肝移植受者术后早期发生获得性丙型肝炎病毒感染三例

目的 分析肝移植术后早期发生获得性丙型肝炎病毒(HCV)感染的临床特点,总结诊断和治疗经验.方法 回顾性分析3例肝移植术后早期发生获得性HCV感染受者的临床资料,评价HCV-RNA检测方法对肝移植术后发生获得性HCV感染的诊断价值,观察丙氨酸转氨酶(ALT)与他克莫司(FK506)的血药浓度、用药剂量及浓度/剂量比值的变化特点.结果 与抗-HCV及移植肝活组织HCV抗原检测相比,HCV-RNA检测可更早确诊HCV感染.3例术后早期发生获得性HCV感染的受者均出现FK506血药浓度异常升高,并伴随出现ALT水平及FK506血药浓度/剂量比值的异常升高.结论 HCV-RNA检测是确诊肝移植术后早期发生获得性HCV感染的最佳方法;确诊后应调整FK506的用药剂量,使其血药浓度维持在治疗窗内,并积极保护移植肝功能.     

他克莫司在20例肝移植中的应用

目的　探讨他克莫司 (FK5 0 6 )在肝移植中的应用方法。方法　 2 0例肝移植患者随机分为FK5 0 6高浓度组、FK5 0 6中浓度组、CsA转换为FK5 0 6组、FK5 0 6转换为CsA组。观察各组临床表现、药物副作用和病理学变化。结果　FK5 0 6高浓度组容易出现感染、药物性肝损害等不良表现 ,FK5 0 6中浓度组虽也出现多种并发症 ,但易于处理。结论　FK5 0 6是一种高效免疫抑制剂 ,FK5 0 6血药中浓度是一种较理想的治疗窗     

Allogeneic hepatocyte transplantation using fk 506

Hepatocyte transplantation is an intriguing alternative to orthotopic liver transplantation. While engraftment of syngeneic hepatocytes can be achieved with relative ease, engraftment of allogeneic hepatocytes has been far more complicated. We used FK 506 (Tacrolimus), a novel and highly efficient immunosuppressant, which has been reported to augment liver regeneration in rats. Recipients of isolated syngeneic (LEW) and allogeneic (Wistar F.) rat hepatocytes (major histocompatibility barrier) recieved different immunosuppressive regiments with FK 506 or Cyclosporine A (CsA). Mature syngeneic hepatocytes could be retrieved up to post op day 300 with the lowest number of hepatocytes on post op day 20. Following allogeneic transplantation, no mature hepatocytes could be identified after post op day 10, though ductular like structures within the spleen were found in FK 506 but not CsA-treated animals. The epithelial cells of ductular like structures exhibit cytological features of CK-19 positive cells. Our results suggest that under CsA or FK 506 immunosuppression long-term survival of mature allogeneic hepatocytes within the spleen cannot be achieved across a major histocompatibility barrier though FK 506 allows engraftment of allogeneic donor type ductular cells.     

儿童肝移植术后罕见药物性肝损害1例报道并文献复习

目的探讨儿童肝移植术后药物性肝损害的诊疗经验。方法回顾性分析1例小儿肝移植术后药物性肝损害病例的临床资料并进行文献复习。结果患儿于肝移植术后1年4月余出现肝功能异常,其中血碱性磷酸酶(alkalinephos phatase,ALP)水平明显升高,经除外急性排斥反应、维生素D缺乏性佝偻病、胆汁淤积性疾病、病毒感染、骨代谢异常、甲状旁腺功能亢进症及血液系统疾患等原因后,考虑为他克莫司(FK506)不良反应所致肝损害,停用FK506,改为麦考酚吗乙酯(MMF)+环孢素(CsA)抗排斥治疗后,患儿肝功能逐渐好转。结论儿童患者的生理及药物代谢具有特殊性,小儿肝移植术后FK506所致药物性肝损害较为罕见,临床上应予以重视。     

他克莫司和环孢素A对肾移植术后患者肝功能影响的临床比较观察

目的:研究和比较他克莫司（FK506）以及环孢素A（CsA)对肾移植术后患者肝功能的影响。方法：将肾移植术后患者随机分为FK506组和CsA组,FK506组8例,CsA组26例。CsA组中出现肝功能异常的6例患者用FK506进行替换治疗。两组均联合应用霉酚酸酯（MMF）和泼尼松（Pred)。结果：观察6个月,FK506组和CsA组中急性排斥的发生率差异 不显著;FK506组中未发现肝功能异常患者,CsA组中有6例患者肝功能异常;肝功能异常的6例患者用FK506替换CsA后,总胆红素（TBIL）、直接胆红素（DBIL）、丙氨酸转氨酶（ALT）相继转为正常。结论：FK506免疫抑制剂效果与CsA相似,但对肝功能影响甚微,适合应用于术前有肝功损害或术后应用CsA后出现肝功能异常倾向的患者。     

Two-year follow-up study of the efficacy and safety of FK 506 in kidney transplant patients

Abstract We conducted a 2-year follow-up study of the efficacy and safety of FK 506 in 104 kidney transplant patients at 32 sites in Japan. The initial daily oral dose of FK 506 was 0.3 mg/kg, which was gradually reduced to 0.15 mg/kg by month 10 and remained stable thereafter. The mean trough level of FK 506 in whole blood and the mean serum creatinine level in year 2 were 7.9 ng/ml and 1.9 mg/dl, respectively. Patient and graft survival rates for all patients were 97% and 92%, respectively. Forty-ix patients (44%) experienced rejection episodes, and 84% of these episodes occurred within 3 months after transplantation. The principal adverse reactions to FK 506 therapy were hyperglycaemia, renal dysfunction and hyperkalaemia. Most of these events were dose-dependent, and disappeared or ameliorated following reduction of the FK 506 dose.     

Focus on intractable rejection: 6-month results of the European multicentre liver study of FK 506 and cyclosporin A

Abstract The incidence of intractable rejection was evaluated during the course of a multicentre, randomised, parallel-group study comparing the efficacy and safety of FK 506 and conventional cyclosporin A-based immunosuppressive regimens in patients undergoing primary liver transplantation. A diagnosis of intractable rejection was made if there was histological evidence of unchanged or worsening acute rejection, or chronic rejection after two discrete courses of antirejection therapy. Antirejection regimens were specific to each centre. Patients who experienced intractable rejection could be withdrawn from the study. Patients who were withdrawn from the cyclosporin A treatment group could subsequently receive FK 506 therapy and vice-versa. Intractable rejection was diagnosed in 32/540 patients (5.9%): 7/267 patients (2.6%) in the FK 506 treatment group and 25/273 patients (9.2%) receiving cyclosporin A therapy ( P < 0.01). Of these 32 patients, 25 were withdrawn from the study: 3 and 22, from the FK 506 and cyclosporin A treatment groups, respectively. All three patients withdrawn from the FK 506 treatment group are alive: two having undergone retransplantation. Of the 22 patients withdrawn from the cyclosporin A group and converted to FK 506 therapy, 6 were retransplanted, 4 of whom subsequently died. A further two patients died without retransplantation. Thus, in 14 of the 16 patients who were still alive at 6 months, the liver graft was saved after conversion to FK 506 treatment. The reduced incidence of intractable rejection in patients receiving treatment with FK 506, together with the successful rescue of patients developing intractable rejection while receiving cyclosporin A, suggests that FK 506 is an effective immunosuppressive agent following orthotopic liver transplantation.     

Insulin-like growth factor-I enhances choleretic action of FK506 in rats

FK506 is an immunosuppressant for organ transplantation in the same clinical settings as cyclosporine (CsA). In the management of liver transplantation, FK506 has advantages over CsA, in terms of rejection and corticosteroid requirements. Recent clinical findings in liver transplant patients indicate that FK506, but not CsA, stimulates choleresis, suggesting that FK506 treatment may accelerate recovery from cholestatic dysfunction through its choleretic action. Recently, we demonstrated in rats that exogenous treatment with insulin-like growth factor I (IGF-I) results in an increase in bile flow and also that FK506 has the potential to increase hepatic production of IGF-I. However, circulating levels of IGF-I in FK506-treated rats were only 30% higher than in nontreated rats. In this study, we evaluated the combined effect of treatment with both IGF-I and FK506 on bile flow in rats to explore the possibility that combination treatment in liver transplant patients could enhance the choleretic action of FK506, benefiting the transplanted liver. Combination treatment of IGF-I with FK506 resulted in a potent and long-lasting increase in bile flow. Overall, this study demonstrated that IGF-I treatment enhanced the choleretic action of FK506, providing potential clinical utility for combination therapy using these two drugs, in treatment after liver transplantation.     

Guillain-Barré syndrome triggered by influenza vaccination in a recipient of liver transplant on FK506.

Guillain-Barré syndrome (GBS) has been rarely reported after liver transplantation and generally has good outcome. We report a liver transplant patient on FK506 (tacrolimus) who developed GBS 6 months after liver transplantation. There was no evidence of liver rejection or active infection. Despite treatment with intravenous immunoglobulin, the patient expired. GBS occurred despite downregulation of T cells by FK506, suggesting that humoral dysfunction might be the predominant mechanism of GBS in this report.     

Functional and morphological changes in rat kidney induced by FK506 and its reversal by various vasodilators]

FK506, a newly developed immunosuppressive agent, has recently been used for human liver and kidney transplantation. The present study was carried out to assess the functional and morphological changes by acute or chronic administration of FK506 in heminephrectomized rats. FK506 was given intravenously at the dose of 0.384 mg/kg/hr for 90 min in acute experiment. FK506 was administered by gastric gavage at doses of 1, 2.5, 5 mg/kg for 21 days. Blood and urinary biochemistry were monitored every week. Inulin and PAH clearance studies were conducted during the infusion of FK506 for acute study, and at day 21 for chronic study. Some of the rats were treated with diltiazem (Dilt), captopril or prazosine for 21 days to prevent FK506 nephrotoxicity. Acute infusion of FK506 did not change renal and systemic hemodynamics. Creatinine clearance showed a dose dependent decrease by 10-20% in the rats with chronic administration of FK506. Inulin/PAH clearance indicated a decrease in glomerular filtration rate and renal plasma flow with an increase in renal vascular resistance. The renal histology showed vacuolization in proximal tubuli and media of smooth muscle cells of arterioles. The administration of Dilt functionally and morphologically improved renal impairment induced by FK506. In conclusion, FK506 induces a dose dependent decrease in renal function with significant histological changes in tubuli and arterioles in rat kidney. Intracellular calcium deregulation seems to be involved in FK506-induced nephrotoxicity.     

Efficacy of transient treatment with FK506 in the early phase on cyclophosphamide-induced bone marrow chimerism and transplant tolerance across MHC barriers

BACKGROUND: The use of mixed allogeneic bone marrow chimerism to induce donor-specific transplantation tolerance has been extensively demonstrated. In the present study, we assessed the effect of combined use of a short course of FK506 and a single-dose cyclophosphamide (CYP) on the induction of tolerance and development of GVHD after allogeneic BMT. MATERIALS AND METHODS: Lewis rat (RT1(l)) recipients received BMT from Brown Norway (RT1(n)) donors on the next day after injection of CYP at a dose of 200 mg/kg. The recipients were further treated with no FK506 (n = 8), 0.3 mg/kg/day FK506 on days 10-16 (n = 6), or the same dose of FK506 on days 0-6 (n = 6). In a subgroup of animals, heterotopic heart transplantation was performed to investigate transplantation tolerance. RESULTS: Six of eight recipient rats that did not receive FK506 died of severe GVHD, while high levels of chimerism were induced. Recipients of FK506 in the later phase developed mild transient GVHD around 2 to 3 weeks after BMT and recovered thereafter; however, the level of chimerism was significantly decreased (2.8 +/- 2.3% on day 100). Treatment with FK506 in the early phase completely prevented the development of GVHD and induced stable allogeneic chimerism in the long-term (13.8 +/- 8.3% on day 100). These recipients with stable chimerism accepted subsequent BN heart allografts indefinitely (>200 days x 5), while rejecting third-party (BUF) heart allografts by day 12. CONCLUSIONS: Early transient FK506 promotes the induction of stable bone marrow chimerism without GVHD after BMT with CYP pretreatment. The timing of treatment with FK506 is critical with a view to preventing GVHD and inducing stable long-lasting chimerism.     

Neurotoxicity after orthotopic liver transplantation in cyclosporin A-and FK 506-treated patients

Abstract Neurotoxicity is a serious complication following orthotopic liver transplantation leading to increased morbidity and mortality. Neurotoxicity may be evoked by various perioperative factors, or may be due to drug-pecific toxicity of immunosuppression. In the present study we evaluated the incidence of central nervous system (CNS) toxicity occurring within the early postoperative period of 121 patients, 61 randomly assigned to FK 506- and 60 to CsA-based immunosuppression as part of a multicentre study. The incidence of moderate or severe CNS toxicity was higher in patients treated with FK 506 (21.3%) than in patients receiving CsA (11.7%). The duration of symptoms was also greater in patients treated with FK 506 than in patients receiving CsA. The incidence of moderate or severe neurotoxicity after retransplantation was markedly greater in patients treated with FK 506 (100% of the patients).     

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.     

Langerhans' cell histiocytosis after living donor liver transplantation: report of a case.

We report a case of Langerhans' cell histiocytosis (LCH) occurring after a living donor liver transplantation (LDLT) for fulminant hepatitis. A 9-month-old girl underwent an LDLT for fulminant hepatitis of an unknown cause. The histology of the native liver did not show any findings of LCH. On postoperative day 42, her Epstein-Barr virus (EBV)-DNA and cytomegalovirus antigenemia were both found to be positive. As a result, she was treated with antiviral agents and a reduction of the immunosuppression dosage. On postoperative day 98, acute rejection occurred, and she was treated with FK506, methylprednisolone, and finally, anti-CD3 murine monoclonal antibody was added. Subsequently, the EBV was re-activated. Thereafter, skin eruptions, swelling of the systemic lymph nodes, and pancytopenia appeared on postoperative day 127. LCH was diagnosed based on the typical histological findings as LCH, CD1a, and S-100-positive cells in her skin and a lymph nodes biopsy. She was treated by chemotherapy. The symptoms disappeared a few weeks after the start of the chemotherapy, and a clinical remission of LCH was obtained. We could not detect any evidence of EBV infection in the tumor cells. In spite of the fact that her LCH lesions thereafter remained in remission, she died of hepatic failure at 22 months after undergoing the liver transplantation. In conclusion, we discuss the factors influencing the occurrence of LCH in our patient after LDLT, while also evaluating the relationship between LCH and the immunosuppressive therapy administered to this patient.     

Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats

BACKGROUND: Posttransplantation osteopenia leading to osteoporosis induced commonly by treatment with immunosuppressants including cyclosporine (CsA) is a severe complication and results in lowering the quality of life in patients receiving organ transplantation. FK506 is a newly developed immunosuppressant and is currently being used for the prevention of rejection after organ transplantation. In this study, to investigate whether FK506 as well as CsA would cause osteopenia or not, we evaluated the effect of FK506 on bone mineral density and several parameters relevant to bone metabolism in comparison with that of CsA using normal rats. METHODS: Ten-week-old male Sprague-Dawley rats were treated with FK506 (vehicle, 1 mg/kg, and 3.2 mg/kg) or CsA (vehicle, 10 mg/kg, and 32 mg/kg) by daily oral gavage for 28 days. Bone mineral density of the femur, plasma insulin-like growth factor I (IGF-I), and urinary deoxypyridinoline were determined by peripheral quantitative computerized tomography, radioimmunoassay, and enzyme-linked immunosorbent assay, respectively. RESULTS: The reduction in bone mineral density of the femur was observed in both FK506- and CsA-treated rats. The reduction in CsA-treated rats, however, was statistically significant and strikingly severe, whereas that in FK506-treated rats was much less severe than CsA. Plasma IGF-I levels were significantly elevated in FK506-treated rats but not in CsAtreated rats. Urinary deoxypyridinoline levels were unchanged in FK506-treated rats but elevated in CsA-treated rats. CONCLUSIONS: Compared with CsA, FK506 does not appear to induce severe osteopenia by high-turnover bone metabolism in the rat by mediating via IGF-I induction in part. The results suggest that FK506 may exert favorable effects on bone metabolism in patients with organ transplantation compared with CsA. To assess this idea, further clinical investigations focused on bone metabolism will be required.     

Nitrosyl hemoglobin detected by near-infrared spectroscopy in rat liver allografts

Near-infrared spectroscopy (NIRS) is a noninvasive biomeasurement system with rays in the near-infrared region that possess high permeability to biological tissues. NIRS was applied to liver allografts undergoing rejection in rats treated with deoxyspergualin (DSG) or tacrolimus (FK506). The nitrosyl hemoglobin (Hb) levels detected in the liver grafts increased 3 days and 5 days after grafting in both allogeneic and syngeneic transplantation. The levels on day 8 remained high in the allogeneic graft, but markedly decreased in the syngeneic graft. Although the serum levels of nitrite and nitrate were extremely low 8 days after grafting in allografted recipients treated with DSG or FK506, the nitrosyl-Hb level in DSG-treated graft was much higher than that in FK506-treated graft. There was no significant difference in survival time between DSG-treated and FK506-treated recipients. In conclusion, DSG and FK506 have a different effect on NO production in allografted liver with ongoing rejection, and circulating nitrite and /nitrate levels do not reflect the local levels of NO in the graft. Received: 3 November 1998 Received after revision: 6 April 1999 Accepted: 14 July 1999     

Decreasing the Epstein-Barr virus load by adjusting the FK506 blood level

To prevent post-transplant lymphoproliferative disease (PTLD), the viral load must be diminished before the symptoms of Epstein-Barr virus (EBV) infection appear. Twenty-three consecutive liver transplant recipients were entered into our study to identify the characteristics of post-transplant EBV-infected patients and to clarify the correlation between the FK506 blood level and EBV load. After transplantation, EBV-DNA appeared more frequently in patients who had been seronegative before transplantation than in seropositive patients (10/13 versus 1/10; P=0.0014). As for rejection, resistance to steroid pulse therapy, and FK506 trough level, there were no significant differences between patients with and without EBV infection. In patients with primary EBV infection after transplantation, there was a strong correlation ( r=0.681) between the FK506 level and the viral load. In liver transplant recipients, especially in those seronegative for EBV, it is necessary to check the viral load by polymerase chain reaction (PCR) carefully after liver transplantation, before any symptom appears.     

Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients

OBJECTIVE: Plasma drug concentrations are generally considered to reflect efficacy and pharmacokinetics more directly than those in whole blood. However, whole blood has been selected as the matrix to monitor concentrations of tacrolimus (FK506), because it is difficult to accurately measure plasma FK506 concentrations. Because FK506 highly and saturably binds in blood cells, a change in hematocrit value (Hct) may affect FK506 pharmacokinetics. Therefore, we investigated effects of Hct on FK506 pharmacokinetics. METHODS: First, we analyzed data on FK506 distribution among human blood cells in vitro. Briefly, we employed an equation, which describes saturable binding of FK506 to blood cells, and simulated plasma FK506 concentrations and clearances using the above equation with respect to a variable Hct. Subsequently, we retrospectively analyzed dosages and whole blood FK506 concentrations to predict plasma FK506 concentrations in living donor transplant recipients. RESULTS: In the simulation study, the Hct changed plasma FK506 concentrations and clearances based in whole blood. In living donor liver transplant recipients, whole blood FK506 concentrations were maintained within a therapeutic range, while the Hct varied after transplantation. The correlation of Hct with the ratio of dose/trough concentrations of FK506 (D/C) in plasma (D/Cp) (R = -0.23, n = 343) was weaker than that for D/C in whole blood (D/CWB) (R = -0.53, n = 343). CONCLUSION: Hct may be an important factor affecting the pharmacokinetics of FK506 in living donor liver transplantation recipients. It may be necessary to take Hct into consideration in the FK506 dosing regimen, especially when the Hct is low.     

临床肝肾移植三例体会

目的　探讨肝肾序贯移植和同期联合移植的手术难点及围手术期处理要点。方法　对2例肾移植术后发生药物性肝损害的病例实施肝移植 ,并对 1例巨大多囊肝、多囊肾的病例实施肝肾联合移植。结果　 2例肾移植术后实施肝移植的病例 ,其中 1例因术后肾功能衰竭导致多器官功能衰竭死亡 ;另 1例术后肝、肾功能良好 ,现已存活 1年。肝肾联合移植病例术中采用肝后腔静脉直接阻断法 ,使重达 10kg的巨大病肝得以顺利切除 ,并采用腔静脉成型术完成改良背驮式肝移植。术后免疫方案采用人源化单克隆抗体达利珠单抗免疫诱导下的以FK5 0 6、霉酚酸酯 (MMF)和激素的三联用药 ,肝、肾功能恢复良好 ,现为术后 6个月。结论　序贯性肝肾移植在术前应该准确评估移植肾功能 ,如果移植肾功能不良 ,应果断选择实施肝肾联合移植。肝后下腔静脉直接阻断法在实施巨大病肝切除时具有较大优势。肝肾联合移植术中及术后建议采用达利珠单抗免疫诱导下的免疫三联用药。     

Distal type of renal tubular acidosis after anti-epileptic therapy in a girl with infantile spasms

An 11-month-old girl was referred to our hospital because of nausea and poor physical activity. She had a 5-month history of infantile spasms, which were successfully treated with valproic acid (VPA) and vitamin B6. Laboratory studies revealed hyperchloremic metabolic acidosis, mainly due to distal type renal tubular acidosis (RTA). Although a renal biopsy, performed 2 months after the onset of RTA, did not demonstrate tubulointerstitial lesions, her clinical course, in which administration of VPA led to an episode of RTA, with gradual subsidence on VPA removal, suggested that the probable causative agent of her distal type RTA was VPA. Although proximal type RTA associated with VPA administration has been reported, distal type is rarely seen. To our knowledge, a similar case has not been reported previously. Received: March 23, 1999 / Accepted: May 29, 1999