Conversion to sirolimus in pediatric renal transplantation recipients

We retrospectively evaluated the efficacy and safety of sirolimus (SRL) in 16 pediatric renal transplant recipients, who were 9.4 +/- 4.1 years of age when they first received SRL. The indications for SRL therapy were rescue from steroid-resistant acute rejection (31.3%), neoplasia (31.3%), diabetes (12.5%), polyomavirus-associated nephropathy (6.3%), chronic allograft dysfunction (6.3%), calcineurin inhibitor nephrotoxicity (6.3%), and hemolytic uremic syndrome (6.3%). Mean follow-up after the switch to SRL was 17.7 +/- 15 months. The final immunosuppression was CNI + SRL + prednisone (PRED) in five patients, SRL + PRED in six, SRL + mycophenolate mofetil (MMF) + PRED in four, and SRL + MMF in one. The use of SRL in these selected pediatric renal recipients was successful, except when creatinine was high at the moment of conversion. Further studies are necessary to assess the beneficial outcomes versus adverse events among the pediatric transplant population receiving SRL for immunosuppression.     

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.     

Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.     

肝移植后因药物不良反应暂停及转换钙调磷酸酶抑制剂的单中心经验

目的 研究肝移植术后暂停及转换钙调磷酸酶抑制剂(CNI)对控制感染和改善受损肾功能的作用.方法 回顾性分析单中心施行的947例原位肝移植的资料,分为2个阶段,第1阶段(2002年1月至2007年12月)有234例肝移植术后发生感染的患者,第2阶段(2008年1月至2010年12月)有101例.2个阶段共有329例受者因CNI肾毒性而造成肾功能损害,其中将CNI转换为SRL者40例(转换组),其余289例采取CNI减量+吗替麦考酚酯(MMF)加量方案(减量组).结果 肝移植术后存活超过1、3和5年者CNI的应用率分别为95.8%、95.3%和97.5%.第2阶段共有17例受者短期停用免疫抑制剂,停药的主要原因是细菌(部分合并真菌)感染(88.2%);2个阶段共有48例患者将CNI转换为SRL,换药主要原因是肾功能损害(83.3%).第2阶段感染患者中短期暂停CNI者15例,占14.9%(15/101),CNI暂停后感染控制的有效率为73.3%(11/15),排斥反应发生率为6.7%(1/15).第2阶段感染患者的累积存活率明显高于第1阶段(P＜0.05).转换组CNI转换前肾小球滤过率为(0.82±0.24)ml/s,CNI转换后6周时为(1.28±0.31)ml/s,6个月时为(1.36±0.32)ml/s,转换后6周和6个月时高于转换前(P＜0.05).CNI调整后6个月时,转换组患者存活率为85.0%,减量组为83.7%(P＞0.05).结论 肝移植术后患者发生感染及肾功能损害时可采取CNI减量甚至短时间停用CNI,或转换使用SRL,此方案是安全、有效的.

Abstract：

Objective To report the results of a single-center, retrospective study on the effect of calcineurin inhibitors (CNI) withdraw for controlling infections and conversion to sirolimus (SRL)for ameliorating renal dysfunction. Methods A total of 947 liver transplant cases from 2002 to 2010were divided into two eras (Jan. 2002 to Dec. 2007 and Jan. 2008 to Dec. 2010). There were 234cases of infections after liver transplantation (LT) in the first era and 101 cases in the second era. And of 329 cases of CNI-related renal dysfunction after LT in two eras, 40 cases (converting group) had converted CNI to SRL, while 289 cases (reducing group) adopted protocol of CNI reducing and mycophenolate mofetil (MMF) raising. Results CNI-based IS took up 95.8 %, 95. 3 %, 97. 5 % of the IS protocols with recipient survival time longer than 1, 3, and 5 years. The primary cause for CNI withdraw was infection (88. 2 %, 15/17) in the second era, and renal dysfunction for conversion to SRL in the two eras (83. 3 %, 40/48). In the second era, 14. 9% (15/101) of the cases of infections after LT experienced CNI withdraw. Of the 15 patients, 11 had effectively controlled the infection (77. 3 %) while rejection rate was 6. 7 % (1/15). The cumulative survival rate of the second era was significantly higher than the first era (P＜0. 05). The glomerular filtration rate (GFR) of converting group at 6th week and 6th month was statistically elevated as compared with that before conversion,respectively (1.28 ± 0. 31, 1.36 ± 0. 32 mL/s vs. 0. 82 ± 0. 24 mL/s, P＜0. 05). Six months after CNI adjustments, survival rate of converting group and reducing group was 85. 0% and 83. 7 %,respectively (P＞0. 05). Conclusion Reducing or even short-term withdraw of CNI may allow the better control of infections after LT, and the conversion from CNI to SRL can ameliorate the CNIrelated nephrotoxicity. These individually tailored IS protocols will benefit the long term survival for LT.     

Conversion to Sirolimus in Kidney-Pancreas and Pancreas Transplantation

Reports on the use of sirolimus (SRL) in pancreas transplantation are still limited. The aim of this study was to evaluate the outcome of SRL conversion in pancreas transplant patients. Among 247 patients undergoing simultaneous kidney-pancreas or solitary pancreas transplantation, 33 (13%) were converted to SRL. The reasons for conversion were calcineurin inhibitors (CNI) nephrotoxicity (n = 24; 73%), severe neurotoxicity owing to CNI (n = 1; 3%), severe and/or recurrent acute rejection episodes (n = 7; 21%), gastrointestinal (GI) side effects of mycophenolate mofetil (MMF; n = 5; 15%), and hyperglycemia (n = 4; 12%).Before conversion, all patients were maintained on a CNI, MMF, and low-dose steroids. They were gradually converted to SRL associated with either CNI or MMF withdrawal. Sixty-three percent (n = 15) of patients who were converted owing to CNI nephrotoxicity, showed stable or improved renal function. At 12 months after conversion, serum creatinine levels were significantly decreased in this group (2.2 ± 0.5 vs 1.6 ± 0.3 mg/dL; P = .001) and C-peptide values increased (2.9 ± 1.1.1 vs 3.1 ± 1.3 nmol/L; P = .018). The only patient with leucoencephalopathy showed improved neurologic status after SRL conversion. All patients converted to SRL because of GI side effects of MMF showed improvements, and none of those converted because of hyperglycemia experienced improvement. There were no episodes of acute rejection after conversion.We concluded that conversion to SRL in pancreas transplantation should be considered an important alternative strategy, particularly for CNI nephrotoxicity and neurotoxicity, and in cases of severe diarrhea due to MMF.     

Long-term effects of calcineurin inhibitor conversion to mycophenolate mofetil on renal function after liver transplantation.

Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppression after liver transplantation. However, CNI treatment is frequently associated with chronic renal failure (CRF). The reduction or interruption of CNI may reduce renal failure. We prospectively studied 49 liver recipients treated with CNI (tacrolimus, n = 14; cyclosporine, n = 35) who secondarily developed CNI-associated CRF and for whom mycophenolate mofetil (MMF) was introduced to reduce or withdraw CNI. The creatinine clearance (CCl; 42.9 +/- 14 ml/minute) increased significantly after CNI reduction (48.8 +/- 17 ml/minute after 1 year, 49.9 +/- 18 ml/minute after 2 years, and 58.4 +/- 20 ml/minute after 3 years, P < 0.0001). CCl decreased during the 2 years before CNI reduction at a rate of -5.6 +/- 5 ml/minute/year; for the 2 years after CNI reduction, CCl increased significantly by +3.2 +/- 4.3 ml/minute/year (P < 0.0001). Ten patients did not have improved renal function after 1 year, but the rate of decrease in CCl slowed after CNI reduction. Three parameters were identified as risk factors for unresponsiveness to CNI reduction: (1) low CCl at MMF introduction, (2) a high rate of CCl decrease during the 2 years before conversion, and (3) alcoholic cirrhosis. The type of CNI molecule used did not impair the renal response. None of the patients developed acute or chronic graft rejection after the reduction or interruption of CNI. In liver recipients with CRF, a reduction or withdrawal of CNI concomitantly with the introduction of MMF was safe and was associated with an improvement in renal function.     

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.     

Conversion from azathioprine to mycophenolate mofetil followed by calcineurin inhibitor minimization or elimination in patients with chronic allograft dysfunction

The purpose of this study was to evaluate the effects of the conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) followed by calcineurin inhibitor (CNI) elimination or minimization in patients with progressive chronic allograft dysfunction (CAD). METHODS: Between November 6, 1999 and February 12, 2003, 169 patients receiving CNI/AZA/prednisone (153 CsA; 14 tacrolimus) were included in this study. Demographics, immunosuppression, graft function, hematology, and biochemistry were obtained before (-6, -3, and -1 month) and 1, 3, 6, 9 and 12 months after and at last follow-up visit after conversion. RESULTS: Mean age was 34 +/- 12 years, 66% males, 51% Caucasian, and 72% living allograft recipients. Mean follow-up times before and after conversion were 32.4 and 19.4 months; 10 patients completed 3 years of follow-up. CNI elimination was performed in 39% and minimization in 61% of patients. Overall there was significantly improved graft function at 1 year after conversion (2.6 +/- 1.0 vs 2.1 +/- 0.6 mg/dL, P = .038). The slopes of the regression lines of 1/Cr vs time were significantly improved from preconversion to after conversion (-0.026 vs +0.007 mg(-1)/dL per day(-1), P = .001). There was a significant decrease in mean systolic (141 +/- 21 vs 135 +/- 22 mm Hg, P = .015) and diastolic (89 +/- 15 vs 84 +/- 14 mm Hg, P = .005) blood pressure values at 1 year. There were four episodes of acute rejection (Banff IA) treated with steroids. Three years after conversion, patient and graft survivals were 95% and 79%, respectively. One patient developed posttransplant lymphoproliferative disease. CONCLUSION: Among patients with CAD, conversion from AZA to MMF followed by CNI minimization or elimination was a safe and effective strategy to preserve or improve graft function.     

Sirolimus attenuates the rate of progression of early chronic allograft nephropathy

Optimal treatment for patients with chronic allograft nephropathy (CAN) is not known. Early intervention is preferred. We examined the benefit of adding sirolimus (SRL; C(0) 5-12 ng/mL: HPLC) on the rate of progression of early CAN. We identified patients with biopsy-confirmed Banff grade 1 CAN. After biopsy, patients were switched to SRL + CsA + prednisolone (SRL), MMF + CsA + prednisolone (MMF), or CsA + AZA + prednisolone (AZA). GFR was estimated by Cockcroft-Gault and MDRD formulae. The rate of GFR decline (delta GFR) was determined by calculating the slope of the regression line of estimated GFR (MDRD and Cockcroft-Gault method) at different times. Statistical analysis was performed by the Wilcoxon test. The 41 patients with CAN grade 1 were assigned to SRL: MMF: AZA = 12: 20: 9. Before biopsy; the graft age for SRL: MMF: AZA were 56 +/- 27: 70 +/- 48: 51 +/- 36 months; and the GFR (MDRD method), 38 +/- 8: 42 +/- 15: 36 +/- 14 mL/min; GFR (C-G method) 45 +/- 13, 42 +/- 12, 41 +/- 15 mL/min; trough CsA levels 152 +/- 36: 145 +/- 46: 177 +/- 61 ng/dL; delta GFR (MDRD method) -0.18 +/- 0.20: -0.15 +/- 0.59: -0.20 +/- 1.08; delta GFR (C-G method) -0.13 +/- 0.37: -0.19 +/- 0.24: -0.65 +/- 0.99. Follow-up time for SRL: MMF: AZA was 19 +/- 4: 35 +/- 32: 59 +/- 54 months. At last follow-up; GFR (MDRD method) for SRL: MMF: AZA were 39 +/- 13: 35 +/- 21: 40 +/- 24 mL/min; GFR (C-G method) 46 +/- 17, 37 +/- 18, 46 +/- 25 mL/min; BP 128 +/- 11/79 +/- 7: 131 +/- 22/80 +/- 14: 132 +/- 20/82 +/- 11 mm Hg; and CsA level 52 +/- 25: 122 +/- 41: 155 +/- 49. After biopsy, statin was prescribed in nine SRL, 10 MMF, and three AZA. ACEI was prescribed in two SRL, three MMF, and two AZA. Compared with the prebiopsy values, the delta GFR (MDRD method) changed to -0.04 +/- 0.31 (SRL; P = .04), -0.17 +/- 0.40 (MMF; P = .60), and -0.97 +/- 1.52 (AZA: P = .16). Delta GFR (C-G method) was also significantly improved in the SRL group (-0.02 +/- 0.47; P = .05) but not in the MMF (-0.13 +/- 0.51; P = .53) or AZA (-0.54 +/- 1.78; P = .44). We concluded that patients with early CAN who are switched to SRL and low-dose CsA have a significant attenuation of the rate of GFR declination when compared with patients who receive MMF or AZA addition.     

Immunosuppression for Dual Kidney Transplantation with Marginal Organs: The Old Is Better Yet

Immunosuppressive protocols in dual kidney transplantation (DKT) are based on calcineurin inhibitors (CNI). We wonder whether a CNI-free immunosuppression can improve outcome in older patients receiving a DKT with marginal donor organs. Thirty-six were treated with CsA, MMF and prednisone (CsA group) and 42 with rATG, SRL, MMF and prednisone (SRL group). Incidence of delayed graft function and acute rejection was 44% and 11% in the CsA group, and 40% and 8% in the SRL group. CMV infection incidence was low in both protocols. Three-year patient survival was 89% in the CsA and 76% in the SRL group. One- and 3-year graft survival after censoring for dead with a functioning allograft was 94.2% and 94% in CsA and 95% and 90% in SRL, respectively. Renal function was similar in both groups whereas proteinuria was higher in the SRL group. Uninephrectomy due to graft thrombosis or urinary-related complications was numerically higher in the SRL (21%) than in the CsA group (8%) (p = 0.13) and it was associated with renal failure and proteinuria. In DKT, a new induction immunosuppressive protocol based on rATG, SRL, MMF and prednisone does not offer any advantage in comparison to the old CsA, MMF and prednisone.     

Timing of sirolimus conversion influences recovery of renal function in liver transplant recipients

Abstract: The long‐term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002–November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (<90 d from LT) (EC) vs. late conversion (LC). Renal function was evaluated using the six‐point modification of diet in renal disease formula (estimated glomerular filtration rate [eGFR]). Forty‐two patients on SRL and 40 on CNI had at least three months of follow‐up and are included in the eGFR evaluation. At all time points after conversion, the EC group demonstrated a significantly higher mean eGFR than those in the LC group. A significant improvement in eGFR was seen within the EC group when comparing eGFR at time of conversion to eGFR at three, six, nine, and 12 months after conversion and last follow‐up. The only improvement in the LC group was from conversion to the three‐month time point. We conclude that EC to SRL results in a profound improvement in eGFR that begins at three months and is sustained beyond one yr.     

Posttransplantation conversion to sirolimus-based immunosuppression: a single center experience

Sirolimus (SRL) has become an option in kidney transplantation, especially among patients who develop chronic allograft nephropathy (CAN). This study sought to evaluate the safety and efficacy of SRL in 103 kidney recipients of mean age 40 years, including 78 recipients of organs from deceased donors. The major reason for conversion was calcineurin inhibitor (CNI) nephrotoxicity (42.3%) followed by CAN (35.4%). A preconversion kidney biopsy was performed in 89 patients with CAN diagnosed in 51. Mean time to conversion was 40.5 months. The new therapy was: SRL/mycophenolate mofetil (MMF)/prednisone (Pred) in 79 patients; SRL/tacrolimus (TAC)/Pred in 15; and other SRL combinations in 9. The target SRL trough level was 5.0 to 8.0 ng/mL. To evaluate the impact of conversion on renal function, we compared the proteinuria and inverse serum creatinine at 3 months before conversion, at conversion, and at 1, 3, 6, 12, and 24 months postconversion. The overall mean follow-up time was 13.2 months. The analysis showed significant improvement in renal function at month 1 postconversion (P<.05) with stabilization thereafter. The SRL/MMF combination frequently induced anemia and/or leukopenia (n=23). Infections included pneumonia (n=10), herpes zoster (n=7), herpes simplex (n=3), cytomegalovirus (n=2), histoplasmosis (n=2), tuberculosis (n=2), and neurocryptococcosis (n=1). Reasons for SRL discontinuation were myelotoxicity (n=4), infection (n=3), nephrotoxicity (n=3), gastrointestinal intolerance (n=3), myopathy (n=1), pneumonitis (n=1), hyperlipidemia (n=1), and other reasons (n=3). Graft loss occurred in 29 patients due to CAN (n=21) followed by death (cardiovascular, n=2; infectious, n=2), acute rejection (n=3), and infection following immunosuppression withdrawal (n=1). We concluded that SRL represented an option but reducing associated immunosuppression should strongly be considered to minimize the frequent side effects, especially infections.     

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.     

Relationship between renal resistance index and renal function in liver transplant recipients after cessation of calcineurin inhibitor

Abstract:  End stage renal disease is a major complication after orthotopic liver transplantation (OLT). Vasoconstriction of renal arterial vessels because of calcineurin inhibitor (CNI) treatment plays a pivotal role in the development of renal insufficiency following OLT. Renal resistance can be measured non-invasively by determining the resistance index (RI) of segmental arteries by color-coded duplex ultrasonography, a measure with predictive value for future renal failure. Sixteen OLT patients on long-term CNI therapy were recruited prospectively and randomly assigned either to receive the m-TOR inhibitor sirolimus (SRL) or to continue on CNI treatment, and were followed for one yr. Serum creatinine (crea) declined after conversion to SRL, whereas it tended to increase in patients remaining on CNI (meanΔ crea SRL: −27, −18, −18, −15 μmol/L; meanΔ crea CNI: 4, 5, 8, 11 μmol/L at 1, 3, 6, 12 months, p = 0.02). RI improved after switching to SRL and was lower on SRL than on CNI (meanΔRI SRL: −0.04, −0.04, −0.03, −0.03; meanΔRI CNI: −0.006, 0.004, −0.007, −0.01 after 1, 3, 6, 12 months, p = 0.016). Individual changes of RI correlated significantly with individual changes of crea ( r  = 0.54, p < 0.001). Conversion from CNI to SRL can ameliorate renal function accompanied by a reduction of intrarenal RI after OLT.     

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.     

Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose (n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 +/- 0.36 versus 1.58 +/- 0.33 mg/dL, P < .001) and BUN (39.2 +/- 11.8 versus 29.9 +/- 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 +/- 10.8 versus 61.6 +/- 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 +/- 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 +/- 19 versus 130 +/- 14 mm Hg, P < .01) and diastolic (82 +/- 9 to 74 +/- 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 +/- 25.9 versus 25.2 +/- 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.     

Predictors of Success in Conversion from Calcineurin Inhibitor to Sirolimus in Chronic Allograft Dysfunction

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long-term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12-15 mg SRL once, then 4-5 mg/day, target trough level 8-12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1-2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 +/- 0.75 to 2.22 +/- 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 +/- 1.02 to 4.44 +/- 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 +/- 516 vs. 1532 +/- 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 +/- 0.5 vs. 1.9 +/- 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 +/- 0.7 vs. 1.7 +/- 0.7; p = 0.048) and number of acute rejections before conversion (0.73 +/- 0.69 vs. 1.27 +/- 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.     

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.     

Calcineurin-inhibitor-sparing immunosuppressive protocols

Calcineurin inhibitors (CNI) have played an important role in improving graft survival. However, the balance between preventing immunologic allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. There are three major CNI-sparing strategies. CNI MINIMIZATION: The advent of mycophenolate mofetil (MMF) allows cyclosporine (CsA) reduction to ameliorate renal function in patients with chronic renal allograft dysfunction, without increasing acute rejection rates. In combination with mTOR inhibitors, very low CNI levels may be sufficient to prevent acute rejection. However, in this association, CNI nephrotoxicity is magnified by pharmacokinetic interaction. CNI WITHDRAWAL: CNI withdrawal has been attempted in regimens containing MMF or sirolimus (SRL). Introduction of MMF in patients with chronic allograft nephropathy (CAN) followed by CNI withdrawal resulted in stabilization or improvement of renal function and hypertension profile, although there is some risk of acute rejection. In regimes based on SRL, CNI withdrawal is a safety strategy, achieving a sustained improvement of renal function, histology, and graft survival. There is not consensus at all whether MMF should be added or not in patients converted from CNI to mTOR inhibitor. CNI AVOIDANCE: Polyclonal-based regimens with MMF and steroids have shown acceptable acute rejection rates, but high rates of cytomegalovirus (CMV) and opportunistic infections. Conversely, anti-IL-2R in combination with MMF and steroids resulted in 50% incidence of acute rejection, thus suggesting that CNI avoidance is not feasible in a regimen based on MMF. Alternatively, a protocol based on anti-IL-2R induction therapy combined with SRL, MMF, and prednisone has shown an efficient prevention of acute rejection, higher creatinine clearance and lower rate of CAN in comparison with a group treated with CNI. New strategies using costimulation blockade may help in the development of safe CNI-free regimens. In summary, in renal transplantation the new immunosuppressive medications have made feasible old aspirations such as minimization, withdrawal, or even avoidance of CNI.