipients had the low-expressive genotype (CYP3A5*3/*3), whereas the other 71 (47.3%) kidney transplant recipients had high-expressive genotype (CYP3A5*1/*1 and CYP3A5*1/*3). The prevalence of high-expressive genotype is higher than previous reports from western countries. Compared with the patients with high-expressive genotype, the average dose-normalized trough level of tacrolimus was significantly higher in patients with low-expressive genotype. Interestingly, when patients converted from twice-daily Prograf to once-daily Advagraf, the percent coefficient of variation of tacrolimus trough level was significantly decreased in patients with high-expressive genotype. ConclusionThis study suggested that there is a potential benefit for kidney transplant recipients with cytochrome P450 3A5 high-expressive genotype (*1/*1 or *1/*3) to convert from Prograf to once-daily Advagraf.

Early conversion from twice-daily tacrolimus to once-daily extended formulation in renal transplant patients before hospital discharge.

Although the once-daily formulation of tacrolimus (ADVAGRAF) is approved in renal transplantation to be used immediately after surgery, conventional twice-daily formulation offers better flexibility to adjust the dosage of tacrolimus during the initial period of transplantation. We retrospectively report here our initial experience with a strategy of an early conversion from PROGRAF to ADVAGRAF before hospital discharge. Forty-eight de novo renal transplant recipients were started on PROGRAF and then switched to ADVAGRAF after a median time of 11 days and 4.5 days, respectively, before discharge. In terms of tacrolimus exposure, great inter-individual heterogeneity was noted, with 56% of patients experiencing a clinically significant modification in post-switch tacrolimus blood trough levels. Modification in post-switch drug exposure was poorly predicted by change in tacrolimus daily dosage. Six-month post-transplant outcome was similar in patients converted to ADVAGRAF to that of patients who had remained on PROGRAF during the same period of time. Our data suggest that an early conversion from PROGRAF to ADVAGRAF during the hospital stay may be safely undertaken, provided tacrolimus exposure is tightly monitored in patients. This strategy might represent an alternative to the immediate post-transplant introduction of ADVAGRAF and needs to be clinically validated in large-scale controlled trials.

Tacrolimus Extended Release Formulation Given As An Alternative To Ciclosporine A In Case Of Renal Impairment After Allogeneic HSCT: Results From a Prospective Pilot Study

Introduction Tacrolimus is a widely used calcineurin inhibitor in allogeneic HCST for prophylaxis and treatment of GvHD. This molecule is now available in both standard-release (Prograf, twice-daily tacrolimus, Astellas Pharma) and extended-release (Advagraf, once-daily tacrolimus, Astellas Pharma) formulations. Compared with the standard-release formulation, the extended-release (ER) tacrolimus has been shown in previous pharmacological studies to provide bioequivalent drug exposure, efficacy and safety. Moreover, this formulation of tacrolimus was followed by a clinically significant improvement in kidney graft function for kidney recipients. Based on these observations, we have conducted a prospective study in wich ciclosporine A (CsA) (Neoral) is switched for tacrolimus ER (Advagraf) in case of renal impairment after alloHSCT. Method We enrolled 16 consecutive patients with renal impairment (serum creatinine >110 µMol/L) from May 2012 to May 2013 during the follow-up at outpatient clinic, the conversion dose was established on an mg:mg basis 1:100 from CsA total oral daily dose to a single dose of oral tacrolimus ER formulation. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L. Tacrolimus ER was given at noon in a single dose one hour before lunch. We evaluated the tacrolimus blood trough level changes after switch, serum creatinine, glycemia, potassium, acute and chronic GvHD. A satisfaction survey for tacrolimus ER treatment was performed 3 months after the switch, the questionnaire included administration compliance questions. Results All patients in this cohort had hematological malignancies, the median age was 52 years (range, 28-66). Eight patients (50%) had a matched related donor, 7 patients (43.75%) had a HLA-10/10 matched unrelated donor and 1 patient underwent alloHSCT with two cord blood units. Seven patients (43.75%) received a myeloablative regimen with 12 Gy TBI and 9 patients (56.25%) a reduced intensity regimen. The stem cell source was bone marrow for 7 patients (43.75%), PBSC for 8 patients (50%) and cord blood for one patient. The status at transplantation was CR1 for 6 patients (37.5%), CR2 or more for 6 patients (37.5%) and partial response for 4 patients (25%). The median follow-up of the cohort was 7 months (range,2-14). Non-parametric tests such as exact Wilcoxon Mann-Whitney test or Kruskal Wallis were performed for the analysis of the physiological parameters. The median of serum creatinine was 112 µmol/L (range, 51-262) with CsA and 87 µmol/L (range, 50-125) with tacrolimus ER (p<.0001) (Figure). The median of potassium level was 4.2 (range, 3.5-5.2) with CsA and 4.0 (3.4-4.5) with tacrolimus ER (p =.001) (Figure). The median time of switch was 45 days (10-162) and the median of serum creatinine in which the switch was realized was 138 µmol/L (range,110-262). Nor patient had diabetes mellitus neither elevation of potassium > 4.5 mmol/L after the switch for tacrolimus ER. The median blood trough level was 300 µg/L (range,100-438) for CsA 14 days after starting and 7.2 (range,3-15) for tacrolimus ER 20 days after starting (Figure). The cumulative incidence of aGvHD grade >1 at 3 months was 25% (95%CI,14-36). After the switch for tacrolimus ER, no patient developped aGvHD. Eight patients (50%) developed aGvHD grade >1 during the prophylaxis with CsA. For 6 patients (37.5%), aGvHD was resolutive after the switch for tacrolimus ER with an association of tacrolimus ER and prednisone or tacrolimus ER alone. For 2 patients (12.5%), aGvHD was resolutive with CsA and prednisone before the switch for tacrolimus ER. Two patients in this study developed severe chronic GvHD after the discontinuation of prophylaxis (5 months and 10 months). One patient received tacrolimus ER with a complete resolution of cGvHD and the second patient is now on therapy with everolimus. All patients in this cohort are alive and all patients except two are still in complete response. Moreover, the satisfaction survey demonstrated that the patients were satisfied with the switch and the one daily formulation of tacrolimus. Conclusion The conversion from oral CsA to oral tacrolimus ER formulation was followed by a clinically significant improvement in kidney function with stable tacrolimus blood trough levels. The patients were satisfied with this formulation of tacrolimus. We have now extended this study to several centers in the aim to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

Significant reduction of Tacrolimus trough level after conversion from twice daily Prograf to once daily Advagraf in Chinese renal transplant recipients with or without concomitant diltiazem treatment

A dose ratio of 1:1 was recommended for the conversion from Standard-release Tacrolimus (Prograf) to Prolonged-release Tacrolimus (Advagraf). We investigated the trough tacrolimus blood level in Chinese kidney transplant recipients after conversion, including subjects receiving concomitant treatment with diltiazem. Eighteen stable renal allograft recipients were followed prospectively for 12 weeks after conversion from Prograf to Advagraf at the same daily dose. Tacrolimus blood trough level decreased significantly within 8 weeks after conversion (p < 0.01). Twelve patients required escalation of the Advagraf dose by 1.10 ± 0.36 mg. For the whole group the daily tacrolimus dose was increased from 0.057 ± 0.032 mg/kg to 0.068 ± 0.033 mg/kg (p < 0.0001). At week 12 the daily dose of Advagraf was 127 ± 32% of the original daily dose of Prograf. In the subgroup of patients receiving diltiazem, their tacrolimus trough level decreased significantly after conversion (p = 0.001), and the daily tacrolimus dose was increased from 0.060 ± 0.036 mg/kg to 0.073 ± 0.036 mg/kg (p < 0.0001). At week 12, their daily dose of Advagraf was 131 ± 34% of the original daily dose before conversion. To conclude, conversion from Prograf to Advagraf in renal allograft recipients with or without diltiazem co-treatment necessitated an increase in the daily dose by approximately 30% to maintain the target blood trough level unchanged.

Clinical Outcome in Cardiac Transplant Recipients Receiving Tacrolimus Retard

Tacrolimus (TAC) retard is a new oral formulation of TAC that is given once instead of twice daily. We investigated the efficacy and safety of TAC retard in heart transplant recipients during a 36-month follow-up period. We included 11 patients receiving TAC retard (once-daily [OD] group) and 11 age- and sex-matched patients receiving TAC (twice-daily [TD] group). The primary endpoint was a composite of death, graft loss, and drug discontinuation (treatment failure). Secondary endpoints were biopsy-proven rejection, malignancy, infection, and safety parameters determined on the basis of laboratory evaluations. In the OD and TD groups, the primary endpoint was reached by 18.2% and 45.54% of patients, respectively (P = .277). In detail, 3-year survivals were 90.0% and 70.0% (P = .291) and freedom from drug discontinuation 90.9% and 77.9% (P = .533), respectively. Freedom from biopsy-proven rejection, malignancy, and infection were similar between the groups. Moreover, biochemical parameters of kidney and liver function, hematologic parameters, and C-reactive protein levels were similar. Despite a remarkably higher prescribed dose, blood trough levels of TAC were below the lower target value in several patients of the OD group at the end of the follow-up period, but in none of the patients in the TD group. In conclusion, this small 3-year follow-up study suggests efficacy and safety in patients receiving TAC retard similar to those in patients receiving TAC. Nevertheless, the required dose of TAC retard for achieving acceptable blood trough levels should be investigated in more detail.

Long-term Follow-up of Stable Kidney Transplant Recipients After Conversion From Tacrolimus Twice Daily Immediate Release to Tacrolimus Once-daily Prolonged Release: A Large Single-Center Experience

BackgroundAdult kidney transplant recipients maintained on tacrolimus twice-daily (Tac BD) were given the opportunity to convert to tacrolimus once daily (Tac QD). Conversion was based upon a 1:1 mg:mg total daily dose ratio. MethodsBetween November 2007 and September 2010, 589 patients were converted at a mean post-transplant period of 4.6 years. We retrospectively reviewed routine clinical records to assess the safety of conversion to Tac QD for up to 12 months post-conversion. ResultsTac QD mean dose barely changed from preconversion values. Mean exposure (tacrolimus trough blood level [Cmin]) remained within the target window but was reduced by 12% (P = NS) with a trend toward less interpatient variability. Renal function at 12 months remained stable within 2.5% of the preconversion mean value. There were 14 (2.4%) cases of biopsy-proven acute rejection: 6 (1.0%) borderline and 8 (1.4%) Banff grade ≥ IA. Actuarial first year post-conversion graft survival was 96.3% and patient survival 99.0%. Twenty-eight patients (4.8%) discontinued Tac QD and were switched to sirolimus: 19 for malignancy, 6 for thrombotic microangiopathy, and 3 with severe vascular changes; 3 patients were reconverted to Tac BD. ConclusionsConversion from Tac BD to Tac QD in renal recipients was accompanied by stable renal function, a low risk of acute rejection, and less interpatient variability in drug exposure.

Tacrolimus Blood Trough Level in Kidney Transllants: What Do We Need the First Month after Transplantation?

Tacrolimus Blood Trough Level in Kidney Transllants: What Do We Need the First Month after Transplantation?

Tacrolimus trough levels before, during and after jejunostomy in a liver transplant patient: A case report

SummaryAlthough the feasibility of oral tacrolimus administration in the presence of jejunostomy has already been reported, few studies monitoring tacrolimus trough blood levels have been analyzed in detail, either during or after a jejunostomy closure. We report on our experience with a 34-year-old patient who underwent liver transplantations, with a proximal jejunostomy constructed a few days prior to the second transplantation. He was administered tacrolimus by a predominantly oral route, and less frequently received it by jejunostomy. The aim of this paper is to discuss this administration strategy and whether a different method could have been more suitable. This case report highlights that during the jejunostomy period, the tacrolimus doses that were required to maintain trough concentrations within the therapeutic range were four times higher than those administered after the closure of the jejunostomy. We observed an increase in the Dose-Normalized Trough Concentration (DNTC) values when tacrolimus was administered for 4 consecutive days by jejunostomy as compared to oral administration, indicating that the relative bioavailability of tacrolimus increased. Moreover, when returning to oral administration, the subsequent DNTC value was halved, highlighting a reduction in the tacrolimus bioavailability. Thus, in such a case, administration by jejunostomy could be more appropriate.

Is there any way to protect from tacrolimus‐induced renal and pancreas injury?

The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. Rats in group I were given saline; rats in group II were injected with tacrolimus; rats in group III were received erythropoietin (Epo) and tacrolimus; while rats in group IV were injected pentoxifylline (Ptx) plus tacrolimus for nine d. On 10th day, blood and tissue samples were taken for biochemical and pathological evaluations. Tacrolimus-injected animals exhibited significant elevation in blood urea nitrogen (BUN), and serum BUN levels were improved in rats pretreated with Ptx. Significantly more apoptotic nuclei were observed in kidneys of tacrolimus group. In rats subjected to tacrolimus and pretreated with Epo, there was significant decrease in apoptotic nuclei staining than those in tacrolimus group. Blood trough levels of tacrolimus were significantly higher in erythropoietin-pretreated group, although same amount of tacrolimus was injected with other groups. Results of our study demonstrated significant antiapoptotic effects of erythropoietin on renal tubules, increasing effect of erythropoietin on tacrolimus blood levels, and insignificant antioxidant effects of both erythropoietin and pentoxifylline on renal and pancreas tissues. Study with clinically greater tacrolimus levels may be useful to confirm these findings.

Unusual high dose of tacrolimus in liver transplant patient, a case report

We describe the case of a liver transplant patient who had great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. The patient was homozygous for the CYP3A5*3 allele. However, the respective donor carried the wild-type CYP3A5*1/*1 genotype. Regarding ABCB1 SNPs at exon 21 and 26, the patient showed the 2677GT and 3435CC genotypes. For the corresponding donor we observed the 2677GG and 3435CC wild-type genotypes. One, two and three weeks after transplantation the patient received daily 0.219, 0.287 and 0.273 mg/kg of tacrolimus, respectively. However, the corresponding tacrolimus trough blood levels were of 4.6, 5.6 and 6.1 ng/mL. The tacrolimus target level of 10.4 ng/mL was finally reached after 1 month of therapy. During the entire period of observation the kidney showed no sign of damage. No other signs of toxicity were reported except for the occurrence of an isolated systolic hypertension. CYP3A5 genotyping may represent a useful tool to better evaluate the appropriate initial dose of tacrolimus for patients carrying a liver with the CYP3A5*1/*1 genotype.

Improved Kidney Graft Function After Conversion From Twice Daily Tacrolimus to a Once Daily Prolonged-Release Formulation

Background Tacrolimus once daily (Tac-QD) formulation has been recently introduced to improve patient adherence to immunosuppressive medications. To evaluate long-term effects of conversion from tacrolimus twice daily (Tac-BID) to Tac-QD on kidney graft excretory function, we retrospectively analyzed kidney graft function after the conversion from Tac-BID to Tac-QD over 24 months. Methods We enrolled 72 kidney transplant recipients, including 19 simultaneous pancreas–kidney cases, who were at least 9 months posttransplantation and showed stable graft function for 6 months. We analyzed kidney graft function (glomerular filtration rate [eGFR] by the Modification of Diet in Renal of Disease equation), tacrolimus daily dose and tacrolimus blood trough level changes over 24 months after conversion. Results All patients completed the 12 months and 56 patients, 24 months observation. At 3 months, the eGFR increased significantly after conversion from 57.1 to 60.0 mL/min/1.73 m 2 ( P = .004) and at 24 months to 66.0 mL/min/1.73 m 2 ( P < .001). Tacrolimus daily dose diminished over time by almost 10%, a difference that reached statistical significance at 18 months. Tacrolimus blood trough levels did not change significantly until 24 months. There was no correlation between eGFR changes during the first 12 months after conversion and changes in tacrolimus blood trough levels ( r = −0.118; P = .33). Conclusion Conversion from Tac-BID to Tac-QD formulation was followed by a clinically significant improvement in kidney graft function upon long-term observation. The improvement seemed to not be related to changes in tacrolimus blood trough levels.

Interaction between tacrolimus and clindamycin.

Sir, Tacrolimus is widely used in organ transplantation to prevent allograft rejection. Its hepatic metabolism via cytochrome P450 (CYP) 3A4 represents the major eliminating process. In addition, its bioavailability depends on intestinal P-glycoproteins (PGP) and CYP3A5 activities. Due to its potential toxicity, tacrolimus usage requires a close drug monitoring, as well as the early identification of any pharmacological interaction. Here, we report on a novel interaction between tacrolimus and clindamycin in a renal transplant recipient with Pneumocystis jirovecii pneumonia (PJP). A 61-year-old woman underwent kidney transplantation from a deceased donor for end-stage renal disease secondary to chronic glomerulonephritis with IgA deposits. Two months later, she presented with grade IV dyspnoea. Maintenance immunosuppression included modified-release (MR) tacrolimus 15 mg/day, mycophenolate mofetil (MMF) 720 mg/day and prednisolone 4 mg/day. Thorax computed tomography showed bilateral ground-glass opacities compatible with PJP, as confirmed by bronchoalveolar lavage analyses. MMF was interrupted, and sulphamethoxazole–trimethoprim (4 × 1280 mg/day) was initiated with methylprednisolone (32 mg/day). The patient's condition declined, requiring mechanical ventilation. From that time, medications were given through a nasogastric tube, and tacrolimus trough level remained stable ∼10 ng/mL while receiving 7 mg/day (Figure 1). Because sulphamethoxazole–trimethoprim treatment induced type IV renal tubular acidosis, antimicrobial therapy was substituted for atovaquone (1500 mg/day) and clindamycin (2400 mg/day IV) on Day 8. Tacrolimus trough level progressively decreased, while its dosage was accordingly increased (Figure 1). Six days later, both atovaquone and clindamycin were interrupted with a progressive return of tacrolimus trough level to baseline. Since the administration of MR tacrolimus through a nasogastric tube may decrease its disposition, the twice-a-day form was initiated (Figure 1). Fibroscopy was performed 10 days after antibiotic withdrawal and disclosed PJP recurrence. Both atovaquone and clindamycin were resumed for 6 days. Again, tacrolimus trough level significantly decreased (Figure 1) though no other medication was initiated. Renal graft function remained stable. Fig. 1 Changes in tacrolimus blood trough level (nanogram per millilitre) and tacrolimus dose (milligram per day) according to atovaquone/clindamycin therapy from Day 4 at the intensive care unit. Advagraf® and Prograft® represent the modified-release ... Because of its extensive metabolism, tacrolimus disposition tightly depends on CYP3A4/5 and PGP activities. Here, a significant decrease of tacrolimus trough level was repeatedly observed when co-administered with atovaquone and clindamycin. Atovaquone is 94% excreted unchanged in faeces, with a modest inhibition of CYP2C19 which is not implicated in tacrolimus metabolism [1]. Conversely, clindamycin metabolism primarily requires its oxidation by CYP3A4/5 and exhibits a clear propensity to induce CYP3A4 activity [2,3]. Thus, similarly to former cases reported under cyclosporine [4], clindamycin may accelerate tacrolimus catabolism. Here, the co-administration of clindamycin and tacrolimus led twice to a significant decrease in tacrolimus trough level. Such temporal relationship is highly suggestive of pharmacological interactions, as supported by a significant Drug Interaction Probability Scale (DIPS) score [5]. In conclusion, the present observation emphasizes the need for a close monitoring of tacrolimus trough level when co-administered with high-dose clindamycin. Conflict of interest statement. None declared.

Safety of Conversion From Twice-Daily Tacrolimus (Prograf) to Once-Daily Prolonged-Release Tacrolimus (Advagraf) in Stable Liver Transplant Recipients

Nonadherence to immunosuppressive regimens among solid organ transplantation to range has been estimated from 15% to 55%. This problem has been identified as a leading cause of preventable graft loss. Tacrolimus once daily Advagraf has been developed to provide a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily tacrolimus (Prograf) to Advagraf in 36 stable liver transplant recipients. The tacrolimus whole blood trough level at T0 was 6.7 ± 2.9 ng/mL with a daily dose of 3.7 ± 1.8 mg. The mean tacrolimus blood trough levels at T1 (7 days) and T2 (14 days) were 5.8 ± 2.5 and 5.8 ± 1.8 ng/mL with mean daily doses of 3.9 ± 1.9 and 4.1 ± 1.8 mg, respectively. There was no significant difference between T0, T1, and T2, either for tacrolimus blood trough levels or for tacrolimus daily dosages. Liver and renal function tests remained stable; no episodes of acute rejection were encountered after the conversion. A switching policy using a dose ratio of 1:1 from twice-daily tacrolimus to once-daily prolonged-release tacrolimus was safely applied to stable liver transplant recipients.

HNF1B-related diabetes triggered by renal transplantation

A 37-year-old man developed cholestasis-associated pruritus followed by overt hyperglycemia (blood glucose level 23 mmol/l), necessitating insulin treatment, within weeks of undergoing renal transplantation. He had a history of gout, but his fasting blood glucose and glycated hemoglobin concentrations had been normal before transplantation. Physical examination; laboratory tests, including assessment of glycated hemoglobin, anti-glutamic-acid-decarboxylase and anti-islet-antigen-2 antibodies, liver enzymes, renal function, tacrolimus blood trough level, exocrine (fecal elastase) and endocrine (C-peptide) pancreatic function; abdominal CT scan; liver biopsy; and screening of the hepatocyte nuclear factor 1 homeobox B (transcription factor 2) gene, HNF1B. New-onset diabetes after transplantation associated with a newly described deletion in HNF1B. Minimization of tacrolimus exposure and withdrawal of steroids considerably reduced the patient's insulin requirement, and cholestasis-related pruritus was dramatically improved by administration of ursodeoxycholic acid. Renal ultrasonography and screening for the HNF1B molecular abnormality were offered to the patient's relatives.

Diabetes Mellitus After Living Donor Liver Transplantation: Data From Mainland China

Most reported data on posttransplantation diabetes mellitus (PTDM) are from Western countries with patients who underwent deceased donor liver transplantation. A retrospective study was performed to assess the prevalence and predictive factors of PTDM in the context of living donor liver transplantation (LDLT) in the Chinese population using the definition of PTDM proposed in 2003 by the World Health Organization and the American Diabetes Association. The prevalence of DM after LDLT in our study was 25% (21/84), and the incidence of PTDM was 14.9% (11/74) with 64% of cases diagnosed within 3 months after LDLT; 9.5% were observed to show impaired fasting glucose postoperatively. Multivariate analysis identified body mass index ≥ 25 kg/m 2 before LDLT as the only independent risk factor for developing PTDM. Only one patient was operated for hepatitis C virus (HCV) infection. Hepatitis B virus (HBV)-related diseases were common in our study population, accounting for 78.6% of all patients. Both HCV and HBV infection status were not independent risk factors for developing PTDM. In addition, a greater tacrolimus trough blood level in the PTDM group versus no-DM group was observed at 3 months post-LDLT (11.03 ng/mL vs 4.87 ng/mL). The mean tacrolimus dose was not significantly different between the two groups. In conclusion, PTDM was prevalent among Chinese LDLT recipients.

Local application of tacrolimus in distal colitis: Feasible and safe

Tacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and safety of tacrolimus for distal colitis. Patients with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2-4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment. Nineteen patients with left-sided colitis (n = 7) or proctitis (n = 12) were treated. Two patients with left-sided colitis had Crohn's disease (CD), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group. This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

Liver transplantation for hepatoblastoma: Indications and contraindications in the modern era

In the past 20 yr, a dramatic improvement has been achieved in the outcome of children with hepatoblastoma by combining cisplatin based chemotherapy and surgery. Treatment of patients in the USA is an exception to the rule that all patients should receive neoadjuvant chemotherapy. It is paramount that surgical resection be complete, both macro- and microscopically. Complete tumor resection can be achieved after chemotherapy with a partial hepatectomy when the intrahepatic extent is limited to 1-3 sectors. In multifocal (and solitary) hepatoblastomas invading all four liver sectors, and in centrally located tumors with close proximity to the major veins, the SIOPEL-1 study and an extensive review of the world experience have shown that primary transplantation provides high, long term, disease-free survival rate in the range of 80%. In contrast, the results of rescue transplants for incomplete tumor resection or disease recurrence after partial hepatectomy are disappointing (in the range of 30%). Hazardous attempts at partial hepatectomy in children with extensive hepatoblastoma should be discouraged. Guidelines are provided for early referral of children with extended hepatoblastoma to a transplant surgeon. There is a trend for a better patient survival after living related liver transplantation. Patients who will become candidates to liver transplantation should be treated with chemotherapy following the same protocols as for children undergoing a partial hepatectomy. There is a concern about cumulative nephrotoxicity of calcineurin inhibitors and chemotherapeutic drugs. Recent data suggest that these patients tolerate lower Tacrolimus trough blood levels than those transplanted for non-malignant conditions, without increasing the risk of acute rejection. Due to the rarity of the disease, these children should be treated in specialized centers.