Proteinuria Developing After Clinical Islet Transplantation Resolves with Sirolimus Withdrawal and Increased Tacrolimus Dosing

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.     

Individualizing early use of sirolimus in renal transplantation

One of the main goals in the current care of kidney transplant recipients is to extend long-term graft survival. Efficacious immunosuppressive agents devoid of nephrotoxicity are needed. In human clinical transplantation, sirolimus combined with other immunosuppressive drugs has proven to be a powerful immunosuppressant capable of preventing acute graft rejection, as well as of improving renal function, renal histology, and graft survival when compared with immunosuppressive regimens that include calcineurin inhibitors. The valuable experience gained through many clinical studies allows clinicians to plan sirolimus use. We present a review of the clinical experience and literature review on the use of sirolimus in the first 12 months posttransplantation.     

Impact of variability of sirolimus trough level on chronic allograft nephropathy

The efficacy of sirolimus is strictly dose-dependent; an inappropriate exposure may cause either rejection episodes or drug toxicity. The variability of sirolimus trough levels (C(0)) may also have an impact on renal allograft function. We prospectively evaluated the impact of the dose-normalized C(0) of sirolimus and the intrapatient coefficient of variation (% CV) on renal allograft function at 6 months after the administration of sirolimus to kidney transplant recipients with chronic allograft nephropathy (CAN). We enrolled 51 recipients with CAN who were treated with sirolimus. The dose-normalized C(0) of sirolimus was 3.8 +/- 1.9 ng/mL/mg. The intra- and interpatient variabilities of sirolimus C(0) were 26.1% and 51.9%, respectively. Based on receiver operating characteristic analysis, patients were divided into 2 groups: group I, sirolimus % CV <22.9% (n = 36) versus group II, sirolimus % CV >22.9% (n = 15). Patients in group II experienced significantly greater risk for progressive deterioration of allograft function (group I vs group II: 11.1% vs 73.3%; P < .05). Multiple logistic regression analysis revealed that higher baseline serum creatinine, but not age, gender, or concomitant immunosuppressants, positively correlated with the sirolimus % CV. In conclusion, both higher baseline serum creatinine and higher intraindividual variability of sirolimus C(0) impact the outcome of renal allograft function in CAN. Thus, we suggest that close monitoring of sirolimus C(0) is necessary for recipients treated with sirolimus, especially for patients with CAN.     

Strategies to prevent chronic allograft nephropathy in kidney transplantation: focus on calcineurin inhibitors

Chronic allograft nephropathy is one of the leading causes of long-term graft failure in kidney transplant recipients. The etiology of this condition is multifactorial, but administration of calcineurin inhibitors is often implicated. With the introduction of newer immunosuppressive agents, strategies for calcineurin inhibitor minimization, avoidance, and withdrawal have been emerging in the literature. These strategies may improve long-term kidney allograft function, but are not without risks. Results from recent clinical trials evaluating the safety and efficacy of these strategies to prevent chronic allograft nephropathy in kidney transplant recipients are summarized and reviewed. Patients who had never received a calcineurin inhibitor or who had cyclosporine withdrawn from their regimens had better kidney function than patients who received or kept receiving a calcineurin inhibitor. The impact of the improvement in kidney function on long-term graft survival remains to be determined. In addition, the benefit in renal function must be weighed against the bone marrow toxicities and/or metabolic complications associated with these regimens.     

Hepatic dysfunction in kidney transplant recipients: prevalence and impact on graft and patient survival

Background Liver disease has emerged as an important cause of morbidity and mortality in renal transplant recipients. Liver insufficiency is the cause of death in up to 28% of long-term survivors after renal transplantation. The aim of this work was to evaluate the prevalence and causes of hepatic dysfunction in renal transplant recipients in Egypt, and its impact on both renal graft function and patient survival. Methods This study comprised 447 kidney transplant recipients who received their grafts between January 1999 and December 2003 at Mansoura Urology and Nephrology Center. Among these recipients, 104 patients showed persistent hepatic dysfunction, while the remaining 343 had normal liver function or transient hepatic dysfunction of less than 6 months’ duration. Results We found that the prevalence of persistent hepatic dysfunction in our recipients was 23.3%. Infections such as hepatitis C virus (HCV;, with longer dialysis duration and blood transfusion as risk factors), HBV, and cytomegalovirus (CMV), were the main causes of persistent hepatic dysfunction. Drugs (e.g., the sirolimus and tacrolimus; cyclosporine; and azathioprine) were also associated with hepatic dysfunction. We did not find a significant impact of hepatic dysfunction on either patient or graft survival. Conclusions Viral infections–especially HCV and CMV–were more prevalent in the group of patients with persistent hepatic dysfunction, with duration of dialysis as an important risk factor for HCV infection. Dose-dependent cyclosporine-induced hepatic dysfunction was observed early post-transplant. Neither tacrolimus- nor sirolimus-associated hepatic dysfunction was dose-dependent. Hepatic dysfunction had no significant impact on either patient or graft survival; however, this finding may be due to the relatively short duration of follow up.     

The Effect of Sirolimus on Prostate‐Specific Antigen (PSA) Levels in Male Renal Transplant Recipients Without Prostate Cancer

In kidney recipients, the immunosuppressant sirolimus has been associated with a decreased incidence of de novo posttransplant malignancies (including prostate cancer). But the effect of sirolimus on the prostate‐specific antigen (PSA) blood level, an important prostate cancer screening tool, remains unknown. We studied male kidney recipients >50 years old (transplanted from January 1994 to December 2006) without clinical evidence for prostate cancer. Pre‐ and posttransplant PSA levels were analyzed for 97 recipients (n = 19 on sirolimus, n = 78 on tacrolimus [control group]). Pretransplant PSA was similar for sirolimus versus tacrolimus recipients (mean, 1.8 versus 1.7 ng/mL, p = 0.89), but posttransplant PSA was significantly lower for recipients on sirolimus (mean, 0.9 versus 1.9 ng/mL, respectively, p < 0.001). The mean difference between pretransplant and posttransplant PSA was ?0.9 ng/mL (50.0%, p = 0.006) for the sirolimus group versus +0.2 ng/mL (+11.8%, p = 0.24) for the tacrolimus group. By multivariate analysis, only pretransplant PSA and immunosuppression with sirolimus independently impacted posttransplant PSA. Our data strongly suggest that sirolimus is associated with a significant PSA decrease in kidney recipients. Future studies must investigate the clinical implications of our findings for the use of PSA for prostate cancer screening in male kidney recipients on sirolimus.     

A Comparison of Long-Term Graft Survival Rates Between the First and Second Donor Kidney Transplanted—The Effect of a Longer Cold Ischaemic Time for the Second Kidney

Prolonged cold ischaemic time (CIT) is associated with delayed initial graft function and may also have a negative impact on long-term graft outcome. We carried out a study comparing the long-term graft survival rates between those recipients who received the first of a pair of donor kidneys versus the recipient of the second graft. Adult kidney transplant recipients who received one of a pair of donor kidneys at our institution between 1989-1995 were included. All recipients received a cyclosporin based immunosupression regimen. Graft survival rates were compared between the 2 groups at 1-, 3-, 5- and 10-year intervals. A total of 520 renal transplant grafts were included in this study. Mean donor age was 35.4 years. Groups were similar for recipient age, gender, number of HLA mismatches, transplant number for that patient and percentage PRA. CIT was the only variable that was significantly different between the two groups; mean of 19.93 h in the first group compared to 25.65 h in the second group. Graft survival rates for the first kidney were significantly better than the second kidney-graft survival at 1 year 88.5% versus 84.7%, at 3 years 81.8% versus 76.7%, at 5 years 72.2% versus 64.9% and at 10 years 55.2% versus 40% (p = 0.012). Patient survival rates were similar in both groups. In our experience, the long-term graft survival rates are significantly better for the first kidney transplanted compared to the second kidney.     

Pregnancy under everolimus-based immunosuppression

The ability to give birth to a live child is one of the best success of kidney transplantation. While there are an increasing number of pregnancies reported in kidney transplant recipients treated with cyclosporine or tacrolimus, there is little evidence of pregnancy among kidney transplant recipients exposed to sirolimus or everolimus. We present the first successful delivery in an organ transplant recipient exposed to everolimus during the whole gestation. The absence of congenital anomalies in the child as well as the recipient's successful renal outcome are promising, although pregnancy in renal transplant recipients exposed to everolimus should be considered at higher risk.     

发生慢性移植肾功能不全者以西罗莫司替换环孢素A的临床疗效

目的 对采用以环孢素A(CsA)为基础免疫抑制剂的慢性移植肾功能不全(CRAD)患者,将CsA转换为西罗莫司(SRL),观察转换后的临床效果和安全性.方法 20例肾移植后出现CRAD的患者,采用突然转换法将CsA替换为SRL(3 mg/d),霉酚酸酯(MMF)和泼尼松(Pred)的剂量维持不变.另随机选取9例仍然使用CsA、MMF和Pred的CRAD患者作为对照.观察血肌酐(Cr)、肾小球滤过率(GFR)和24 h尿蛋白定量的变化情况以及SRL的不良反应.结果 对照组与转换组在患者年龄、性别构成比、移植后时间、转换时的血Cr水平和转换时免疫抑制剂用量等方面的差异均无统计学意义.随访1年,转换组有18例完成观察,其中11例(61.1%,11/18)转换有效,7例(38.9%,1/18)转换无效.转换有效者和转化无效者在转换时的血Cr、移植后时间、GFR及24 h尿蛋白定量等方面的差异有统计学意义.转换有效者的血Cr明显下降,GFR明显升高,而转换无效者的血Cr呈进行性升高,GFR呈进行性下降.转换治疗期间,1例出现急性排斥反应,经冲击治疗后逆转.完成随访的18例中,2例发生感染,3例出现皮疹,3例出现腹泻,2例出现口腔溃疡,8例出现骨髓抑制,6例转氨酶升高,10例出现高血脂,4例出现低血钾,没有患者因为上述不良反应而退出观察.结论 肾移植后采用以CsA为基础的免疫抑制方案者,若出现CRAD,可以将CsA替换为SRL,部分患者的肾功能得到改善,但转换应在移植肾功能发生严重损害前进行.     

Long-term graft outcomes after steroid withdrawal in African American kidney transplant recipients receiving sirolimus and tacrolimus

BACKGROUND: We previously reported excellent short-term outcomes in African American kidney transplant patients receiving tacrolimus/sirolimus and withdrawn from corticosteroid therapy three months after transplantation. We now report the long-term outcomes of patients subjected to this protocol. METHODS: In all, 47 African American kidney transplant recipients were enrolled in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids, without antibody induction therapy. Eligible patients were withdrawn from prednisone between three and five months posttransplant, and followed for acute rejection and changes in renal function. Outcomes (group 1, n=32) were compared to those of patients deemed not to be candidates for steroid withdrawal (group 2, n=15). RESULTS: After a mean follow-up of 48.5 months, 13 of 32 patients (41%) in group 1 developed acute rejection; only 13 patients (41%) remain steroid-free. Nine of 13 rejection episodes were associated with noncompliance. Graft loss occurred in 8 of 32 patients (25%) in group 1 and in 5 of 15 patients (33%) in group 2 (P=NS). Serum creatinine rose from 1.4+/-0.41 to 2.45+/-1.7 mg/dL in group 1 (P=0.004) and from 2.1+/-0.45 to 2.62+/-1.2 mg/dL (P=NS) in group 2. Among 13 patients in group 1 who remain steroid-free, creatinine concentration has risen from 1.28+/-.0.37 prior to steroid withdrawal to 1.64+0.54 at last follow-up (P=0.027). CONCLUSIONS: Late noncompliance and/or rejection in African Americans withdrawn from steroids have a negative impact on long-term graft function and survival. Steroid withdrawal may be associated with long-term deterioration of renal function, even in the absence of overt acute rejection.     

Sirolimus in kidney transplantation from marginal donors

Nephrotoxicity caused by calcineurin inhibitors can lead to either delayed graft function or long-term decline of renal function after kidney transplantation. Therefore, recipients of renal transplants from marginal donors require non-nephrotoxic immunosuppression. Eighteen patients received kidney transplants from marginal donors, with a calcineurin inhibitor-free immunosuppressive regimen, based on basiliximab, mycophenolate mofetil, steroids, and sirolimus. Renal graft biopsy was performed in all cases before surgery. Mean follow-up was 11.8 months. We report immediate renal function in 9 patients, delayed graft function in 5 and acute tubular necrosis in 4 patients. One patient was successfully treated for biopsy-proven acute rejection. Hypercholesterolemia and hypertriglyceridemia were the most common adverse effects (n = 13) associated with arthralgia (n = 2) and thrombocytopenia (n = 2). Five patients underwent a switch to tacrolimus, due to sirolimus-induced side effects. Immunosuppression without the use of calcineurin inhibitors is a safe and effective regimen in kidney transplantation, although sirolimus-related side effects still represent a morbidity factor in these patients.     

Posttransplantation acute tubular necrosis: risk factors and implications for graft survival

Previous studies aimed at identifying the causes, risk factors, and outcome of kidney transplant recipients with delayed graft function (DGF) have yielded controversial results. We retrospectively analyzed the causes and risk factors for DGF in 263 cadaveric kidney transplantations from November 1988 to March 1997 in one center. Causes of DGF were assessed by postoperative graft evolution and graft biopsy. Univariate and multivariate analysis were used to investigate the risk factors for DGF induced by acute tubular necrosis (ATN). Seventy-six patients (29%) had DGF, which was caused by ATN in 70 patients (92.1%) and acute rejection (AR) in 6 patients (7.9%). Therefore, we focused on risk factors and consequences for ATN-induced DGF. In monofactorial analysis, ATN was significantly associated with greater weight and presence of an atheromatous disease in both donor and recipient. Other risk factors for ATN were older age of donor, recipient American Society of Anesthesiology (ASA) physical status category IV, cold ischemia time (CIT), and transplantation using the right kidney. The multivariate analysis showed that donor and recipient weight, donor age, transplantation using the right kidney, preservation in Eurocollins solution, ASA score, and CIT were associated with ATN. The incidence of rejection and renal function were not different at 3 months or 1 and 5 years. ATN is the main cause of DGF in kidney transplant recipients. ATN is caused by donor and recipient vascular background, grafting the right kidney, and CIT. ATN does not appear to have an adverse effect on long-term kidney function.     

Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity

Abstract: Background: The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation. Materials and methods: A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors’ personal files were reviewed. Results: Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization. Conclusions: Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.     

Optimizing the clinical utility of sirolimus‐based immunosuppression for kidney transplantation

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long‐term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection‐associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long‐term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI‐based regimens to sirolimus. Sirolimus‐containing regimens are associated with preservation of good renal function, with promising characteristics for improving long‐term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low‐dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI‐free combination with mycophenolate mofetil (following CNI‐to‐sirolimus conversion at 3‐6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.     

肝移植术后西罗莫司的替换治疗

目的 探讨肝移植术后应用西罗莫司的抗排斥替换治疗效果。方法 回顾性分析50例肝移植或肝肾联合移植患者替换西罗莫司前后肝肾功能的改善情况及副作用和排斥反应的发生率。34例联合应用小剂量FK506，9例联合应用骁悉，2例联合应用新山地明。5例术后远期患者，替换前仅用FK506，替换后单用西罗莫司。结果 24例患者因肝功能不良而替换西罗莫司，其中16例（66．7％）肝功能明显改善；18例患者肾功能不良，其中13例（72．2％）在2个月内肾功能明显好转；8例患者因大剂量应用FK506但其浓度未达到6ng／ml而替换西罗莫司，移植术后肝肾功能恢复良好，未出现排斥反应。本组中应用西罗莫司后出现急性排斥反应3例（6％），改用FK506后急性排斥反应治愈。11例（22％）出现白细胞及血小板减少，9例（18％）胆固醇和甘油三酯升高。这些副作用均在西罗莫司应用1月后出现，当停药或对症处理后消失。本组中未出现肝动脉血栓形成、伤口愈合不良等并发症。结论 肝移植术后应用钙调磷酸酶抑制剂发生肝肾功能不良或不能达到理想药物浓度时，西罗莫司是有效的抗排斥替代药物。     

Sirolimus used during pregnancy in a living related renal transplant recipient: a case report

OBJECTIVES: The majority of pregnancies after transplantation reported in the literature occurred in patients treated with a combination of calcineurin inhibitors, prednisolone, and azathioprine. There is little experience with newer drugs. We report a successful pregnancy in a kidney recipient with exposure to sirolimus-based immunosuppression. METHODS: We describe a case of successful delivery in a 30-year-old woman who became pregnant 1 year and 8 months after a living related renal transplantation. She received sirolimus, cyclosporine, and prednisolone before conception and during the first and second trimesters of gestation. RESULTS: The female recipient received sirolimus in combination with cyclosporine and prednisolone. During follow-up, her serum creatinine values were stable with pregnancy occurring at 1 year and 8 months after transplantation. At 27 gestational weeks, sirolimus was discontinued and she was maintained on cyclosporine and prednisolone. There were no signs or symptoms of graft rejection. A Cesarean section was performed at 39 weeks of gestation to deliver a healthy, 2994-g, Apgar 10, male infant. The renal function of the female recipient continued to be stable after delivery. CONCLUSION: To date, pregnancies in renal transplant recipients are still considered high risk. The U.S. National Transplantation Pregnancy Registry (NTPR) has reported increased rates of maternal and fetal complications. There have been no live births reported to the NTPR about female recipients exposed to sirolimus throughout gestation. We report a live birth without a structural defects with successful delivery after sirolimus use during the first and second trimesters of gestation.     

Interstitial Fibrosis Quantification in Renal Transplant Recipients Randomized to Continue Cyclosporine or Convert to Sirolimus

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between-group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R²= 0.07). By multivariate analysis diabetic patients had more fibrosis than non-diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1-year biopsies.     

Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.     

Early steroid withdrawal therapy in renal transplant recipients: a steroid-free sirolimus and CellCept-based calcineurin inhibitor-minimization protocol

BACKGROUND: Maintenance steroid therapy is associated with significant morbidity and mortality in renal transplant recipients. Elimination of the many long-term side effects of corticosteroids, including those that impinge on cardiovascular risk, remains a laudable goal in designing immunosuppressive protocols. However, concern persists that prednisone-free maintenance immunotherapy in kidney transplant recipients will result in an increase incidence of acute rejections, renal dysfunction and ultimate graft loss. METHODS: From 24 March 2003 to 1 December 2004, 84 kidney transplant recipients (61 deceased donor, 23 living donors) discontinued prednisone on post-operative day 6. Immunotherapy consisted of polyclonal antibody induction (thymoglobulin) for five d and prednisone intraoperatively with a rapid taper over the next six d. Maintenance therapy consisted of a sirolimus and CellCept-based calcineurin inhibitor-minimization protocol. Tacrolimus and mycophenolate mofetil (CellCept) were initiated on day 0. Sirolimus immunotherpay was started on post-operative day 6 concomitant with the cessation of steroids. We compared outcomes with that of our historical controls, treated with sirolimus and tacrolimus, who did not discontinue steroids. In addition, we analyzed outcomes independently for recipients of living and deceased donors in the steroid-free protocol. RESULTS: The recipients on prednisone-free maintenance immunosuppression had excellent 2.5-yr actuarial patient survival (97%), graft survival (93%), and acceptable acute rejection-free graft survival (89%). The mean serum creatinine level (+/-SD) at one yr was 1.5 +/- 0.6 mg/dL and at two yr was 1.5 +/- 0.6 mg/dL. We noted that 5% of recipients developed cytomegalovirus (CMV) syndrome; 1%, polyoma nephropathy; 1%, post-transplant lymphoproliferative disorder (PTLD), and 5% developed post-transplant diabetes mellitus (PTDM). In all, 91% of kidney recipients with functioning grafts remain steroid-free as of 31 December 2005. When compared with historical controls, the recipients on the early steroid-withdrawal (ESW) protocol had comparable graft survival, acute rejection-free survival, graft function, but significantly better patient actuarial survival (p = 0.048). In addition, recipients on the steroid-free protocol had decreased prevalence of four risk factors for cardiovascular disease when compared with historical controls: hypertension (p = 0.008), hyperlipidemia (p = 0.003), weight gain (p = 0.024), and incidence of PTDM (p = 0.015). CONCLUSION: Early steroid-withdrawal in renal transplant recipients with a sirolimus and CellCept-based calcineurin inhibitor-minimimization protocol can effectively reduce many of the steroid-related side effects, decrease risk factors for cardiovascular disease, and is associated with improved recipient survival without compromising graft function.     

Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation

m-TOR inhibitors (e.g. sirolimus) are well-tolerated immunosuppressants used in renal transplantation for prophylaxis of organ rejection, and are associated with long-term graft survival. Early use of sirolimus is often advocated by clinicians, but this may be associated with a number of side-effects including impaired wound-healing, lymphoceles and delayed graft function. As transplant clinicians with experience in the use of sirolimus, we believe such side-effects can be limited by tailored clinical management. We present recommendations based on published literature and our clinical experience. Furthermore, guidance is provided on sirolimus use during surgery, both at transplantation and for subsequent operations.