A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Tacrolimus-induced posterior reversible encephalopathy syndrome following liver transplantation

In this editorial,we talk about a compelling case focusing on posterior reversible encephalopathy syndrome(PRES)as a complication in patients undergoing liver transplantation and treated with Tacrolimus.Tacrolimus(FK 506),derived from Streptomyces tsukubaensis,is a potent immunosuppressive macrolide.It inhibits Tcell transcription by binding to FK-binding protein,and is able to amplify glucocorticoid and progesterone effects.Tacrolimus effectively prevents allograft rejection in transplant patients but has adverse effects such as Tacrolimus-related PRES.PRES presents with various neurological symptoms alongside elevated blood pressure,and is primarily characterized by vasogenic edema on neuroimaging.While computed tomography detects initial lesions,magnetic resonance imaging,especially the Fluid-Attenuated Inversion Recovery sequence,is superior for diagnosing cortical and subcortical edema.Our discussion centers on the incidence of PRES in solid organ transplant recipients,which ranges between 0.5 to 5+ACU-,with varying presentations,from seizures to visual disturbances.The case of a 66-year-old male status post liver transplantation highlights the diagnostic and management challenges associated with Tacrolimus-related PRES.Radiographically evident in the parietal and occipital lobes,PRES underlines the need for heightened vigilance among healthcare providers.This editorial emphasizes the importance of early recognition,accurate diagnosis,and effective management of PRES to optimize outcomes in liver transplant patients.The case further explores the balance between the efficacy of immunosuppression with Tacrolimus and its potential neurological risks,underlining the necessity for careful monitoring and intervention strategies in this patient population.

Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation

Tacrolimus(Tac)is currently the most common calcineurin-inhibitor employed in solid organ transplantation.High intra-patient variability(IPV)of Tac(Tac IPV)has been associated with an increased risk of immune-mediated rejection and poor outcomes after kidney transplantation.Few data are available concerning the impact of high Tac IPV in non-kidney transplants.However,even in kidney transplantation,there is still a controversy whether high Tac IPV is indeed detrimental in respect to graft and/or patient survival.This may be due to different methods employed to evaluate IPV and distinct time frames adopted to assess graft and patient survival in those reports published up to now in the literature.Little is also known about the influence of high Tac IPV in the development of other untoward adverse events,update of the current knowledge regarding the impact of Tac IPV in different outcomes following kidney,liver,heart,lung,and pancreas tran-splantation to better evaluate its use in clinical practice.

Reversible Chronic Interstitial Nephritis Induced by Tacrolimus —Tacrolimus Chronic Interstitial Nephritis

Calcineurin inhibitors (CNI) are potent immunosuppressive agents in prophylaxis against graft rejection and autoimmune diseases including primary glomerulopathies. Previous research showed reversible;acute afferent arteriolar vasculopathy and irreversible chronic interstitial fibrosis associated with CNI nephrotoxicity. In this case report we describe a patient, with minimal change disease, that had developed chronic and progressive renal disease while receiving therapeutic dose of Tacrolimus. His serum creatinine had reached 537 umol/L and his nephrotic state worsened. Kidney biopsy showed chronic interstitial nephritis. Tacrolimus was discontinued and he was treated with 1 mg/kg prednisone in addition to Mycophenolate mofetil (MMF) 1 g twice daily. By the 2nd month;serum creatinine returned to normal and by the 3rd month serum albumin too. After 1 month of therapy;the dose of Prednisone was tapered down gradually till 5 mg daily by the end of 3rd month. Moreover, the dose of MMF was reduced to 500 mg X2 by the end of 3rd month. After 2 years of follow up;he remained stable and without relapse of NS or renal failure. In conclusion, reversible renal disease, due to chronic interstitial nephritis can be induced by CNI which is amenable to treatment with Prednisone and MMF.

Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation

BACKGROUND Clinical factors predicting graft survival(GS)after ABO-incompatible(ABOi)liver transplantation(LT),and differences between recipients with and without hepatocellular carcinoma(HCC)are unclear.AIM To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without(HCC)in ABOi living-donor liver transplantation(LDLT).METHODS We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT,including 47 patients with HCC.RESULTS The 1-,3-,5-,and 10-year GS rates were 85.9%,73.3%,71.4%,and 71.4%,respectively,and there were no significant differences between HCC and non-HCC recipients.In multivariate Coxregression analyses,tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT,in addition to the antibody-mediated rejection(AMR)were associated with poor-graft outcomes.In HCC patients,AMR[hazard ratio(HR)=63.20,P<0.01]and HCC recurrence(HR=20.72,P=0.01)were significantly associated with poor graft outcomes.HCCs outside Milan criteria,and tacrolimus concentrations at 4 wk post-LT>7.3 ng/mL were significant predictive factors for HCC recurrence.After propensity score matching,patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival.CONCLUSION Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence.Therefore,careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype

BACKGROUND Tacrolimus extended-release tablets have been Food and Drug Administrationapproved for use in the de novo kidney transplant population.Dosing requirements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression.Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus,but this has not been established for tacrolimus extended-release tablets in the de novo setting.AIM To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype.METHODS Single-arm,prospective,single-center,open-label,observational study(ClinicalTrials.gov:NCT037-13645).Life cycle pharma tacrolimus(LCPT)orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight.If weight is more than 120%of ideal body weight,an adjusted body weight was used.LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL.Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion.RESULTS Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(6 d vs 13.5 d vs 4.5 d;P=0.025).Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(16 mg vs 16 mg vs 12 mg;P=0.010)(0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg;P=0.018).CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers(7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL;P=00.008).No differences were identified with regards to kidney graft function at 30-d post-transplant.Serious adverse events were reported for 13(36%)patients.CONCLUSION Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacrolimus to achieve target trough concentrations.We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Relationship Between the Efficacy of Low-Dose Glucocorticoids Combined with Tacrolimus in the Treatment of Adult Idiopathic Membranous Nephropathy and the Level of Serum Anti-PLA2R Antibodies

Objective:To further evaluate the efficacy and safety of low-dose glucocorticoids combined with tacrolimus in the treatment of adult idiopathic membranous nephropathy(IMN)in a clinical setting.Methods:We carried out a single-center prospective study of 88 patients with IMN who were admitted into the Affiliated Hospital of Hebei University from January 2019 to December 2021,and the participants were divided into two groups based on their serum anti-PLA2R antibody levels:the negative group and the positive group.46 patients were positive for anti-PLA2R antibodies and 42 were negative.Results:After 6 months of treatment,the serum albumin,cholesterol,and 24h urine protein quantification in the anti-PLA2R negative group improved more significantly compared to the positive group(P<0.05);after 6 months of treatment,the remission rate of the positive group was significantly lower than that of the negative group,and(P<0.05);Conclusion:After treatment with tacrolimus combined with low-dose glucocorticoids,patients with idiopathic membranous nephropathy who were tested positive for anti-PLA2R antibodies had a higher overall remission rate compared those who were tested negative for serum anti-PLA2R antibodies.

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied.Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy.Patients were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient mortality.RESULTS Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,respectively.Donor age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across groups.After a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.

Tacrolimus对糖尿病大鼠肾脏巨噬细胞Toll样受体2与4表达的影响

目的探讨Toll样受体(Toll-like receptor,TLR)2和TLR4在糖尿病大鼠肾脏巨噬细胞的表达水平及tacrolimus对其的调节作用。方法将40只Wistar大鼠随机分为对照组、模型组、tacrolimus(0.5、1.0 mg.kg-1)给药组,通过腹腔注射链脲佐菌素(STZ)诱导糖尿病模型,4周后测大鼠血糖、相对肾质量、尿白蛋白排泄率(UAER),应用免疫组化单染及双染方法检测肾组织ED-1+细胞、NF-κB-p-p65+细胞及ED-1+TLR2+细胞、ED-1+TLR4+细胞的表达。结果 ta-crolimus 1.0 mg.kg-1给药组大鼠相对肾质量明显低于模型组(P<0.05),tacrolimus(0.5、1.0 mg.kg-1)给药组大鼠UAER较模型组明显减少(P<0.05或P<0.01)。免疫组化显示:模型组大鼠肾组织ED-1+、ED-1+TLR2+、ED-1+TLR4+及NF-κB-p-p65+细胞数明显高于对照组(P<0.01),tacrolimus 0.5与1.0 mg.kg-1给药组ED-1+细胞数与模型组比较无差异,而ED-1+TLR2+、ED-1+TLR4+及NF-κB-p-p65+细胞数则明显低于模型组(P<0.05)。结论糖尿病大鼠肾脏巨噬细胞TLR2和TLR4的过度表达与巨噬细胞的活化及由此引发的炎症反应有关,tacrolimus可通过直接或间接作用下调肾脏巨噬细胞TLR2与TLR4表达,从而抑制与TLR-NF-κB信号转导及调控途径有关的炎症反应。

''Minimizing tacrolimus' ' strategy and long-term survival after liver transplantation

AIM: To investigate the effect of the ‘‘minimizing tacrolimus' ' strategy on long-term survival of patients after liver transplantation(LT).METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus(TAC)exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were eval-uated by the χ2 test. Routine monitoring of blood TAC concentration(TC) was performed using the PRO-TracTM Ⅱ Tacrolimus Elisa Kit(Diasorin, United States). RESULTS: Of 235 subjects enrolled in the study, 124(52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups(911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation(SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups(1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.CONCLUSION: The early ‘‘minimizing tacrolimus' ' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.

cuff技术血管连接法及Tacrolimus免疫抑制效果研究

ＤＡ和Ｌｅｗｉｓ鼠分别作为移植的供受体。采用ｃｕｆ微血管吻合技术，建立大鼠异位心脏移植模型，移植术后分别使用不同浓度的Ｔａｃｒｏｌｉｍｕｓ与非治疗组比较，观察Ｔａｃｒｏｌｉｍｕｓ对同种心脏移植的免疫抑制作用。结果表明：使用Ｔａｃｒｏｌｉｍｕｓ组的移植物生存时间较对照组明显延长（Ｐ＜０．０５）。提示Ｔａｃｒｏｌｉｍｕｓ对大鼠同种心脏移植排斥反应有明显的抑制作用。

最新的免疫抑制剂——FK506(Tacrolimus)

最新的免疫抑制剂———ＦＫ５０６（Ｔａｃｒｏｌｉｍｕｓ）中山医科大学肿瘤研究所（５１００６０）潘启超随着器官移植的发展，免疫抑制剂的需要日益迫切，早些时已有环胞霉素（ＣｙｃｌｏｓｐｏｒｉｎＡ，ＣｙＡ）的出现，近年又有ＦＫ５０６（Ｔａｃｒｏｌｉｍｕｓ...

Cyclosporine versus tacrolimus in patients with HCV infection after liver transplantation:Effects on virus replication and recurrent hepatitis

AIM： To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus （HCV） replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS： The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. RESULTS： HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant （P=0.49 at 12 too）. In addition, recurrent hepatitis as determined by serum transarninases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo （P= 0.34）.CONCLUSION： Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV- infected patients after liver transplantation.

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation

AbstractAIM： To investigate the impact of minimum tacrolimus（TAC） on new-onset diabetes mellitus （NODM） afterliver transplantation （LT）.METHODS： We retrospectively analyzed the data of973 liver transplant recipients between March 1999and September 2014 in West China Hospital LiverTransplantation Center. Following the exclusion ofineligible recipients, 528 recipients with a TAC-dominantregimen were included in our study. We calculatedand determined the mean trough concentration ofTAC （cTAC） in the year of diabetes diagnosis in NODMrecipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value forpredicting NODM 6 mo after LT was identified usinga receptor operating characteristic curve. TAC-relatedcomplications after LT was evaluated by χ^2 test, andthe overall and allograft survival was evaluated usingthe Kaplan-Meier method. Risk factors for NODM afterLT were examined by univariate and multivariate Cox regression.RESULTS： Of the 528 transplant recipients, 131（24.8%） developed NODM after 6 mo after LT, andthe cumulative incidence of NODM progressivelyincreased. The mean cTAC of NODM group recipientswas significantly higher than that of recipients in thenon-NODM group （7.66 ± 3.41 ng/mL vs 4.47 ± 2.22ng/mL, P 〈 0.05）. Furthermore, NODM group recipientshad lower 1-, 5-, 10-year overall survival rates （86.7%,71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P 〈0.05） and allograft survival rates （92.8%, 84.6%, and75.7% vs 96.1%, 91%, and 86.1%, P 〈 0.05） thanthe others. The best cutoff of mean cTAC for predictingNODM was 5.89 ng/mL after 6 mo after LT. Multivariateanalysis showed that old age at the time of LT （〉 50years）, hypertension pre-LT, and high mean cTAC （≥5.89 ng/mL） after 6 mo after LT were independent riskfactors for developing NODM. Concurrently, recipientswith a low cTAC （〈 5.89 ng/mL） were less likely tobecome obese （21.3% vs 30.2%, P 〈 0.05） or todevelop dyslipidemia （27.5% vs 44.8%, P 〈0.05）,chronic kidney dysfunction （14.6% vs 22.7%, P 〈 0.05）,and moderate to severe infection （24.7% vs 33.1%, P〈 0.05） after LT than recipients in the high mean cTACgroup. However, the two groups showed no significantdifference in the incidence of acute and chronicrejection, hypertension, cardiovascular events and newonsetmalignancy.CONCLUSION： A minimal TAC regimen can decreasethe risk of long-term NODM after LT. Maintaining a cTACvalue below 5.89 ng/mL after LT is safe and beneficial.

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.

Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth

AIM: Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immunosuppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma.METHODS: We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots.RESULTS: Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment.CONCLUSION: Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.

Reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation

Sinusoidal obstruction syndrome(SOS), previously known as hepatic veno-occlusive disease, is a rare disorder in solid organ transplant patients, and is an uncommon complication after liver transplantation. Severe SOS with hepatic failure causes considerable mortality. Tacrolimus has been reported to be an offending agent, which potentially plays a role in the pathophysiological process of SOS. SOS due to tacrolimus has been reported in lung and pancreatic transplantations, but has never been described in a liver transplant recipient. Herein, we present a case of SOS after liver transplantation, which was possibly related to tacrolimus. A 27-year-old man developed typical symptoms of SOS with painful hepatomegaly, ascites and jaundice after liver transplantation, which regressed following withdrawal of tacrolimus. By excluding other possible predisposing factors, we concluded that tacrolimus was the most likely cause of SOS.

Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level

To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form.RESULTSThere were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035).CONCLUSIONIncidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point.