Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors.

BACKGROUND: The development of posttransplantation diabetes mellitus has a major impact on the quality of life and long-term outcome. METHODS: One hundred thirty-nine patients without known glucose metabolism abnormalities and treated with FK-506, methylprednisolone, and mycophenolate mofetil/azathioprine were analyzed for incidence of and risk factors for developing impaired fasting glycemia (IFG) and diabetes mellitus (DM). RESULTS: Using the American Diabetes Association criteria, 15% developed IFG and 32% developed DM in the first year after transplantation. High trough levels of FK-506 during the first month after transplantation (especially >15 ng/ml) and high body mass index (BMI) were significant risk factors for IFG or DM. Patients with (steroid-treated) acute rejections in addition to high trough levels of FK-506 were most prone to develop DM, whereas high BMI conferred risk of developing IFG. Patients with posttransplantation glycemic abnormalities also had higher levels of serum triglycerides at the time of transplantation, but they needed a lower dose of FK-506 to obtain higher trough levels of FK-506, suggesting metabolic differences already present before transplantation. The only risk factor retained for persistent IFG or DM beyond the first year was a higher number of trough levels of FK-506 >15 ng/ml during the first month after transplantation. CONCLUSIONS: Induction with an FK-506 based immunosuppressive regimen resulted in a high incidence of glucose metabolism disorders in renal transplantation recipients. Higher trough levels of FK-506 during the first month, acute rejections, and higher BMI were the most obvious risk factors.     

他克莫司抗同种肾移植排斥反应的临床研究(附136例报道)

目的 研究他克莫司（ＦＫ５０６）在同种肾移植术后抗排斥反应的效果及毒副作用。方法 １３６例肾移植患者在术后２４ｈ开始服用ＦＫ５０６,起始量０．１５ｍｇ．ｋｇ＾－１,ｄ＾－１,同时口服霉酚酸酯（ＭＭＦ）１．０ｇ／ｄ、泼尼松（Ｐｒｅｄ）３０ｍｇ／ｄ。观察ＦＫ５０６的治疗效果、理想的治疗窗及毒副反应。结果 肾移植术后１３６例应用ＦＫ５０６的患者中,肾功能２～７ｄ恢复正常为９６例,８～１５ｄ恢复正常为２３     

Effects of combination treatment with FK506 and cyclosporine on survival time and vascular changes in renal-allograft-recipient dogs

In our previous experiments studying the effects of FK506 on renal allografting in the dog, we encountered two major problems. One problem was anorexia and the other problem was vascular changes mainly in the recipient heart. Anorexia was generally dose dependent, but the vascular changes were seen to be more prominent at lower doses rather than at higher immunosuppressive doses. The present study was undertaken to study these two problems. A nonanorexic, vascular change-related, nonimmunosuppressive dose of FK506 was combined with a low dose of cyclosporine or prednisolone in beagle dogs after renal allografting. Treatment with either FK506 alone at a dose of 0.32 mg/kg or cyclosporine alone at 2.5 mg/kg was not effective in prolonging renal recipient survival. The recipient dogs died of rejection, and a variety of vascular changes were observed in the hearts of both groups. Combined treatment with FK506 and cyclosporine at these same doses resulted in statistically significant prolongation of the survival time of the renal recipient (P less than 0.01), and histologic studies showed that the frequency and severity of the vascular changes were suppressed in the recipient receiving the combined treatment. The combination of FK506 and prednisolone at 0.5 mg/kg was not effective in prolonging survival. Furthermore, the extent of vascular changes was similar to those found in recipients receiving FK506 alone. The data suggest that combined treatment with low doses of both FK506 and cyclosporine acted synergistically in prolonging canine renal allografts and that the vascular changes frequently seen at low doses of FK506 were reduced by additional immunosuppression with a low dose of cyclosporine.     

Optimal serum trough levels of FK506 in renal allotransplantation of the beagle dog

The present study was performed to estimate the optimal serum trough levels of FK506 (FK) for prophylactic use and for the treatment of acute rejection in renal allotransplantation of the beagle dog. The serum trough levels of an immunosuppressive dose of FK 1.0 mg/kg p.o. ranged from 0.1 to 0.4 ng/ml. The data indicate that the effective serum trough level is about 100 times lower than that of cyclosporine, as was already observed in previous in vitro studies. Combining treatment with a nonimmunosuppressive dose of cyclosporine of 2.5 mg/kg could lower the effective trough levels of FK. By the combining treatment, 2 out of 5 renal recipient dogs survived with well-functioning grafts as long as 60 days with the trough levels between 0.04 and 0.07 ng/ml. High-dose 5-day i.m. FK treatment of 0.5 or 1.0 mg/kg was effective in the reversal of acute rejection, with peak serum trough levels during successful rejection therapy ranging between 0.28 and 3.7 ng/ml. Two dogs died of malaise or pneumonia with peak trough levels of 2.25 and 2.78 ng/ml. Among the wide range of the effective trough levels for successful acute rejection therapy, those above 2.0 ng/ml seem to be toxic in some renal-transplanted dogs.     

Mycophenolate-Induced Hepatotoxicity Precipitates Tacrolimus Nephrotoxicity in a Kidney Transplant Recipient: A Case Report

Mycophenolate (mycophenolate mofetil [MMF]; mycophenolate sodium [MPS]) and tacrolimus (FK-506) are commonly and concomitantly used to prevent rejection in organ transplant. Mycophenolate-induced hepatotoxicity causing the reduced FK-506 metabolism with nephrotoxicity may be less appreciated, leading to inappropriate management. We describe a new living donor kidney recipient receiving pretransplant and post-transplant immunosuppressants including oral mycophenolate (MMF 1 g daily) and tacrolimus (FK-506 4-8 mg daily) who developed progressive liver dysfunction (up to 10-fold increase) despite the reduced FK-506 dosage (6 mg daily). A thorough investigation including infection, inflammation, and autoimmune hepatitis were unremarkable. With a withdrawal of MMF, his liver function improved, but persistently higher trough serum FK-506 level (12-15 ng/mL) and increased serum creatinine were notable. Moreover, the reintroduction of MPS with the reduced FK-506 dosage (4 mg daily) worsened liver function along with FK-506 nephrotoxicity (serum creatinine from 1.4-2.4 mg/dL). The replacement of MPS with mammalian target of rapamycin inhibitor not only resolved liver injury but also normalized serum FK-506 level and kidney function. Mycophenolate should be kept in mind as a cause of drug-induced hepatotoxicity that can reduce tacrolimus metabolism, leading to FK-506 nephrotoxicity and acute kidney injury in organ transplant.     

Combination use of suboptimal dose of FK 506 and cyclosporine in canine lung transplantation.

The immunosuppressive potency and the side effects of combination therapy with FK 506 and cyclosporine A were studied in dogs that had undergone lung transplantation. The animals were divided into four groups: group A (one third optimal FK 506 dose: FK 506, 0.03 mg/kg intramuscularly) (n = 5), group B (one third optimal cyclosporine dose: cyclosporine 6 mg/kg orally) (n = 5), group C (one third FK 506 and one third cyclosporine optimal doses): FK 506, 0.03 mg/kg intramuscularly plus cyclosporine 6 mg/kg orally) (n = 5), and group D (half FK 506 plus half cyclosporine optimal doses: FK 506, 0.05 mg/kg intramuscularly, plus cyclosporine, 10 mg/kg orally) (n = 10). Assessments including chest x-ray film, fiberoptic bronchoscopy, hematologic and biochemical tests, FK 506 and cyclosporine blood trough level measurement, right pulmonary artery occlusion test, and histopathologic observations were performed. In group A two of five dogs survived 28 days and three died on postoperative days 7, 14, and 21. In group B one dog survived 28 days and four died on postoperative days 9 (two dogs), 14, and 21. Histologic examination showed severe rejection in both group A and group B. In group C all five dogs survived 28 days but showed mild rejection. In group D one dog died of intestinal bleeding on postoperative day 7 and nine survived 28 days. No pathologic changes were observed except in one case of mild rejection. The ventilation function of the transplanted lung was poor in groups A, B, and C but good in group D. No abnormal rise of FK 506 and cyclosporine trough levels was observed. There were no significant side effects and abnormal hematologic and biochemical data except in one dog in group D. We concluded (1) the combination of FK 506, 0.03 mg/kg, and cyclosporine, 6 mg/kg, is much more effective than either drug used singly, (2) the combination of FK 506, 0.05 mg/kg, and cyclosporine, 10 mg/kg, prevents rejection with tolerable side effects, and (3) no worse side effects are caused by combination therapy with FK 506 and cyclosporine than by either one used singly.     

Severe elevations of FK506 blood concentration due to diarrhea in renal transplant recipients

BACKGROUND: The rate of metabolism in the intestine of oral administered FK506 decreases as FK506 passes on to the lower intestine. In transplant recipients with diarrhea given oral FK506, the main areas for absorption of FK506 shift to the lower intestine, where the ability to metabolize FK506 is weaker. Therefore it is considered likely that when FK506 is administered to recipients with diarrhea, the blood concentration of FK506 will be higher. MATERIAL AND METHODS: Twenty recipients experiencing episodes of diarrhea were investigated to determine the trough level of FK506 and the time required for the FK506 trough level to return to the level that obtained before diarrhea. AUC0-4h and Cmax of FK506 were investigated in eight recipients. In cases with severe diarrhea, the daily fluctuations of FK506 blood concentration were also investigated. RESULT: The FK506 trough level (p < 0.0001), AUC (p = 0.0173), and Cmax (p = 0.0173) were found to be significantly higher during episodes of diarrhea. In almost all cases, it took between 2 and 4 wk for the elevated FK506 trough level to return to its previous level following a bout of diarrhea. In the daily fluctuations of FK506 concentration, Tmax was prolonged. In some cases, the concentration was highest just before administration of FK506, when it should have been at trough level. CONCLUSIONS: Diarrhea caused significant elevations of trough level, AUC0-4h and Cmax of FK506, and the prolongation of Tmax in renal transplant recipients administered FK506.     

Tacrolimus- (FK 506) based immunosuppression in severe systemic lupus erythematosus

In a 30-year-old male patient systemic lupus erythematosus was diagnosed based on the presence of 8 out of 11 ARA criteria. Disease onset was acute and included renal function impairment with biopsy-proven lupus nephritis (WHO class IV) requiring renal replacement therapy. Although conventional immunosuppressive therapy regimens proved effective in controlling disease activity, all of the administered drugs were accompanied by serious side effects: bilateral femur head necrosis with corticosteroids, allergic skin reaction in response to azathioprine, nephrotoxicity with cyclosporine, nausea and abdominal pain with mycophenolate mofetil and life-threatening septicemia with cyclophosphamide treatment. In search for alternative treatment options, tacrolimus (FK506, trough serum levels 3-6 ng/ml) was started. FK506 was well-tolerated and lupus activity completely resolved within 7 months after initiation of therapy. During 36 months of follow-up no arthritic complaints occurred and renal function stabilized at a serum creatinine of 2.1 mg/dl with negative anti-ds-DNA antibodies and ANA titers. In conclusion, FK506 may be considered as alternative immunosuppressive for maintenance treatment in patients with severe lupus erythematosus and side effects to conventional regimens.     

慢性移植肾肾病患者使用他克莫司联合麦考酚吗乙酯替代环孢素为基础的免疫抑制剂方案的疗效分析

目的探讨应用以环孢素(cyclosporine,CsA)为基础免疫抑制剂的慢性移植肾肾病(chronic allograft nephropathy,CAN)患者转换为他克莫司(tacrolimus,FK506)联合麦考酚吗乙酯(mycophenolate mofetil,MMF)治疗的疗效及安全性。方法使用CsA为基础免疫抑制方案的CAN患者76例,转换为FK506+MMF,随访6个月,根据移植肾穿刺病理结果将患者分为伴有慢性排斥反应组(CR组,41例)和不伴有慢性排斥反应组(non-CR组,35例)。观察两组的疗效及不良反应。结果 CR组好转27例(66%),稳定9例(22%),无效5例(12%);non-CR组好转11例(31%),稳定15例(43%),无效9例(26%),CR组疗效优于non-CR组(P0.05)。CR组和non-CR组转换后,24h尿蛋白定量均有所降低,高血压和高脂血症的病例数有所减少,而且未出现继发性高血糖、严重感染等不良反应。结论 CAN患者使用FK506+MMF替代CsA为基础的免疫抑制剂方案是安全有效的。     

肾移植术后肝功能异常患者用他克莫司替换环孢素A疗效的初步观察

目的　观察他克莫司 (FK5 0 6 )替换环孢素A(CsA)并联合应用霉酚酸酯 (MMF)及泼尼松 (Pred)防治肾移植术后肝功能异常患者的有效性及安全性。方法　肾移植术后 8例肝功能异常患者 (男性 5例 ,女性 3例 ,平均 38.2 3岁 ) ,用FK5 0 6替换CsA治疗 ,停用CsA 2 4h后 ,开始给予FK5 0 6。FK5 0 6初始剂量根据患者体重、肝功能损害程度及术后时间确定 ,服药 1周后 ,根据全血FK5 0 6谷值浓度调整剂量 ,使其谷值浓度维持于 5～ 15 μg/L。结果　用FK5 0 6替换CsA ,1个月后患者血中直接胆红素从替换前的 (2 2 .6 6± 17.19) μmol/L下降至 (7.0 5± 2 .32 ) μmol/L ,P <0 .0 5 ;间接胆红素从替换前的 (4 2 .15± 34.15 ) μmol/L下降至 (14.5 4± 2 .5 9) μmol/L ,P <0 .0 5 ;血清丙氨酸转氨酶从替换前的 (83 .0 0± 93 .14)IU/L下降至 1个月后的 (2 9.5 0± 15 .41)IU/L ,P >0 .0 5 ;血清肌酐从 (177.91±86 .41) μmol/L下降至 (135 .92± 34.0 5 ) μmol/L ,P >0 .0 5。 3例腹水的患者均于药物替换 1个月后完全消失。仅有 1例患者出现便秘、食欲下降伴上肢颤抖。结论　用FK5 0 6替换CsA并联合应用MMF及Pred对防治肾移植术后肝功能异常是安全和有效的措施     

采用程序化肾活检评估肾移植后低水平和标准水平他克莫司的疗效

目的以程序化肾活检评估低水平与标准水平他克莫司(FK506)的免疫抑制方案的疗效及其安全性。方法采用前瞻性、开放、随机对照研究,将48例首次接受尸体肾移植受者按随机数字分为两组:低水平FK506组(低FK506组,24例)和标准水平FK506组(标准FK506组,24例)。两组患者均采用麦考酚吗乙酯(MMF)+FK506+肾上腺皮质激素(激素)的三联免疫抑制方案,两组的MMF与激素用法相同。标准FK506组的FK506血药谷浓度:在入组后前3个月维持在10～12 ng/ml,3个月后维持在8～10 ng/ml。低FK506组的FK506血药谷浓度:入组后头2个月为8～10 ng/ml,第3个月为3～7 ng/ml,3个月后为3～5 ng/ml。术后定期随访1年,内容包括测定FK506血药谷浓度,检测肾功能[血清肌酐(Scr)、内生肌酐清除率(endogenous creatinine clearancerate,Ccr)]、空腹血糖、糖化血红蛋白、血清白蛋白、血脂。同时于术后3个月和12个月予以程序化移植肾活组织检查(活检),了解急性排斥反应(AR)发生情况、病理损伤指标评分及慢性移植物损伤指数(chronic allograft damage index,CADI)变化。观察术后1年的人、肾存活率及不良事件发生情况。结果移植术后1年,与标准FK506组比较,低FK506组:(1)FK506血药谷浓度较低(P<0.01),且达到目标水平的患者所占比例较高;(2)Ccr水平较高,(83±14)ml/min比(62±16)ml/min,P<0.05;(3)血糖水平较低(P<0.05);(4)根据程序化肾活检的结果,间质纤维化、肾小管萎缩和肾小球硬化评分较低(均为P<0.05);(5)AR发生率及其严重程度相似,术后1年人、肾存活率相近,均为100%(均为P>0.05)(6)术后1年的肺部感染与新发糖尿病的发生率较低(分别为P<0.05和P<0.01)。结论采用程序化肾活检评估疗效结果可靠,并有助于发现移植肾的慢性化改变,移植术后早期适度降低FK506血药谷浓度对于移植肾和患者均有较大益处,且不增加发生排斥反应的风险。     

肾移植术后患者应用西罗莫司对他克莫司剂量的影响

目的观察肾移植术后联合应用西罗莫司(雷帕霉素)对他克莫司(FK506)剂量的影响。方法60例肾移植术后患者随机分为两组,研究组30例,免疫抑制方案采用西罗莫司+他克莫司+泼尼松;对照组30例,采用麦考酚吗乙酯(MMF)+他克莫司+泼尼松联合治疗。术后随访2年,比较两组的人、肾存活率,急性排斥反应率,他克莫司用量,肾功能变化和不良事件发生率。结果研究组、对照组全部如期完成观察,两组的人肾存活率均为100%,研究组、对照组急性排斥反应发生率分别为7%(2/30)、10%(3/30),经肾上腺皮质激素(激素)冲击治疗后逆转;研究组在维持他克莫司血药浓度与对照组相当情况下,其用量低于对照组,比较差异有统计学意义(P0.05)。两组的不良事件发生率相近(60%比70%,P0.05)。结论联合西罗莫司+他克莫司+泼尼松方案用作肾移植术后免疫抑制治疗是安全有效的,且能减少他克莫司的剂量。     

Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil.

The management of liver transplant recipients with renal function impairment remains controversial because cyclosporine withdrawal from triple immunosuppression regimens may be followed by graft rejection. A nonnephrotoxic and powerful immunosuppressant such as mycophenolate mofetil (MMF) could allow a reduction of cyclosporine dosage or its withdrawal and an improvement in renal function in these patients. Eleven patients with serum creatinine levels greater than 1.5 mg/dL, normal graft function, and a rejection-free period of at least 1 year started MMF at a dose of 2000 mg/d (reduced in case of adverse events) while cyclosporine dosage was slowly reduced. At last follow-up (63 +/- 5 weeks), 7 patients remained free of cyclosporine (6 of those patients are also free of steroids), 2 patients reduced their cyclosporine dose, and 2 patients developed mild acute rejection that responded to a switch to tacrolimus therapy. Serum creatinine and urea levels in the 7 patients free of cyclosporine decreased from 2.22 +/- 0.13 to 1.90 +/- 0.19 mg/dL (P =.05) and 0.95 +/- 0.10 to 0.60 +/- 0.10 g/L (P <.001), respectively. Creatinine clearance increased from 38.16 +/- 5.60 to 47.01 +/- 6. 76 mL/min (P =.005). Control of arterial hypertension also improved. Tolerance to MMF was good, but 6 patients required dose reductions, mainly because of asymptomatic anemia. In conclusion, in liver transplant recipients with stable graft function, MMF may allow cyclosporine dose reduction or discontinuation, thus improving renal function and the control of arterial hypertension. This change of treatment must be carefully monitored because of the frequent need for MMF dose reduction and the risk for rejection.     

Mycophenolate mofetil monotherapy in stable liver transplant patients with cyclosporine-induced renal impairment: a preliminary report.

BACKGROUND: Cyclosporine is the most common maintenance immunosuppressant in liver transplants patients, but it is often associated with nephrotoxicity. METHODS: We evaluated the safety and efficacy of monotherapy with mycophenolate mofetil (1 g twice daily) in five stable liver transplant patients with cyclosporine-induced renal impairment despite reduction of cyclosporine to subtherapeutic levels. Follow-up was 8.4+/-2.4 (range: 6-12) months. RESULTS: No major side effects have been observed to date. Serum creatinine levels were significantly reduced from a median of 201 micromol/L before to 142 micromol/L at 3 months after mycophenolate (P=0.04) and remained low at 6 months. New onset cellular rejection occurred in only one patient after 3 months on mycophenolate monotherapy, and it responded completely to an intravenous course of methylprednisolone. CONCLUSIONS: Monotherapy with mycophenolate mofetil in a dose of 1 g twice daily seems to significantly improve cyclosporine-induced renal impairment in stable liver transplant patients without major side effects or significant risk of rejection.     

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.     

Dosing of MMF in combination with tacrolimus for steroiD-resistant vascular rejection in pediatric renal allografts

Abstract SteroiD-resistant vascular rejection was treated in seven adolescent renal allograft recipients using the combination of mycopheno-late mofetil (MMF) and tacrolimus (FK506). Since there are no published pediatric dose recommendations for MMF using this combination, trough concentrations and pharmacokinetic profiles were used for therapeutic drug monitoring. In order to keep the mycophenolic acid (MPA) concentrations between 2–5 μg/ml, mean MMF doses were reduced from 600 to 250 mg/m² b. i. d. Apparent clearance of MPA decreased from 5 to 1 ml/min per kg within 2 weeks. Pharmacokinetic monitoring revealed substantial variability among patients of both MMF and FK506. The MPA dose ranged from 178 to 1008 mg/m² per day to achieve an area under the curve (AUC) of 59.9 μg × h/ml ± 10.5 SD (range 49–65 μg). FK506 dose ranged from 1.3 to 8.8 mg/m² per day to achieve an AUC of 116 ng × h/ml ± 27 SD (range 83–145). We recommend adjusting MMF doses using therapeutic drug monitoring.     

Effects of immunosuppressants on induction of regulatory cells after intratracheal delivery of alloantigen

BACKGROUND: We previously reported that intratracheal delivery (ITD) of alloantigen generated regulatory cells in mice. Here, we examined the effect of various doses of conventional immunosuppressants (FK506, cyclosporine A, azathioprine, mycophenolate mofetil, and rapamycin) on inducing regulatory cells in our model. METHODS: CBA mice (primary recipients) were given C57BL/6 splenocytes by ITD and either no additional treatment or various doses of an immunosuppressant. Seven days later, splenocytes from these mice were adoptively transferred into naive secondary CBA recipients that underwent C57BL/6 cardiac grafting the same day. RESULTS: Adoptive transfer from primary recipients given ITD of splenocytes alone induced prolonged allograft survival in secondary recipients (median survival time [MST], 50 days), suggesting that regulatory cells were generated. When ITD of alloantigen was combined with daily administration of 0.1 mg/kg FK506 or 0.2 mg/kg rapamycin, graft survival was similarly prolonged (MST 55 and 50 days, respectively). When combined with 20 or 40 mg/kg MMF or 0.4 mg/kg rapamycin, the majority of recipients demonstrated indefinite survival (MST, >100 days in all groups). When ITD of alloantigen was combined with 0.3, 0.5, or 1.0 mg/kg FK506; 5, 10, or 25 mg/kg cyclosporine A; or 1.0 or 2.0 mg/kg azathioprine, allografts were rejected acutely (MST 7-13 days). CONCLUSION: Generation of regulatory cells by ITD of alloantigen was facilitated by mycophenolate mofetil and high doses of rapamycin but abrogated by cyclosporine A, azathioprine, and high doses of FK506. Low doses of rapamycin and of FK506 did not interfere with generation of regulatory cells.     

The use of FK-506 for small intestine allotransplantation. Inhibition of acute rejection and prevention of fatal graft-versus-host disease.

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F1 progeny are performed so that graft rejection alone is genetically permitted (F1----LEW) or GVHD alone permitted (LEW----F1) or that both immunologic processes are allowed to occur simultaneously (ACI----LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI----LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.     

Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy--a clinicopathologic study of 96 patients.

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.     

肾移植早期快速激素减量安全性分析

目的观察肾移植受者早期快速激素减量的安全性。方法 108例肾移植受者,在含肾上腺皮质激素(激素)的常规三联免疫抑制方案的基础上,分别接受抗胸腺细胞免疫球蛋白(ATG)或抗CD25单抗诱导治疗,于肾移植术后1个月末泼尼松减量至5～10 mg/d。统计术后1、2和3年人/肾存活率,术后1年内的急性排斥反应发生率、移植后感染发生率;记录术后1、6、12个月泼尼松的用量及环孢素(CsA)、他克莫司(FK506)、麦考酚吗乙酯(MMF)的用量,随访期间监测血压、血清肌酐(Scr)、空腹血糖水平。结果受者术后1、2和3年人/肾存活率分别为98%/95%、96%/96%和93%/93%。术后1年急性排斥反应发生率为13%,移植后感染发生率为13.9%。术后12个月内,肾移植受者CsA、FK506、MMF平均用量呈下降趋势。术后1、3、6、12个月泼尼松用量分别为(9.26±2.11)mg/d、(7.42±2.20)mg/d、(6.15±1.94)mg/d、(6.24±2.18)mg/d。术后1年血清肌酐水平为(100±23)μmol/L,收缩压为(127±10)mmHg,舒张压为(81±6)mm-Hg,空腹血糖水平为(5.35±1.44)mmol/L。结论在小剂量抗体诱导、保证钙调磷酸酶抑制剂(CNI)目标浓度,保证机体处于足量免疫抑制的情况下,肾移植术后1个月内快速减少激素至5～10mg/d,移植肾功能正常稳定,同时有助于减少激素不良反应,减少移植后近期感染风险,安全性良好。