Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

BACKGROUND: Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. METHODS: CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR < or =50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. RESULTS: In the SRL group, GFR increased from 47.0+/-18.0 to 61.2+/-22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5+/-12.7 to 53.9+/-19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2+/-15.8 to 83.5+/-27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5+/-14.0 mL/min to 36.4+/-12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299+/-622 mg/day to 517+/-795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637+/-806 vs. 514+/-744 mg/day, P=0.39). Uric acid decreased from 7.6+/-2.4 to 6.2+/-1.9 mg/dL (P=0.0007) in the SRL group. CONCLUSIONS: Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.     

Proteinuria following a switch from calcineurin inhibitors to sirolimus

BACKGROUND: Sirolimus is an alternative option for kidney transplant patients treated with calcineurin inhibitors (CNI) when renal function is deteriorating. However, the incidence of proteinuria following a switch from CNI to sirolimus has caused concern, and was therefore investigated here. METHODS: In a retrospective study, 68 renal transplant recipients were switched from CNI to sirolimus. Proteinuria was measured using 24-hour urine collection before the switch and collections 3, 6, 12, and 24 months thereafter. In addition, proteinuria was measured in patients who had to be switched back to CNI due to side effects. Survival analyses were performed. RESULTS: Baseline proteinuria was 0.39+/-0.69 g/day in all 68 patients. It increased to a mean 1.44+/-1.90 g/day at 3 months (P<0.001) and remained elevated at 6, 12 and 24 months. When sirolimus was withdrawn after the CNI-sirolimus switch for 19 patients, proteinuria decreased from 1.95+/-2.06 g/day to 0.9+/-1.4 g/day (P<0.05). Proteinuria above 0.3 g/day before the CNI-sirolimus switch correlated significantly with the decrease of renal function thereafter. CONCLUSION: CNI-treated kidney transplant recipients may develop reversible proteinuria when switched to sirolimus.     

Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients

Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy. METHODS: Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent. RESULTS: One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m(2) vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr. conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI.     

Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure

BACKGROUND: Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil [MMF] and sirolimus [Sir]) treatment on renal function. METHODS AND RESULTS: Thirty-one HTx patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine greater than 1.9 mg/dL were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Mean patient age was 50+/-14 (range 19-74) years. Conversion was started with 6 mg Sir, continued with 2 mg, and the dose was adjusted to achieve target trough levels between 8 and 14 ng/mL. MMF was continued with trough level adjusted (1.5-4 microg/mL). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up (first and every 3 months after conversion) included endomyocardial biopsies, echocardiography, and laboratory studies. Survival was 90% after a mean follow-up of 13+/-95 months. No acute rejection episode was detected during the study period. Renal function improved significantly after conversion: creatinine preconversion vs. postconversion: 3.14+/-0.76 mg/dL vs. 2.14+/-0.83 mg/dL, P =0.001. Cystatin preconversion vs. postconversion: 2.95+/-1.06 mg/L vs. 2.02+/-1.1 mg/L, P =0.01. In three patients, hemodialysis therapy was stopped completely after conversion. Graft function remained stable. Fractional shortening preconversion vs. postconversion: 36.9+/-6% vs. 36.4+/-6%. There were no serious adverse events. One patient had to be excluded because of noncompliance. CONCLUSIONS: Conversion from CNI-based immunosuppression to MMF and Sir in HTx patients with chronic renal failure was safe, preserved graft function, and improved renal function.     

Conversion from calcineurin inhibitors to sirolimus in kidney transplant patients reduces the urinary transforming growth factor-beta1 concentration

INTRODUCTION: Chronic allograft dysfunction (CAD) is the main cause of late transplant failure. Although several etiologies have been postulated, toxicity for calcineurin inhibitors (CNIs) is one of the most important causes of CAD, characterized by arteriolar hyalinosis, luminal narrowing, increased glomerulosclerosis, and tubulointerstitial damage. It's known that in transplant patients with CAD, fibrogenic mediators such as transforming growth factor beta (TGF-beta) are increased. Sirolimus is an immunosuppressive agent with a distinct mechanism of action compared with CNI. AIM: This study assessed variations in levels of fibrogenic mediators among CAD patients treated with CNIs, before and after conversion to sirolimus. PATIENTS AND METHODS: We studied twelve renal transplant patients with CAD on CNI treatment. TGF-beta in plasma and urine, endothelin-1, and vascular endothelial growth factor (VEGF) were studied before and 8 months after conversion to sirolimus treatment. RESULTS: TGF-beta urine levels decreased from 24.7 +/- 11.2 to 12.8 +/- 5.1 ng/24 h (P = .049). In plasma, a similar decrease trend was observed (22.2 +/- 32 to 10.3 +/- 3 ng/mL), although it was not significant (P = .079). Endothelin-1 showed a decrease (8.1 +/- 3 to 5.2 +/- 1.1 pmol/L; P = .1) and VEGF in plasma increased from 34.3 +/- 37 to 92.2 +/- 86 pg/mL (P = .051). CONCLUSIONS: Patients undergoing conversion from CNI to sirolimus treatment for CAD presented a significant decrease in TGF-beta urine levels, representing a decreased mediator of the CAD fibrogenic process.     

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.     

Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus.

BACKGROUND: Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients. METHODS: In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion. RESULTS: After a mean post-conversion follow-up of 27+/-1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4+/-14.9 to 53+/-16.3 ml/min at D30 (P = 0.01), and to 54.7+/-20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7+/-21.7, 52.8+/-20 and 51.7+/-20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P < 0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30. CONCLUSION: Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.     

西罗莫司替代钙调磷酸酶抑制剂方案治疗肾移植后“爬行肌酐”患者的疗效观察（附28例报告）

目的探讨采用西罗莫司替代钙调磷酸酶抑制剂（CNI）方案治疗肾移植后＂爬行肌酐＂患者的临床疗效。方法具有＂爬行肌酐＂表现的28例患者中,术后采用以环孢素（CsA）为主的三联免疫抑制方案20例,采用以他克莫司（FK506）为主的三联免疫抑制方案8例。患者确诊后即停用CsA或FK506,24h后给予西罗莫司,初始剂量6mg,维持剂量为2mg/d,以后根据西罗莫司的血药浓度来调整剂量,使其血药谷浓度维持在5～9μg/L,药物替代前后麦考酚吗乙酯（MMF）及肾上腺皮质激素（激素）的用量不变。随访6个月,定期观察移植物肾功能,记录排斥反应的发生情况,并监测血常规、血糖、血脂、肝功能等指标。结果移植物肾功能明显改善16例,患者的血清肌酐（Scr）由替代前（205±20）μmo1/L降为替代后的（153±18）μmo1/L,内生肌酐清除率（Ccr）由（51±3）ml/min升高为（56±3）ml/min（均为P〈0.05）;移植物肾功能维持稳定8例,移植物肾功能继续恶化2例。治疗中,1例发生急性排斥反应,移植肾失功并恢复血液透析,1例西罗莫司替代后出现明显骨髓抑制而放弃替代治疗,恢复替代前的免疫抑制方案。结论西罗莫司替代CNI治疗肾移植后＂爬行肌酐＂患者是一种比较安全并有效的方法,可明显改善移植物肾功能,但会使患者血脂升高。     

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.     

Conversion from calcineurin inhibitors to sirolimus in patients with chronic renal allograft dysfunction

BACKGROUND: Chronic renal transplant dysfunction in part may be due to the nephrotoxic effects of calcineurin inhibitors, which are still the mainstay of immunosuppressive therapy. Sirolimus, a new immunosuppressive compound devoid of significant nephrotoxicity, might therefore exhibit beneficial effects when used in renal transplant recipients with graft dysfunction. METHODS: Twelve renal transplant recipients included in this study had all been receiving calcineurin inhibitors for more than 12 months, and were free of rejection for more than 12 months. However, they demonstrated moderate renal dysfunction with serum creatinine values ranging from 1.8 to 4.0 mg/dL (164 to 351 micromol/L). After reaching a sirolimus level of 10 to 20 ng/mL, calcineurin inhibitor therapy was withheld. RESULTS: One month after initiation of sirolimus therapy, all patients were off calcineurin inhibitors. The average daily sirolimus dosage was 5.8+/-3.4 mg. No acute rejection episode and no graft failure was observed. No patient required hemodialysis or admission to the hospital. Calculated creatinine clearance increased from 63.4+/-9.9 to 69.2+/-9.7 mL/min (P=.0368) and serum bicarbonate increased from 20.8+/-3.17 to 22.5+/-3.7 meq/L (P=.001). Serum cholesterol increased from 180+/-26.5 to 239+/-28.8 mg/dL (4.65+/-0.69 to 6.18+/-0.74 mmol/L, P<.001), triglycerides increased from 155+/-53 to 289+/-123 mg/dL (1.75+/-0.6 to 3.26+/-1.39 mmol/L) and low-density lipoprotein cholesterol increased from 99+/-32 to 131+/-25.1 mg/dL (2.56+/-0.83 to 3.39+/-0.65 mmol/L, P=.01). Arterial blood pressure remained well controlled (126+/-15.6/74+/-8.9 vs 134+/-16.8/83+/-9.7). CONCLUSION: Conversion from calcineurin inhibitor therapy to sirolimus in patients more than 1 year after transplantation with impaired organ function is feasible, safe, and associated with a trend toward improved renal function.     

Effect of early conversion from CNI to sirolimus on outcomes in kidney transplant recipients with allograft dysfunction

Background: Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL. Methods: We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography. Results: Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m2.7 vs. 1.0 ± 10.1 g/m2.7, p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis. Conclusions: Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.     

Calcineurin inhibitor withdrawal and conversion to mycophenolate mofetil and steroids in cardiac transplant recipients with chronic renal failure: a word of caution

Abstract: Background: Chronic renal failure (CRF) is a common complication of calcineurin inhibitor (CNI)‐based immunosuppression following cardiac transplantation (HTx). The aim of this prospective study was to evaluate the impact of an immunosuppressive conversion from CNIs to mycophenolate mofetil (MMF) and steroids in cardiac transplant recipients with CRF on renal and cardiac graft function. Methods: Since 1999, 12 HTx recipients (10 men; 58 ± 3.6 yr of age; 8.7 ± 4.2 yr after HTx) with CNI‐based immunosuppression and a calculated creatinine clearance (CreaCl) <50 mL/min were included. Most patients (10/12) were on cyclosporine and two patients were on tacrolimus prior inclusion. MMF was started with 0.5 g/d and adjusted according to the target trough levels (2–4 ng/mL). Prednisone dosage was 0.4 mg/kg. Subsequently, CNIs were completely withdrawn. Acute rejection episodes were excluded one and three months after conversion by endomyocardial biopsy and by echocardiography every three months thereafter. Results: After a mean follow‐up of 20 ± 16 months, CreaCl improved significantly: pre‐conversion vs. post‐conversion: 32.8 ± 12.2 mg/dL vs. 42.8 ± 21.14 mg/dL, p = 0.03. However, four acute rejection episodes occurred and patients were reconverted to CNIs. Additionally, six patients had a new onset of graft vessel disease (GVD) one yr after conversion. As a result of these adverse events, the study was stopped after inclusion of only 12 of the scheduled 30 patients. Conclusions: Conversion to MMF and steroids after HTx improves renal function, but increases the risk for recurrent rejection and GVD. Therefore, MMF and steroids should only be considered in patients with a markedly low risk for rejection.     

Antithymocyte globulin induction allows a prolonged delay in the initiation of cyclosporine in heart transplant patients with postoperative renal dysfunction

The authors evaluated the efficacy of antithymocyte globulin (ATG) induction and delayed initiation of cyclosporine (CsA) in heart transplant (HTx) patients with postoperative renal dysfunction (RD). The authors compared 15 adult HTx patients with postoperative RD (serum creatinine [SCr] > or =150 microM) to 17 controls without postoperative RD. ATG was given daily (1.5 mg/kg/day for 5 days) in controls and every 2 to 5 days in RD patients (total lymphocyte count <200/mm). All patients received corticosteroids and mycophenolate mofetil. The initiation of CsA was delayed in RD patients until SCr had decreased to less than 150 microM (day 12 +/- 8 vs. 2 +/- 1, P<0.0001). One-year patient survival and acute rejection rates were 87% and 27% in RD patients and 88% and 59% in controls, respectively (P=not significant). SCr improved in RD patients and did not differ from controls after the first month. The authors' results suggest that marked prolongation of the period of ATG induction permits a safe delay in the initiation of CsA in HTx patients with postoperative RD.     

Long‐term results after conversion from calcineurin inhibitors to sirolimus in renal transplant patients

Martinez‐Mier G, Avila‐Pardo SF, Mendez‐Lopez MT, Budar‐Fernandez LF. Long‐term results after conversion from calcineurin inhibitors to sirolimus in renal transplant patients.
Clin Transplant 2010: 24: 467–473.
© 2009 John Wiley & Sons A/S. Abstract: Background: Calcineurin inhibitors (CNI) toxicity is one of the contributing factors for the development and progression of chronic allograft dysfunction (CAD). Conversion to sirolimus (SRL) from CNI improves renal function kidney in transplant recipients. Methods: A retrospective review from patients abruptly converted from CNI to SRL over a three yr period is reported. Results: Thirty‐nine patients were converted 55.2 ± 58 months after renal transplantation. 24 month patient and graft survival was 100% and 92%. Acute rejection incidence was 7.6%. Overall, serum creatinine (SCr) and Cockcroft–Gault creatinine clearance (CGCrCl) improved. In responders, SCr improved from 2.48 ± 0.8 to 1.94 ± 0.8 mg/dL (p < 0.05) CGCrCl improved from 37.8 ± 17.4 to 51.9 ± 23.8 mL/min at two years. An increase in proteinuria was observed from conversion to month 12 in responders (189.4 ± 512.8 to 488.3 ± 890.6 mg/day, p < 0.05) and from conversion to month six in non‐responders (1179.4 ± 2001.1 to 2357 ± 4172.9 mg/day, p < 0.05). Low proteinuria had positive predictive value for renal response after conversion. Conclusion: Conversion from CNI to SRL with CAD is associated with improved renal function with an increase in proteinuria. Low proteinuria is a possible positive predictive factor for successful conversion.     

Sympathetic dystrophy associated with sirolimus therapy

The reflex sympathetic dystrophy syndrome (RSDS) in organ transplant recipients has only previously been reported in patients treated with calcineurin inhibitors. We retrospectively analyzed 393 renal transplant patients treated with sirolimus, 9 of whom developed RSDS. All the patients reported varying degrees of pain in the legs, affecting the knees, ankles, and/or feet, plus cutaneous erythema. The onset of pain ranged from 1-6 months after transplantation. At the time of diagnosis of RSDS, the mean serum creatinine was 1.4 mg/dL (range 1.0-1.7) and bone scintigraphy with 99mTc pyrophosphate showed increased uptake in all cases. The symptoms remitted 3-10 months after treatment (mean, 4 months) with calcitriol, with or without nifedipine or calcitonin, and in one case with suppression of sirolimus. We conclude that sirolimus therapy may induce RSDS in renal transplant recipients.     

Predictors of improvement in renal function after calcineurin inhibitor withdrawal for post-liver transplant renal dysfunction

BACKGROUND: Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined. METHODS: Retrospective analysis of 33 post-transplant patients with creatinine clearance (CrCl) below 50 mL/min who were changed from CNI to either MMF or AZA. Following CNI withdrawal patients were divided into two groups: those with improved CrCl after switching and those without, to identify the variables associated with improved renal function. RESULTS: Variables associated with improved CrCl were: absence of hypertension or diabetes, shorter time between transplantation and switch, deterioration in CrCl in months prior to switch and treatment with MMF (compared with AZA). CONCLUSIONS: Our findings suggest CNI withdrawal should be targeted to a subgroup of patients whose renal function is most likely to improve.     

Observation of efficacy and safety of converting the calcineurin inhibitor to sirolimus in renal transplant recipients with chronic allograft nephropathy

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of converting from a calcineurin inhibitor (CNI) to sirolimus among renal transplant recipients with chronic allograft nephropathy (CAN). METHODS: In 16 patients with CAN, substituted sirolimus for CsA or FK506 and observed the incidence of acute rejection and changes in serum creatinine, triglycerides, cholesterol, blood uric acid, and peripheral blood leukocyte/platelet counts within 12 months. All recipients underwent an allograft biopsy before conversion. The targeted sirolimus level was 4-8 ug/L. RESULTS: After conversion to sirolimus, the creatinine level of 7 cases decreased and the efficacy rate was (43.8%). No acute rejection occurred during the follow-up. The cases with hypercholesteremia increased from 3 to 7 after conversion; hypertriglyceridemia increased from 3 to 5; leukopenia occurred in 2; subnormal platelet counts increased from 2 to 3; and hyperuricemia increased from 6 to 7. Meanwhile, the average level of peripheral blood leukocytes obviously decreased in the first month, the average peripheral blood cholesterol increased over 12 months, but the average content of peripheral blood platelets, triglyceride and blood uric acid failed to display as statistic difference. Eight patients showed C4d deposition in peritubular capillary in graft tissue before conversion, 7 cases of whom showed no improvement in renal function. In 6 cases there was no C4d deposition in peritubular capillary in graft tissue. Only 2 of 6 cases showed no improvement in renal function. There were 6 patients whose creatinine level was <2.48 mg/dL before conversion, and renal function in 5 of them improved in a year after conversion. In contrast, among 10 patients whose blood creatinine level was >2.48 mg/dL, only 2 cases improved. CONCLUSION: It is safe for patients with CAN to use substitute sirolimus for CNI; the incidence of acute rejection did not increase. In this study, 43.8% of patients showed improved renal function. The main adverse reactions after conversion to sirolimus were hypercholesteremia and decreased peripheral blood leukocytes. The serum creatinine level and the deposition of C4d in peritubular capillary were important factors influencing therapeutic efficacy.     

Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

Background

Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation.

Methods

The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 ± 12.3 years and time since transplantation 8.7 ± 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 ± 0.9 to 1.69 ± 0.5 mg/dL, P = .01) and CrCl (24.9 ± 6.5 to 45.7 ± 17.2 mL/min, P = .005) at 6 months follow-up.

Conclusion

The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.     

Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria.

The aim was to evaluate long-term graft survival and function after conversion to sirolimus (SRL) for chronic calcineurin inhibitor (CNI) toxicity and the predictive value of baseline proteinuria. This is a follow-up conversion study of 59 renal transplant patients with deteriorating graft function and histologic signs of CNI toxicity. Previously, baseline proteinuria <800 mg/day was identified as a short-term predictor for successful conversion. Follow-up was 5.3 +/- 0.8 (3.7-6.8) years. Patient survival was 88%, graft survival 38%. Creatinine clearance at the last follow-up was 33.7 +/- 14 ml/min, proteinuria 826 +/- 860mg/day. Baseline proteinuria <800 mg/day was associated with better graft survival. In a cox analysis including proteinuria >800 mg, glomerular filtration rate, age at conversion, chronic Banff score at conversion and time after transplantation at conversion, higher proteinuria was associated with a relative risk of graft loss of 3.98. Prognosis of chronic allograft dysfunction is poor. However, conversion to SRL remains an option for patients with low baseline proteinuria, which can slow down deterioration of graft function during a follow-up period of up to 5 years.     

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.