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.     

他克莫司替代环孢素A延缓移植肾早期发生的慢性功能丧失

目的探讨他克莫司(FK506)替代环孢素A(CsA)延缓移植肾早期发生的慢性肾功能衰竭的可行性。方法选取1999年1月至2002年5月间病理诊断为慢性移植肾肾病肾功能不全的肾移植受者93例。随机将受者分为2组,A组(50例):用FK506替换CsA,替换剂量比例约为1∶75,其它免疫抑制剂不变;B组(43例):CsA和其它免疫抑制剂均不作调整。比较两组受者3年后的肾功能、内生肌酐清除率(Ccr)减损量、血浆转化生长因子β1(TGF-β1)浓度和急性排斥反应发生率等。结果替换治疗3年后,A组有31例(62.0%)受者移植肾功能稳定或好转,而B组除4例(9.3%)肾功能稳定外,其他受者肾功能均进行性减退;A、B两组Ccr减损量分别为(0.172±0.164)ml/s和(0.359±0.292)ml/s;A、B两组血浆TGF-β1浓度分别为(17.4±8.8)μg/L和(39.5±11.0)μg/L。两组间各结果相比较,差异均有统计学意义(P<0.01)。两组急性排斥反应发生率分别为14.0%和11.6%,差异无统计学意义(P>0.05)。结论以FK506替代CsA可延缓早期发生的慢性移植肾肾病受者肾功能衰竭的速度。     

Conversion from cyclosporine to tacrolimus for chronic allograft nephropathy

We investigate the effect of conversion from a cyclosporine (CsA) based-regimen to a tacrolimus (FK506)-based regimen with respect to graft renal function induced by chronic allograft nephropathy (CAN). Thirty-one patients with a histological diagnosis of CAN were included after other causes of chronic graft dysfunction had been excluded. Conversion to FK506 was undertaken at an initial dose of 0.15 mg/kg/d, which was subsequently adjusted to maintain FK506 whole blood trough levels between 5 and 10 mug/L. The rate of decline of renal function before and after the FK506 conversion was represented by regression lines (slope) of the reciprocal of serum creatinine versus time. To evaluate the effect of conversion on allograft function, we gathered data on serum lipids, blood glucose, proteinuria, and hypertension. When postconversion slopes were compared to preconversion slopes for each patient, 20 patients (64.5%) showed positive regression lines and four patients (12.9%), less negative. Seven patients (22.6%) displayed an increased rate of decline in renal function with regression lines becoming more negative. FK506 was associated with a significant decrease in lipid levels, proteinuria, and hypertension. No patient returned to dialysis at the end of the 36-month follow-up. Conversion from a CsA-based regimen to a tacrolimus-based regimen was an effective alterative for salvage of patients with abnormal graft renal function induced by CAN.     

环孢素A转换为他克莫司对慢性移植肾肾病患者的治疗效果

目的 探讨由环孢素A(CsA)转换为他克莫司(Tac)为主的免疫抑制方案对慢性移植肾肾病(CAN)患者的治疗效果.方法 选择接受同种肾移植后发生CAN的患者153例,患者肾移植后均采用CsA、吗替麦考酚酯(MMF)及泼尼松(Pred)的免疫抑制方案.根据是否以Tac替换CsA将患者分为两组.(1)CsA组:45例,进入研究后患者维持原免疫抑制方案.(2)Tac组:108例,进入研究后将CsA转换为Tac,停用CsA后立即开始服用Tac,MMF和Pred的用法同CsA组.对所有患者随访12个月,观察人/移植肾存活率、急性排斥反应发生率、移植肾功能、24 h尿蛋白定量、移植肾穿刺病理学活检及免疫抑制剂的不良反应等指标.结果 随访12个月时,CsA组和Tac组患者存活率均为100%,移植肾存活率分别为86.6%和93.5%(P＜0.05);急性排斥反应发生率分别为4.4%(2/45)和3.7%(4/108)(P＞0.05),6例发生急性排斥反应的患者均经甲泼尼龙冲击治疗3 d后逆转.Tac组患者移植肾功能明显改善,并且出现重度蛋白尿、重度肾间质纤维化和肾小管萎缩的患者比例较CsA组显著减少(P＜0.05).Tac组有13.8%(15例)的患者出现轻度血糖增高,发生率显著高于CsA组的4.4%(2例)(P＜0.05);Tac组有22.2%(24例)的患者发生高血压,发生率显著低于CsA组的55.6%(25例)(P＜0.05);17例因使用CsA而出现牙龈增生和多毛症者,经转换治疗后,症状均明显好转.结论 由CsA转换为Tac为主的免疫抑制方案能够显著改善CAN患者的移植肾功能,延缓CAN的发展,转换过程中未发生严重Tac不良反应并且改善了使用CsA时出现的不良反应.

Abstract：

Objective To investigate the effect of conversion from cyclosporine A (CsA) to tacrolimus (Tac) on chronic allograft nephropathy (CAN). Methods 153 CAN patients undergoing kidney transplantation received CsA, mycophenolate mofetil (MMF) and prednisone (CsA-MMF-Pred) regimen after kidney transplantation, and divided into 2 groups according to whether CsA were maintained in the immunosuppressive regimen: CsA + MMF + Pred group (CsA group, n = 45); Tac + MMF + Pred group (Tac group, n = 108). The patients were followed up with patient/kidney survival rate, acute rejection incidence, renal function, 24-h proteinuria and adverse events of immunosuppressive drugs for 12 months. Results Compared with CsA group, the transplanted kidney survival rate was significantly higher in Tac group (93. 5 % vs 86.6 %, P＜0. 05). Acute rejection (AR) was diagnosed in 4. 4 % (2/45) of recipients in CsA group and 3. 7 % (4/108) in Tac group (P＞0. 05) respectively. Acute rejection (2 cases in CsA group and 4 in Tac group) was reversed by 500 mg of methylprednisolone for consecutive 3 days, and the patients in Tac group showed a significantly lower degree of interstitial fibrosis and tubular atrophy (IF/TA) (P＜0. 05).Renal allograft functions and 24-h proteinuria during a follow-up period of 12 months were significantly improved in Tac group (P ＜ 0. 05). Incidence of mild hyperglycemia in Tac Group (13.8 %, 15/108) was significantly higher than in CsA group (4.4 %, 2/45), and that of hypertension in Tac group (22. 2 %, 24/108) was significantly lower than in CsA group (55.6 %,25/45). CsA-related side effects (such as hirsutism and gingival hypertrophy) in 17 patients were greatly improved after conversion from CsA to Tac treatment. Conclusion The conversion from CsA to Tac on the patients with CAN can improve renal allograft function, retard the progression of renal allograft dysfunction, reduce the incidence of CsA-related side effects and not generate serious adverse effects of Tac.     

慢性移植肾肾病患者将环孢素A转换为他克莫司的临床观察

目的 探讨慢性移植肾肾病（CAN）患者以他克莫司（FK506）替换环孢素A（CsA）的临床效果。方法 根据是否以FK506来替换CsA，将97例诊断为CAN的患者分成两组，CsA组39例，维持原免疫抑制方案（CsA、霉酚酸酯和泼尼松联用）不变，采用替换方案的FK506组58例，除将CsA切换为FK506外，其它用药同CsA组。两组均随访1年以上，监测血胆固醇总量（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、尿素氮、肌酐、白蛋白及24h尿蛋白定量等生化指标的变化情况，观察随访期间药物的不良反应。结果 CsA组的血脂水平无明显变化，而FK506组除HDI，外，TC、LDL及TG等均较CsA组有不同程度的下降（P〈0．05，P〈0．01）。CsA组血肌酐继续上升，而FK506组的血肌酐下降，两组比较，差异有统计学意义（P〈0．01）；CsA组有3例移植肾功能丧失。FK506组需用降压药维持血压的例数少于CsA组（P〈0．05）；FK506组血清白蛋白水平显著高于CsA组（P〈0．05），24h尿蛋白定量显著低于CsA组（P〈0．01）。FK506组震颤发生率较CsA组高（P＜0．01），而高血压、毛发增多及牙龈增生的发生率均显著低于CsA组（P＜0．05）。结论 CAN患者在以FK506替换CsA后，脂质代谢异常等到明显改善，肾功能减退得到延缓。     

用他克莫司替换环孢素A预防和治疗肾移植后慢性移植肾肾病

目的 观察用他克莫司（FK506）替换环孢素A（CsA）预防和治疗肾移植术后慢性移植肾肾病的有效性和安全性。方法 回顾性分析36例肾移植术后移植肾功能异常，病理检查确诊为慢性移植肾肾病（CAN）患者的临床资料。所有患者术后均采用以CsA为主的免疫抑制方案，临床确诊为CAN后，用FKS06替换CsA。FK506的起始剂量为原CsA剂量的1／50～1／100，维持剂量则根据患者的体重、发病情况、肾移植时间及FK506的血药谷值浓度确定，其他免疫抑制剂用量不变。观察换药后的移植肾功能变化，同时监测血糖、血脂和FK506的血药浓度。结果 用FK506替换治疗6个月后，患者的移植肾功能较替换前明显好转（P＜0．05），胆固醇、甘油三酯较替换前降低（P＜0．05），但血糖升高，出现新发糖尿病2例。结论 用FK506替换CsA可改善移植肾功能，提高移植肾的长期存活率。     

Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients

BACKGROUND: A number of institutions have reported favorable results in renal transplant patients after conversion from cyclosporine (CsA) to tacrolimus at the time of acute rejection, but no prospective, controlled study has been performed to date. Here, we report the first randomized study comparing patients whose therapy was changed at a first episode of acute rejection to tacrolimus with those who were maintained on CsA microemulsion (ME). METHODS: This 3-month, prospective, open, multicenter, parallel-group study was conducted at 15 centers in seven European countries. In total, 119 renal graft recipients experiencing a first biopsy-proven acute rejection episode while receiving CsA-ME were randomized (1:1) to start tacrolimus-based therapy (n=61) or to continue CsA-ME-based therapy (n=58). RESULTS: Baseline characteristics were comparable for both groups. The initial rejection episode responded to steroid treatment in 93.4% (tacrolimus) and 63.8% (CsA-ME) (P=0.001), respectively. In patients at risk, the incidence of recurrent rejection events within 3 months was significantly lower with tacrolimus therapy (5/57, 8.8%) compared with CsA-ME therapy (15/44, 34.1%) (P=0.002). Patient and graft survival were similar in both study groups 3 months after randomization. The most frequently reported adverse events were increased serum creatinine (29.5% vs. 22.4%), hypertension (24.6% vs. 22.4%), and urinary tract infection (18.0% vs. 20.7%) for tacrolimus versus CsA-ME. Tremor was more common in tacrolimus treated-patients (17.4% vs. 2.1%, P=0.011). CONCLUSIONS: Early conversion to tacrolimus therapy benefited the resolution of acute rejection episodes and significantly reduced the risk of recurrent rejection compared with continuation of CsA-ME.     

Treatment with OKT3 and cyclosporine for acute allograft rejection

In summary, we believe that our experience with concomitant use of OKT3 and either reduced-dose CyA for treatment of renal allograft rejections or full-dose CyA therapy for treatment of liver allograft rejection is both safe and possibly more effective in reversing allograft rejection than use of the antibody alone. This strategy has also allowed us to use this MAb therapy without incurring the untoward consequence of the development of hightiter anti-OKT3 antibodies that could preclude its subsequent reuse.     

Slowing the progression of chronic allograft nephropathy by conversion from cyclosporine to tacrolimus: a randomized controlled trial

BACKGROUND: Chronic allograft nephropathy (CAN) is a multifactorial process with immunologic and nonimmunologic factors. Because tacrolimus (Tac) has been ascribed a beneficial effect on some of these factors when compared to cyclosporine A (CyA), a randomized controlled trial was conducted to investigate whether conversion from CyA to Tac can ameliorate the progression of renal dysfunction in kidney transplant recipients (KTR) with CAN. METHODS: Of the 46 patients with biopsy-proven CAN enrolled, 24 were converted from CyA to Tac, whereas 22 patients were maintained on CyA. Serum creatinine (SCrea), lipid profiles and an antihypertensive score (AHS) were determined after 3, 6 and 12 months. AHS is based on the total number and dosages of antihypertensive medications used. SCrea and AHS were additionally evaluated at 36 months. RESULTS: SCrea was decreased in the Tac group (Tac(baseline): 297 +/- 67 micromol/L; Tac(6): 261+/- 70 micromol/L, P < 0.001; Tac(12): 254 +/- 55 micromol/L, P < 0.001; Tac(36): 255 +/- 78 micromol/L, P = 0.235), whereas a significant increase of SCrea was detected in the CyA group (CyA(baseline): 279 +/- 77 micromol/L, CyA(12): 333 +/- 98 micromol/L, P < 0.001; CyA(36): 317 +/- 89 micromol/L, P < 0.001). Compared to CyA therapy, SCrea in the Tac group declined after 12 and 36 months (P = 0.011 and 0.048, respectively) as well as AHS (Tac(12): 59 +/- 13, CyA(12): 83 +/- 14, P < 0.001; Tac(36): 60 +/- 12, CyA(36): 84 +/- 14, P < 0.001). LDL cholesterol was lower in the Tac group after 12 months (Tac(12): 2.5 +/- 0.5 mmol/L, CyA(12): 3.5 +/- 0.6 mmol/L, P < 0.001). CONCLUSION: Conversion from CyA to Tac in KTR with CAN improves allograft function, lowers blood pressure, and reduces LDL cholesterol. This superior profile may translate into improved long-term graft survival.     

Early conversion from cyclosporine to tacrolimus increases renal graft function in chronic allograft nephropathy at BANFF stages I and II

Switching from cyclosporine to tacrolimus without steroid pulse was suggested as a therapeutic option in chronic allograft nephropathy (CAN). Thirty‐one renal transplant recipients with CAN were prospectively converted from cyclosporine to tacrolimus (group A), in parallel 31 matched cyclosporin A (CsA) patients (group B) without CAN were followed up for 30 months. In six matching patients of groups A and B inulin and para‐aminohippurate (PAH)‐clearances and mycophenolate were measured over a span of 3 months. Transplant biopsies of group A were scored according to BANFF. While group A presented with transplant dysfunction compared with group B before switching (2.7 ± 0.16 mg/dl vs. 1.7 ± 0.09 mg/dl; P < 0.001), transplant function was equal 30 months later: it ameliorated in group A (2.0 ± 0.18 mg/dl vs. 2.7 ± 0.16 mg/dl; P < 0.001) and decreased in group B (1.9 ± 0.13 mg/dl vs. 1.7 ± 0.09 mg/dl, P < 0.05). Especially, patients with biopsy scores I and II according to BANFF benefited from tacrolimus. Within 3 months, mycophenolate acid (MPA) levels increased under tacrolimus (P < 0.05) whereas inulin and PAH‐clearances remained unchanged. At switching, antihypertensive treatment was more intense in group B, but this difference evened out. Adverse side effects were more frequent under tacrolimus. Patients with mild to moderate CAN significantly benefited from switching to tacrolimus. Increased MPA‐levels under tacrolimus might have contributed to this effect.     

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection.

BACKGROUND: Chronic lung allograft rejection, commonly manifest as obliterative bronchiolitis (OB/BOS), hinders long-term survival after lung transplantation (LT). OB/BOS is traditionally treated with augmented immunosuppression and results in short-term stabilization in pulmonary function for most patients. However, peribronchiolar fibroproliferation and airway obstruction usually recur despite initial improvements seen with increases in immunosuppression. In this observational, uncontrolled study, the effect of sirolimus, a novel immunosuppressant with anti-proliferative activity, was assessed in LT patients with OB/BOS. METHODS: Between June 1999 to November 2000, LT recipients with newly diagnosed or progressive OB/BOS received sirolimus in combination with a calcineurin inhibitor (CI) and prednisone. Pulmonary function, laboratory data and adverse effects were monitored for the first 24 weeks of therapy. RESULTS: Sirolimus was utilized in 12 LT recipients with OB/BOS. After drug initiation, 58% of patients required a reduction in CI dose to maintain appropriate CI trough concentrations. Despite CI dose reduction, serum creatinine rose in 75% of patients. Unexpected adverse effects included anemia of chronic disease (100%), edema (50%) and malignancy (17%). For the group, the rate of change in FEV(1) and FEF(25%-75%) was unchanged with sirolimus, but individual responses varied. CONCLUSIONS: For the group, the decline in pulmonary function was not affected by the addition of sirolimus. However, among individuals with rapidly declining pulmonary mechanics, sirolimus resulted in stabilization or improvement in pulmonary function. Significant adverse effects resulted from combination sirolimus plus CI therapy. Until optimal dosing strategies and a more complete adverse effect profile are established, combination therapy should be utilized cautiously in these patients.     

Successful conversion from cyclosporine to tacrolimus for gastric motor dysfunction in a lung transplant recipient

BACKGROUND: Conversion after transplantation from cyclosporine to tacrolimus is often performed because of recurrent acute/chronic rejection or unacceptable side effects such as nephrotoxicity, arterial hypertension, and cosmetic disorders. Although gastrointestinal discomfort is often reported after transplantation, it is usually not considered a sufficient reason for conversion, although tacrolimus seems beneficial with regards to gastric motor activity in renal transplant patients. METHODS: A lung transplantation was performed in a 41-year-old woman with alpha-1 antitrypsin deficiency emphysema. Because the patient presented severe symptoms of nausea, vomiting, and dyspepsia, without obvious endoscopic explanation, that resulted in highly variable cyclosporine trough levels, she was converted from cyclosporine to tacrolimus. RESULTS: After conversion, dyspepsia, nausea, and vomiting resolved. Neurological complications caused by a transient high trough level of tacrolimus resolved completely upon dose reduction with tacrolimus trough levels remaining very stable afterwards. CONCLUSION: Tacrolimus may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastric motor dysfunction.     

Post-operative conversion from cyclosporine to tacrolimus in heart transplantation: a single-center experience.

BACKGROUND: Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients. METHODS: Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed. RESULTS: During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation. CONCLUSIONS: Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.     

Fas ligand gene transfer combined with low dose cyclosporine A reduces acute lung allograft rejection

Abstract The interaction between Fas and its ligand (FasL) induces apoptosis in the Fas‐expressing cell. We hypothesized that liposome‐mediated FasL gene transduction to the lung allograft, in addition to low‐dose immunosuppression, might reduce acute rejection. Orthotopic left lung allotransplantation was performed in male rats (Brown Norway to Fischer F344). FasL gene transfer was performed by use of the plasmid pBCMGSNeo carrying the gene coding for murine FasL and the cationic liposome GL#67:DOPE. Six hundred and sixty micrograms of DNA in 250 μl H₂O and 0.5 μmol GL#67 in 250 μl H₂O were diluted to 5 ml with saline solution. This emulsion (20 °C) was instilled retro‐gradely through the left pulmonary vein after flushing with LPD solution (20 ml, at 4 °C). Subsequently, the graft was stored at 10 °C for 3 h. A single dose of cyclosporine A (CsA; 2.5 mg/kg i. m.) was given to all groups 48 h after the transplantation. In group 1 (n = 6), FasL/GL#67 was instilled as described. In group 2 (n = 5), GL#67 was given without DNA. Group 3 (n = 5) animals received CsA only. Five days after transplantation, gas exchange was assessed after exclusion of the contralateral native lung (FiO₂ = 1.0). Grafts were flushed with saline solution and fixed in formaldehyde for histological evaluation. No statistical difference in gas exchange (PaO₂) between the two control groups 2 (6.4 ± 0.4 kPa) and 3 (7.4 ± 0.4 kPa) could be detected 5 days postoperatively (P = 0.9). In contrast, grafts transduced with FasL (group 1) had significantly better gas exchange on postoperative day 5 (PaO₂: group 1 37.0 ± 10.6 kPa vs group 2 6.4 ± 0.41 kPa; P = 0.002). Two animals in group 1 revealed no or only minimal improvement in gas exchange. Histologically, all lung specimen of all groups showed signs of acute rejection (A2). Leukocyte infiltrates, rated by two independent observers, were less severe in all group 1 animals. Liposome‐mediated FasL gene transfer at the time of harvest in combination with low‐dose CsA reduces acute rejection in four out of six animals in this model of rat lung allotransplantation.