Rescue therapy with tacrolimus (FK 506) in renal transplant recipients —a Scandinavian multicenter analysis

All renal allograft recipients (n = 32) in Sweden and Norway who were converted from cyclosporin(CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection (n = 21), chronic rejection (n = 4), and suspected CyA toxicity (n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow-up of 46 (2–143) weeks. Overall graft survival was 59%, with graft survival 52% in patients converted because of acute rejection, 50% in patients converted because of chronic rejection, and 83% in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosuppressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.     

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.     

Steroid withdrawal 3 months after liver transplantation - does FK 506 confer any advantage over cyclosporin?

Abstract Eighty-one liver recipients were randomised to FK 506 Or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-even FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-paring effect.     

FK 506 rescue therapy for intractable liver allograft rejection

Abstract Intractable liver allograft rejection remains an important cause of graft loss. In this Present study, we evaluated the role of oral FK 506 in 30 rejection episodes resistant to conventional cyclosporin-based triple immunosuppression in a series of 28 patients. Rejection was reversed in 11 (91.7%) of 12 patients for intractable acute rejection and in 10 (58.8%) of 17 patients for chronic rejection. A progressive decline in serum bilirubin was observed within 14 days in those successfully salvaged and a serum bilirubin of less than 200 μmol/1 at the time of FK 506 conversion in the chronic rejection subgroup was found to be good predictor of response (specificity 100%, sensitivity 60%). New onset diabetes mellitus (29%) and reversible renal impairment (32%) were the commonest adverse events observed. Eleven (52%) of the responding patients successfully discontinued corticosteroid medication and are currently on FK 506 monotherapy. FK 506 therapy has a significant impact in the control of both intractable acute and chronic allograft rejection with an acceptable toxicity profile.     

Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation

Abstract In order to avoid the side effects of tacrolimus (FK506), a low-dose FK506-based regimen was started from 1 June 1991. The dose was adjusted to maintain the FK506 whole blood trough level at 15–20 ng/ml for 7 days postoperatively, at 10–15 ng/ml for 2 months, and under 10 ng/ml thereafter. The graft survival rates at 3 years and 5 years were 87.8 and 82.3 % (FK506) vs 86.8 and 86.8% [cy-closporine (CyA)]. The incidence of acute rejection within the first 90 days was 31.6% in the FK506 group which was lower than the 57.1% of the CyA group ( P - 0.0585). Grades of acute rejection episodes over IIA in the FK506 group were 20 %, which was lower than the 37 % in the CyA group. The mean oral dosages of FK506 were 0.061 and 0.04 mg/kg per day at 3 and 5 years, respectively. The incidence of new onset diabetes was 27.8% in the FK506 group and 17.1 % in the CyA group. However, insulin therapy was withdrawn in all patients of the FK506 group within 5 months. The percentage of patients who required an antihypertensive agent was 28.6 % and 40 % in the FK506 group and 73.2% and 88 % in the CyA group at 1 and 3 years, respectively ( P < 0.05). Nephrotoxicity was seen in 20% of the FK506 group and 14.3 % of the CyA group. Hypercholesterolemia was less frequent in the FK506 group than the CyA group. The FK506-based regimen described here is a protocol with the potential to reduce its adverse effects. The whole blood concentration of FK506 should be monitored and blood levels maintained in the range of 5–10 ng/ml after 90 postoperative days for optimal efficacy and minimal toxicity.     

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.     

Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Liver transplantation for primary biliary cirrhosis: influence of primary immunosuppression on survival

INTRODUCTION: Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. PATIENTS AND METHODS: Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). RESULTS: The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly (P = .001) more side effects. CONCLUSION: Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.     

Activation of nuclear factor-kappa B and macrophage invasion in cyclosporin A-and tacrolimus-treated renal transplants

This retrospective study was designed to compare the efficacy of cyclosporin A (CyA) and tacrolimus (FK506) on chronic rejection (CR) associated with nuclear factor-kappa B (NF-kappaB) activation and macrophage invasion. Non-episodic day 50 protocol renal biopsy was performed in 63 consecutive patients with renal transplants from living donors, treated with either CyA or FK506. Southwestern histochemistry for NF-kappaB, immunostaining for CD68, and Banff classification were performed, and these findings were compared with outcome over 34 +/- 13 months. Compared with specimens from FK506-treated patients (n = 20), specimens from CyA-treated patients (n = 43) showed a significant increase in tubulointerstitial CD68-positive cells (1.5 +/- 0.9 vs. 0.9 +/- 0.8, p < 0.01), although no significant differences were observed in NF-kappaB activation. Specimens with Banff acute rejection (AR) grade > or = 1A (n = 20) showed increased macrophages (p < 0.01) compared with specimens with AR < 1A (n = 43). Specimens from patients with clinical AR prior to day 50 biopsy (n = 23) also showed increased macrophage invasion (p < 0.01) compared with specimens from patients without prior clinical AR (n = 40). The cumulative well-functioning (serum creatinine < 1.5 mg/dL) graft survival rate was significantly lower in patients with increased tubulointerstitial CD68-positive cells (n = 63, p < 0.05). Our findings suggest that tacrolimus is more effective than CyA against CR with respect to macrophage invasion and AR.     

肾移植急性排斥后环孢素切换成他克莫司对移植肾的影响

目的 探讨肾移植术后急性排斥发生后环孢素（CsA）切换成他克莫司（FK506）抗排斥治疗对移植肾的影响。 方法 回顾性分析本中心肾移植患者发生病理证实的急性排斥86例,经过抗排斥治疗后有23例由CsA治疗切换成FK506为基础的免疫抑制治疗（FK506组）,63例继续应用CsA为基础的免疫抑制治疗（CsA组）。比较两组临床资料,包括性别、年龄、冷和热缺血时间、淋巴毒、术前群体反应性抗体（PRA）水平、人类白细胞抗原（HLA）错配、血脂、血清肌酐、血尿酸、再次排斥的发生率和移植肾存活等情况。 结果 抗排斥治疗后1年内再次病理证实的排斥率,FK506组显著低于CsA组[1/23（4.35%）比16/63（25.40%）,P = 0.033]。FK506组急性排斥发生后5年内的移植肾存活率为100%,高于CsA组的81.4%。FK506组急性排斥发生后24个月及36个月血尿酸分别为（265.5±147.9） μmol/L和（245.8±88.9） μmol/L,均显著低于CsA组的（428.5±119.3） μmol/L和（441.2±125.3） μmol/L（P < 0.01）。 结论 肾移植术后急性排斥发生后由CsA治疗切换成FK506治疗可降低再次排斥的发生率,而降低血尿酸水平有利移植肾的存活。     

FK506与CsA在肾移植术后抗排斥的临床应用

目的 比较他克莫司(FK506)与环孢素A(CsA)预防肾移植术后排斥反应的效果和安全性。方法 肾移植患者53例分成两组,FK506组为28例,CsA组为25例。其中CsA组因肝功能损害3例,难治性急性排斥反应1例而改换成FK506。FK506起始用0.2mg·kg~(-1)·d~(-1),CsA起始用6mg·kg~(-1)·d~(-1),同时分别联合应用MMF0.75g,每日2次口服,以及术后三天大剂量甲基强的松龙(MP)静滴,第三天改强的松口服,所有病例均严密观察并行血、尿等生化分析。结果 FK506组移植肾功能好,平均7.5天脱酐水平降至平均99.5μmol/L,2例出现排斥反应,经MP连续3d冲击后治愈。CsA组19例移植肾功能良好,6例出现急性排斥,其中3例经MP连续3d冲击后治愈,2例应用OKT3后急性排斥逆转,1例术后3d出现急性排斥经MP与OKT3治疗后改换成FK506,另3例肝损害呈进行性转氨酶升高改换成FK506。FK506组有血糖升高6例(18.8%),高血压5例(15.6％),感染7例(21.9％)。CsA组血糖升高2例(9.5％),高血压5例(23.8％),感染4例(19.0%)。结论肾移植术后应用FK506疗效确切,能有效防治难治性排斥的发生、发展,降低急性排斥的发生率,特别是在乙肝抗原阳性、肝功能受损者比CsA优越。     

Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection

Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. METHOD: Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). RESULTS: Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. CONCLUSION: The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.     

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.     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

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     

他克莫司与环孢素A在尸肾移植中应用的长期疗效和安全性比较

目的　比较他克莫司 (FK5 0 6 )和环孢素A(CsA)在尸肾移植中应用的长期疗效和安全性。方法　 2 10例尸肾移植患者分为FK5 0 6组和CsA组 ,随访 12～ 32个月 ,观察两个组血药浓度变化、急性排斥和慢性排斥反应发生率、人 /肾 1年存活率、血肌酐、肝功能、血糖及血脂水平、药物不良反应、感染发生率以及FK5 0 6逆转顽固性急性排斥反应的效果。结果　血中FK5 0 6和CsA浓度谷值的变化趋势基本相同。FK5 0 6组与CsA组相比 ,急、慢性排斥反应发生率明显降低 (P <0 .0 5 ) ;肝功能异常发生率、高脂血症和牙龈增生发生率以及术后 3个月血肌酐水平均明显降低 (P <0 .0 5 ) ;高血糖和震颤发生率明显升高 (P <0 .0 5 ) ;感染发生率及人 /肾 1年存活率的差异无显著性。结论　与CsA相比 ,FK5 0 6是一种更高效的免疫抑制剂 ,长期使用可以有效降低肾移植后急、慢性排斥反应的发生率 ,有利于移植肾功能的恢复。     

Impact of changing immunosuppressive monotherapy from Cyclosporin A to Tacrolimus in long-term,stable liver transplant recipients

A number of studies have reported a lower atherogenic lipid profile in liver transplant recipients under tacrolimus (FK506) than in those under cyclosporine A (CyA) immunosuppression. This has mainly been attributed to the steroid-saving effect of FK506. However, the effects of converting CyA to FK506 monotherapy on lipid metabolism have not been specifically investigated. In 20 patients with stable graft function, immunosuppressive monotherapy was switched from CyA to FK506 because of CyA-related side-effects (hypertension, nephrotoxicity, hypercholesterolaemia). Serum lipid levels were measured before and 3, 6 and 12 months after conversion. In 5 patients, a modification of immunosuppression became necessary during the study period (4 were reconverted to CyA, 1 to glucocorticoids). In the remaining 15 patients on FK506 monotherapy, 12 months after conversion, a slight decrease in mean serum cholesterol, a slight increase in LDL, but a significant decrease in mean serum HDL were observed, resulting in a significant increase in Chol/HDL and LDL/HDL ratios. Conversion of immunosuppressive monotherapy from CyA to FK506 had no beneficial effect on the atherogenic lipid profile in this selected study population of long-term liver transplant survivors.     

普乐可复预防同种肾移植排斥反应的研究

目的 评价并比较新型免疫抑制普乐可复（ＦＫ５０６）对预防同种肾移植受者排斥反应的疗效及安全性。方法 随机将９８例肾移植受者分成２组。（１）ＦＫ５０６组（ｎ＝４０）;主要用药为ＦＫ５０６＋霉酚酸酯（ＭＭＦ）＋泼尼松（Ｐｒｅｄ）;（２）环孢素９Ａ（ＣｓＡ组）（ｎ＝５８）;主要用药为;ＣｓＡ＋ＭＭＦ＋Ｐｒｅｄ。结果 ２组受者平均随访时间为１２．５个月。     

A prospective randomized trial comparing the efficacy of tacrolimus versus cyclosporine in black recipients of primary cadaveric renal transplants.

BACKGROUND: We performed a prospective randomized trial to compare the efficacy and safety of tacrolimus (FK506) versus cyclosporine (CSA) in black primary cadaveric renal transplant (CRT) recipients. METHODS: Between December 1994 and February 1997, 35 black primary CRT recipients were enrolled in this trial. All patients received 7 days of induction therapy with OKT3. Fourteen patients received FK506 and prednisone only. Twenty-one patients received CSA, azathioprine, and prednisone. The two groups were comparable in terms of age, gender, plasma renin activity, human leukocyte antigen mismatches, and cause of renal failure. RESULTS: Patient and graft survival were 12 of 14 (86%) for the FK506 group and 20 of 21 (95%) for the CSA group (P = 0.71). Three patients died owing to cardiac events with functioning grafts. Acute rejection was 2 of 14 (14%) for the FK506 and 8 of 21 (38%) for the CSA group (P = 0.25). Two other patients on CSA were converted to FK506 as rescue for OKT3-resistant rejection. Mean serum cholesterol at 1 year was 198 +/- 45 mg/dL for the FK506 group and 244 +/- 49 mg/dL for the CSA group (P = 0.03). Mean serum creatinine at 1 year was 1.39 +/- 0.38 mg/dL for the FK506 group and 1.94 +/- 0.64 mg/dL for the CSA group (P = 0.02). CONCLUSION: Patient and graft survival were similar in both groups at 1 year posttransplant. Although statistically not significant, the incidence of acute rejection was lower in the FK506 group. Furthermore, FK506-treated patients had significantly lower serum creatinine and cholesterol levels at 1 year posttransplant.     

Augmentation of ischemia/reperfusion injury to endothelial cells by cyclosporin A

Ischemia/reperfusion (I/R) carries significant injury to endothelial cells in transplanted organs and is an important factor in chronic rejection. Immunosuppressive drugs, notably cyclosporin A (CyA) and FK506, can potentially augment this injury. Here, our goal was to determine the combined effects of I/R and CyA or FK506 on endothelial cells. Transformed mouse endothelial cells (SVEC 4-10) were subjected to ischemia or I/R for 2-24 hours by incubating cells in 100 per cent N2 (ischemia) followed by 5 per cent CO2 and 95 per cent O2 (reperfusion) for 24 hours. In separate experiments, CyA or FK506 was added to cells subjected to ischemia or I/R. Nonviable cells were determined by Trypan blue exclusion assay. All experiments (done in triplicate) were analyzed by Student's t test. Increasing ischemia times resulted in a greater number of nonviable cells (2% nonviable cells at 0 hours and 57% at 24 hours of I/R). Addition of CyA significantly increased the number of nonviable cells when compared with the control (I/R only) group (P = 0.014). Interestingly, FK506 did not increase the percentage of nonviable cells compared with the control group (P = 0.2). Unlike FK506, CyA augments I/R injury to endothelial cells in vitro. These findings could be relevant in chronic rejection and transplantation.