Sirolimus conversion in liver transplant recipients with renal dysfunction: a prospective, randomized, single-center trial

This pilot trial was designed to assess the safety and efficacy of SRL in liver transplant recipients with renal dysfunction. Forty patients with renal dysfunction (24-hr CrCl 40-80 mL/min) were randomized to be withdrawn from the calcineurin inhibitor (CNI) and receive sirolimus (SRL) or to continue CNI (control arm). Improvement in 24-hour CrCl was seen in the SRL arm at 3 months (75 mL/min SRL vs. 56 mL/min control, P=0.012), whereas at 12 months there was a trend toward improvement in the SRL arm (72 mL/min SRL vs. 58 mL/min control, P=0.09). Two patients, one in each arm, developed steroid-sensitive rejection. Side effects of SRL were limited and included hyperlipidemia requiring treatment (15%), pruritis (5%), and mouth sores (25%). In this trial, SRL-based immunosuppression was a safe alternative to CNI. Although early improvements were observed, withdrawing CNI and replacing it with SRL did not result in a statistically significant improvement in renal function at 12 months of follow-up.     

A randomized controlled trial of late conversion from calcineurin inhibitor (CNI)-based to sirolimus-based immunosuppression in liver transplant recipients with impaired renal function.

Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m2; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m2; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P=0.02), but not at 12 months (P=0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.     

Sirolimus-based immunosuppressive therapy in liver transplant recipient with tacrolimus-related chronic renal insufficiency

BACKGROUND: While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity. METHODS: Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion. RESULTS: Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 +/- 12.48 micromol/L to 130.1 +/- 5.573 micromol/L), and over the next 60 days after conversion (97.86 +/- 11.69 micromol/L to 90.7 +/- 8.95 micromol/L) (P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period. CONCLUSIONS: SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.     

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation

Early conversion to a calcineurin‐inhibitor (CNI)‐free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1‐year renal function as compared with a cyclosporine (CsA)‐based regimen (SMART core‐study). This observational follow‐up describes 132 patients followed up within the SMART study framework for 36 months. At 36 months, renal function continued to be superior in SRL‐treated patients [ITT‐eGFR_@36m: 60.88 vs. 53.72 (CsA) ml/min/1.73 m², P = 0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36 months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA‐treated patients. In a multivariate analysis, donor age >60 years, S‐creatinine at conversion >2 mg/dl, CMV naïve(‐) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36 months. Early conversion to a CNI‐free SRL‐based immunosuppression is associated with a sustained improvement of renal function up to 36 months after transplantation. Patient selection will be key to derive long‐term benefit and avoid treatment failure using this mTOR‐inhibitor‐based immunosuppressive regimen.     

西罗莫司在肝移植术后肾功能异常患者中的应用

目的 探讨西罗莫司替换钙调磷酸酶抑制剂治疗肝移植术后肾功能不全的安全性和有效性.方法 北将肝移植术后发生肾功能不全的62例患者随机分为对照组和转换组.对照组29例,继续采用Tac(或CsA)、MMF及Pred的方案,血Tac(或CsA)浓度调整在治疗窗范围的下限;转换组33例,用SRL替换原方案中的Tac(或CsA),SRL的起始用量为2 mg/d,以后根据血SRL浓度及不良反应作相应调整,Tac(或CsA)减少至原用量的1/3～1/2,3 d后停用,MMF和Pred的用法不变.转换治疗后,对患者的肝肾功能、急性排斥反应及存活率进行随访监测,并观察患者在转换治疗期间发生的不良反应.结果 共有49例患者痊愈或者好转,13例死亡,对照组死亡8例,转换组死亡5例.随访9～51个月,转换组存活患者肝功能稳定,均未发生急性排斥反应.两组存活患者肾功能恢复后均未再出现反复,且转换组患者肾功能恢复时间明显缩短,治疗效果较好.转换组存活患者未发生严重不良反应,与对照组肺部感染发生率的比较,差异无统计学意义(P>0.05).结论 肝移植术后并发肾功能不全时,采用西罗莫司替换原免疫抑制方案中的CNI治疗是安全有效的.     

Impact of Calcineurin‐Inhibitor Conversion to mTOR Inhibitor on Renal Allograft Function in a Prednisone‐Free Regimen

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone‐free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow‐up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy‐proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone‐free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.     

Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients.

Sirolimus (SRL) has been proposed to replace calcineurin inhibitors (CNI) in case of CNI-induced toxicity. The aim of this study was to evaluate the efficacy and safety of conversion from CNI to SRL in maintenance liver transplantation (LT) patients. Between 2002 and 2006, conversion was performed in 48 patients (17 female, 31 male; mean age 57 +/- 10 yr) after a median delay of 19.4 months (range 0.2-173 months) after LT. Indication for conversion was renal impairment (RI) (78%), CNI neurotoxicity (13%), or post-LT cancer (9%). Median follow-up was 22.6 +/- 11 months. Median SRL dosage and trough levels were 2.4 +/- 1.3 mg and 8.1 +/- 2.7 microg/L. Immunosuppression consisted of SRL alone (33%), or SRL + mycophenolate mofetil (MMF) (39%), SRL + prednisone (15%), SRL + CNI (4%), or SRL + MMF + prednisone (8%). Mean glomerular filtration rate (GFR) improved from 33 to 48 mL/minute in patients with severe RI (P = 0.022) and from 56 to 74 mL/minute in patients with moderate RI (P = 0.0001). After conversion, main complications were albuminuria (36%), hyperlipidemia (49%), dermatitis (14%), edema (14%), oral ulcers (12%), joint pain (4%), infection (2%), and pneumonia (2%). Acute rejection (AR) occurred in 17% of the patients. SRL was withdrawn in 17% of the patients. In conclusion, conversion from CNI to SRL is safe and is associated with significant renal function improvement.     

Influence of sirolimus on proteinuria in de novo kidney transplantation with expanded criteria donors: comparison of two CNI-free protocols.

BACKGROUND: The contribution of mammalian target of rapamycin (mTOR) inhibitors to proteinuria is controversial. The aim was to analyse proteinuria in suboptimal kidney calcineurin inhibitor-(CNI) free de novo immunosuppression. METHODS: All patients from our centre with donors >60 years and CNI-free treatment were included (n = 108). Patients were divided into two groups: (i) SRL group: sirolimus (SRL) + prednisone + mycophenolate mofetil (MMF) + antiCD25; (ii) MMF group: prednisone + MMF w/ or w/o antiCD25 (n = 75). Follow-up was 12 months. RESULTS: Donors were slightly younger in the SRL group (68 vs 71 years; P < 0.05), receptor age (67 vs 65 years) was not significantly different. Patient survival in the MMF group was 88 vs 94% in the SRL group, however, these differences did not reach statistical significance. One-year graft survival censored for death was 83% in the MMF group and 94% in the SRL group. Acute rejection rate was 45% in the MMF and 15% in the SRL group (P < 0.01). The incidence of CNI introduction was higher in the MMF-group (35 vs 5; P < 0.05). The intention-to-treat analysis revealed significant differences of proteinuria [SRL vs MMF at 12 months: 461 (163-6988) vs 270 (53-3029) mg/day], which did not exist in the on-therapy (OT) analysis [SRL vs MMF at 12 months: 357 (199-1428) vs 279 (53-3029) mg/day]. New onset nephrotic range proteinuria seemed to occur slightly more frequently in SRL patients (3/33 vs 1/75; P = 0.049), however, all four cases occurred in a context of recurrent disease, or previous drug-independent damage or non-adherence. All of these patients were converted to CNI. CONCLUSION: SRL-based compared with MMF-based treatment in kidney transplantation with advanced age donors is associated with an acceptable outcome, however, with increased proteinuria in the intention-to-treat analysis. A large subgroup of the patients in the MMF group experienced acute rejection and required conversion to CNI.     

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.     

A Randomized Controlled Trial of Late Conversion from CNI-Based to Sirolimus-Based Immunosuppression Following Renal Transplantation

Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimus-based immunosuppression would affect the progression of renal impairment. In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-to-treat. Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode. In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.     

肝移植术后根据肝活检结果转换西罗莫司治疗:附12例报告

目的 探讨肝移植术后西罗莫司转换治疗后的有效性与安全性.方法 对12例肝移植术后完全停用钙调磷酸酶抑制剂(calcineurin Inhibitor,CNI)改用西罗莫司治疗至少1个月以上的病人进行随访,观察转换治疗后排斥反应的发生及CNI相关肾功能损害和肝功能恢复情况.结果 12例肝移植病人术后平均11个月开始西罗莫司转换治疗,治疗时间平均为14个月,平均随访时间为37个月.采用西罗莫司转换治后,12例中有6例肝穿证实未出现排斥反应.发生CNI相关肾损害的7例中有5例肾功能恢复正常,但有1例反而引起蛋白尿.反复肝功能异常的4例没有改善.结论 我们的小样本临床资料表明,对于某些经过选择的肝移植病人,例如合并CNI相关性肾损害者,可以尝试在肝穿活检指导下进行西罗莫司转换治疗.     

Differences in proteinuria and graft function in de novo sirolimus-based vs. calcineurin inhibitor-based immunosuppression in live donor kidney transplantation

BACKGROUND: Calcineurin inhibitor(CNI)-free protocols using sirolimus (SRL) in kidney transplantation have proven effective, although reports have linked SRL to proteinuria. We sought to investigate this link and its impact on graft function. METHODS: We retrospectively analyzed 184 live donor kidney transplant recipients who exclusively received de novo CNI-based (n = 106) or SRL-based (n = 78) regimens. Estimated glomerular filtration rate (GFR) and semi-quantitative dipstick proteinuria measurements were obtained at one, six, 12, and 24 months and six and 12 months, respectively. RESULTS: SRL-treated patients had higher frequencies of proteinuria (> or =1+) at 6 months (40.8% vs. 21.4%, P = 0.006) and 12 months (37.8% vs. 18.4%, P = 0.004) than those treated with CNI. Independent predictors of proteinuria at 12 months were GFR at one month (OR 0.62 per 10 ml/min/1.73 m, P<0.001), delayed graft function (OR 11.5, P = 0.02), and a SRL-based regimen (OR 4.18, P=0.002). By univariable analysis, SRL vs. CNI patients had higher GFR at each point. SRL-treated patients without proteinuria had higher GFR at 12 months compared to CNI-treated patients with and without proteinuria (66 vs. 50 or 56 ml/min/1.73 m, P < 0.05). No difference in GFR was seen between SRL-treated patients with proteinuria vs. CNI-treated patients without proteinuria (57 vs. 56 ml/min/1.73 m, P > 0.05). Absence of proteinuria and a SRL-based regimen remained independently associated FS with higher GFR at 12 months by multivariable analyses. CONCLUSIONS: De novo SRL-based immunosuppression is associated with a higher frequency of semi-quantitative proteinuria, however, estimated graft function at 1 year posttransplant remains superior to that of CNI-treated patients. Nevertheless, the long-term implications of these findings need to be determined.     

Conversion to Sirolimus in Renal Transplant Recipients: A Single‐Center Experience

Maintenance immunosuppression with calcineurin inhibitors (CNI) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. Sirolimus (SRL) is a nonnephrotoxic immunosuppressive agent. We retrospectively analyzed our experience with kidney transplant recipients who were converted from CNI to SRL. A total of 58 renal transplant recipients were converted from CNI to SRL. SRL was started at a dose of 0.075 mg/kg and, at the same time, CNI dose was reduced by 50% daily for 3 days. SRL trough levels were targeted between 8 and 12 ng/mL. When target trough levels were achieved, CNI was withdrawn. The main indications for switching were posttransplant malignancies (n = 32) and chronic allograft nephropathy (CAN) (n = 10). The mean time from transplantation to conversion was 84 ± 71 months. Mean serum creatinine level was 1.63 ± 0.52 mg/dL before conversion. Serum creatinine levels at the 1, 3, 6 months, and 1, 2, 3 years after conversion were 1.64 ± 0.58 mg/dL (P = 0.67), 1.52 ± 0.53 mg/dL (P = 0.414), 1.62 ± 0.62 mg/dL (P = 0.734), and 1.48 ± 0.58 mg/dL (P = 0.065), 1.58 ± 0.53 mg/dL (P = 0.854), 1.88 ± 0.77 mg/dL (P = 0.083), respectively. Daily proteinuria levels increased from 0.04 ± 0.11 g/day at baseline to 0.55 ± 1.33 g/day (P = 0.037) after conversion, in the responders group. In the nonresponders group, baseline proteinuria was 0.13 ± 0.25 g/day, and increased to 1.44 ± 2.44 g/day after conversion (P = 0.008). SRL was discontinued in 16 patients (31%) because of the occurrence of severe side effects. The proportion of patients remaining on SRL therapy over time was 43.1% at 1 year, 15.5% at 2 years after conversion, and 10.3% at 3 years after conversion. SRL conversion may be very useful in patients suffering from neoplasia; however, frequent side effects related with this intervention should be considered, and routine conversion from CNI to SRL to reduce nephrotoxicity should be discouraged.     

Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial

As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.     

Sirolimus dosage during and after conversion from calcineurin inhibitor therapy to sirolimus in chronic kidney transplant patients

Sirolimus (SRL) is an alternative to calcineurin inhibitors (CNI) in kidney transplant patients with chronic allograft dysfunction. METHODS: 33 patients were converted to SRL receiving a single loading dose of 15 mg and initial maintenance dose of 5 mg/day. CNI was reduced by 50% on day 1 and tapered during 4-6 weeks after achieving SRL target (8-12 ng/ml). Concomitant immunosuppressive therapy remained unchanged. RESULTS: Patient survival was 100% and graft survival was 85% after 1 year. Mean SRL dose decreased from 5 mg/day initially to 2.8 +/- 1.3 mg/day. SRL dose-adjusted trough concentration did not change significantly over time. Dose-adjusted trough concentrations of CNI before conversion and of SRL after 1 year did not correlate. We observed no severe infections, however, one rejection Banff Ia occurred 7 months after conversion associated with subtherapeutic SRL trough concentration. Adverse events were anemia, dyslipidemia, epistaxis, stomatitis, and bronchiolitis obliterans which occurred mainly during the conversion phase. CONCLUSION: Overlapping conversion from CNI to SRL in chronic kidney transplant patients is possible and safe. However, further studies are necessary with shorter overlap and lower SRL loading and initial maintenance dose which might lead to a decrease in the high number of adverse events in the overlap phase.     

Sirolimus in pediatric renal transplantation

Side effects of calcineurin inhibitors (CNIs) include nephrotoxicity and hypertension. Moreover, children have a higher risk of infections and posttransplantation lymphoproliferative disorders. We retrospectively evaluated the efficacy and safety of Sirolimus (SRL) in 18 patients, who were 10.52 +/- 5.03 years at time of transplantation and received a CNI as the core immunosuppression. The most common indications for starting SRL therapy were chronic allograft nephropathy, Epstein-Barr virus-associated neoplasia, and thrombotic microangiopathy. The patients were converted to SRL at 49.14 +/- 45.9 months posttransplantation. Mean follow-up after the switch to SRL was 13.83 +/- 7.24 months. All patients who began SRL therapy remained on that medication. We observed a significant improvement (P < .05) in glomerular filtration rate assessed using the Schwartz formula at 3 months, which was sustained thereafter. There were no changes in proteinuria, plasma lipids, and platelet number. Although the prevalence of hypertensive patients decreased during follow-up, it was not significant. There was one steroid-sensitive, acute rejection episode. Serious adverse events included 1 death due to a relapse of B lymphoma, 1 sepsis, and 1 pancreatic pseudo-cyst. Adverse events were present in 17% of patients: 3 Herpes Simplex infections, and 1 dose-related lymphedema. Further studies are necessary to assess the impact of adverse events in the pediatric transplant population receiving SRL as immunosuppression.     

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination

BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.     

哪些患者可以从转换西罗莫司中受益?

目的 评价西罗莫司(SRL)替代钙调磷酸酶抑制剂(CNl)类药物的安全性和可行性.方法肾移植术后>3个月,以CNI为基础免疫抑制剂患者157例,按转换SRL的原因分A组(计划性转换,62例)、B组(SCr升高,50例)、C组(高胆红素,37例)和D组(肿瘤,8例),以SRL为基础免疫抑制剂,撤除CNI类药物,观察急性排斥反应和不良事件发生率,随访时间为6个月. 结果 移植肾和患者均存活.发生急性排斥反应2例.SCr和尿酸在转换后1个月开始下降,而肌酐清除率(CCr)开始升高,转换前后尿酸比较差异有统计学意义(P<0.01).A组转换前和转换后1个月SCr分别为99.04、91.86 μmol/L,转换前后比较差异有统计学意义(P<0.01);CCr转换前为70.50ml/min,转换后升至78.27 ml/min.B组转换前和转换后1个月SCr分别为142.96、128.15/μmol/L,CCr分别为47.66、53.38 ml/min.C组SCr分别为97.09、88.34 μmol/L,CCr分别为69.38、75.66 ml/min.D组SCr分别为97.46、88.91 gmol/L,CCr分别为62.29、67.64 ml/min.C组总胆红素和直接胆红素分别由转换前的平均30.45和15.15 μmol/L降至转换后12.13和3.70μmol/L,转换前后比较差异有统计学意义(P<0.01).转换后主要不良事件包括:发热11例(7.0%);总胆固醇和甘油三酯升高者分别由转换前的36例(22.9%)和57例(36.3%)增至转换后的58例(36.9%)和73例(46.5%);转换前有蛋白尿13例(8.3%),转换后增至18例(11.5%). 结论 肾移植术后早期将CNI类药物转换为SRL安全、有效.SCr已升高者要尽早转换SRL治疗,CNI导致高胆红素、高尿酸血症和移植后肿瘤患者均可从转换SRL中受益.     

The effect of sirolimus in the development of chronic allograft nephropathy

PURPOSE: The effect of sirolimus (SRL) in renal function was studied in renal transplant recipients. PATIENTS AND METHODS: We studied 20 patients who underwent live related kidney transplantation 1 to 2 years prior under cyclosporine (CsA) treatment and displayed serum creatinine values between 2 and 3 mg/dL. The patients were randomized into 2 groups prospectively. The calcineurin inhibitors (CNI) group continued taking CsA; the SRL group underwent a switch from CsA to SRL. Biopsies were performed to assess chronic allograft nephropathy (CAN) findings and TGFbeta1 in the transplanted kidneys at the beginning and the end of the study. Creatinine clearance, serum creatinine, and proteinuria values were detected in the beginning as well as at 1, 3, 6, and 12 months later. RESULTS: At the beginning of the study, the creatinine clearance and serum creatinine levels were 52.21 mL/min and 2.05 mg/dL in the CNI group and 47.76 mL/min and 2.13 mg/dL in the SRL group, respectively. At 12 months, these values were 48.11 mL/min and 2.57 mg/dL in the CNI group and 50.45 mL/min and 2.12 mg/dL in the SRL group, respectively. Creatinine clearance values between the 2 groups at 12 months were statistically different. Although it was not significant, there was a tendency toward decreases inflammatory infiltration and TGFbeta1 levels in the SRL group compared with the CNI group on the second biopsies. CONCLUSION: Pathologic findings of CAN development, serum creatinine, and creatinine clearance values were ameliorated in the SRL group. We concluded that SRL positively affected long-term graft survival.     

High Incidence of Rejection Episodes and Poor Tolerance of Sirolimus in a Protocol With Early Steroid Withdrawal and Calcineurin Inhibitor–Free Maintenance Therapy in Renal Transplantation: Experiences of a Randomized Prospective Single-Center Study

Immunosuppressive maintenance therapy after kidney transplantation leads to various undesired side effects such as calcineurin inhibitor (CNI)–associated nephrotoxicity or elevated cardiovascular risk due to posttransplantation diabetes and hypertension. These effects show negative impacts on long–term allograft function as well as patient morbidity and mortality. Therefore, we used an immunosuppressive regimen with early corticosteroid withdrawal (ESW), maintenance therapy containing tacrolimus, sirolimus (SRL), and mycophenolate sodium for 3 months followed by a prospective randomized trial comparing a CNI free versus a low-dose CNI therapy. The primary endpoint was 6-month graft function. Among 75 patients, ESW was performed after 4 days in 65 patients. Over the following 3 months before randomization to CNI-free maintenance therapy, we experienced a high number (25%) of SRL discontinuations due to adverse events, including leukopenia, anemia, arthritis, and pneumonitis. In addition there were significantly more allograft rejection episodes in the CNI-free group (P = .017) during the study period leading to a switch from SRL to a CNI. Despite the higher rate of rejection episodes in the CNI-free groups, glomerular filtration rates (GFR) at 6 months were comparable between the study groups (P = .25). After 1 year only 9.2% (6/65) of all patients treated with SRL remained on this drug. Conclusion, there was an unacceptably high rate of SRL intolerance using an ESW and CNI-free immunosuppressive regimen combined with a significantly higher rate of rejection episodes.