Conversion from sirolimus to everolimus in kidney transplant recipients receiving a calcineurin-free regimen

Carvalho C, Coentrão L, Bustorff M, Patrício E, Sampaio S, Santos J, Oliveira G, Pestana M. Conversion from sirolimus to everolimus in kidney transplant recipients receiving a calcineurin‐free regimen.
Clin Transplant 2011: 25: E401–E405. © 2011 John Wiley & Sons A/S. Abstract: Background: Everolimus (EVL) and sirolimus (SRL) were introduced into immunosuppressive regimens, in an attempt to replace or reduce the dose of the nephrotoxic calcineurin inhibitors (CNI). In our institution, due to an administrative decision, conversion from SRL to EVL, was carried out, providing us the opportunity to investigate the effectiveness and safety profile of both drugs and to review the practical conversion dose between them. Methods: We retrospectively analyzed the medical records of 51 maintenance kidney transplant recipients receiving an SRL‐based CNI‐free regimen, who were switched to EVL. SRL dose was concentration controlled to a through level of 4–8 ng/mL. Patients were converted to a variable dose of EVL that was adjusted to achieve a trough concentration of 3–8 ng/mL. Results: SRL mean dose at time of conversion was 2.0 ± 0.9 mg/d. Initial EVL mean dose was 1.3 ± 0.5 mg/d. Six months after conversion, mean EVL trough level was 6.2 ± 2.8 ng/mL. EVL dose at this point was 2.0 ± 0.9 mg/d, which was not statistically different from SRL dose at the time of conversion (p = 0.575), suggesting a conversion factor of 1:1. During this six month period post conversion, no significant changes were observed in serum creatinine, hematocrit level, platelet count, proteinuria or lipid levels. No patient experienced an acute rejection episode. Conclusions: Conversion from SRL to EVL in renal transplant recipients receiving a CNI‐free immunosuppressive regimen can be performed safely with a low trough level range of EVL. We report for the first time a conversion factor between SRL and EVL.     

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.     

The role of mammalian target of rapamycin inhibitors in the management of post‐transplant malignancy

Post‐transplant malignancies, which occur either de novo or as cancer recurrences, are due to chronic exposure to immunosuppressive agents and are often more aggressive than those that develop in the non‐transplant setting. Mammalian target of rapamycin (mTOR) inhibitors have antitumor and immunosuppressive effects. The dual effects of this class of agents may provide adequate immunosuppression to prevent organ rejection while simultaneously reducing the risk of post‐transplant malignancy. mTOR inhibitors have become established approved agents for treating renal cell carcinoma and other cancers and, as reviewed herein, accumulating experience among organ transplant recipients collectively points toward a potential to prevent the development of de novo malignancies of various types in the post‐transplant period. To date, most research efforts surrounding mTOR inhibitors and cancer control in the transplant population have been in the area of skin cancer prevention, but there have also been interesting observations regarding regression of post‐transplant Kaposi's sarcoma and post‐transplantation lymphoproliferative disorder that warrant further study.     

Effect of mTOR inhibitor on body weight: from an experimental rat model to human transplant patients

The aim was to study the influence of sirolimus (SRL) on body weight in a rat model and in kidney transplant patients. Wistar rats (15 weeks old) were either treated with vehicle (VEH; n = 8) or SRL (n = 7) 1.0 mg/kg three times per week for 12 weeks. Body mass and food intake were measured weekly. Adipocyte diameter was determined in hematoxylin–eosin stains. The body mass index (BMI) obtained from clinical kidney transplant trials comparing SRL‐based with cyclosporine‐based therapy was analyzed. Animals: SRL produced a decrease of the weight gain curve. At the end of the study, mean body weight in the SRL group was lower than in the VEH group (356 vs. 507 g, P < 0.01) in spite of comparable food intake normalized for body weight was not different. Mean adipocyte diameter was 36 μm in VEH and 25 μm in SRL rats (P = 0.009). Mean SRL blood trough concentration was 38 ng/ml. Kidney transplant patients: Two years after transplantation, BMI was significantly lower in the SRL‐based treatment arm compared to cyclosporine (24.17 ± 2.99 vs. 25.97 ± 5.01 kg/m², P = 0.031). SRL treatment leads to less body mass. Adipocyte cell diameter was reduced in SRL‐treated animals. A possible explanation may be the effects of SRL on metabolic regulation and cell growth.     

Mammalian target of rapamycin inhibition after solid organ transplantation: can it,and does it,reduce cancer risk?

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been increasingly used as immunosuppressants for recipients of solid organ transplants. Over the years, potential advantages unique to this class of immunosuppressants have been recognized, including chemoprevention by virtue of their antiproliferative effects. Prevention of malignancy after transplant through mTOR inhibitor‐based immunosuppression may have a specific practical application in transplant recipients with preexisting malignancy including hepatocellular carcinoma or cholangiocarcinoma. This review will reveal how the biochemistry of the mTOR pathway, as it pertains to chemoprevention, can support a clinical role for mTOR inhibitors in the prevention of malignancies, recurrent or de novo, after solid organ transplantation in selected patients.     

Chronic allograft nephropathy – a clinical syndrome: early detection and the potential role of proliferation signal inhibitors

Abstract: Chronic allograft nephropathy (CAN) leads to the majority of late graft loss following renal transplantation. Detection of CAN is often too late to permit early intervention and successful management. Most current strategies for managing CAN rely on minimizing or eliminating calcineurin inhibitors (CNIs) once CAN has become established. The proliferation signal inhibitors everolimus and sirolimus have potent immunosuppressive and antiproliferative actions, with the potential to alter the natural history of CAN by reducing CNI exposure whilst avoiding acute rejection. Whilst data will be forthcoming from a number of clinical trials investigating this potential, we discuss early detection of CAN and the rationale for a role for this class of agent.     

Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions

Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.     

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.     

Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up.

BACKGROUND: Whether corticosteroid and immunosuppressive therapy may be safely withdrawn in patients with proliferative lupus nephritis is still unclear. METHODS: In 32 patients with biopsy-proven proliferative lupus nephritis previously put into remission, therapy was gradually tapered off. RESULTS: When immunosuppressive therapy was stopped (median: 38 months; 25th-75th percentile: 24-81 months, after biopsy), 24 patients were in complete remission and eight had a median proteinuria of 1.05 g/24 h (25th-75th percentile: 0.91-1.1 g/24 h) with normal renal function. After stopping therapy, patients were followed for a median of 203 months (25th-75th percentile: 116-230 months). Fifteen patients (Group 1) never developed lupus activity. The other 17 patients (Group 2) developed lupus exacerbations in a median of 34 months (25th-75th percentile: 29-52 months) after stopping therapy and were re-treated. The only significant differences between the two groups were the longer median durations of treatment, 57 months (25th-75th percentile: 41.5-113.5 months) vs 30 months (25th-75th percentile: 18-41 months; P<0.009), and remission, 24 months (25th-75th percentile: 18-41) vs 12 months (25th-75th percentile: 7-20 months; P<0.02), before stopping therapy in Group 1 than in Group 2. At last follow-up, 12 patients of Group 1 were in complete remission, two had mild proteinuria and one had died. In Group 2, one patient died, 14 were in complete remission, one had mild proteinuria and in another patient serum creatinine doubled. CONCLUSIONS: Some patients with severe lupus nephritis who enter stable remission can be maintained without any specific treatment for many years. Those patients who have new flares can again go into remission with an appropriate treatment. The longer the treatment and remission before withdrawal, the lower the risk of relapse.     

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.     

Pulse cyclophosphamide induction treatment in Thai children with diffuse proliferative lupus nephritis

Aim: To report the effectiveness of pulse cyclophosphamide induction therapy and to identify predictors for unresponsiveness to treatment in Thai children. Methods: Children with biopsy‐proven diffuse proliferative lupus nephritis admitted to Chiang Mai University hospital between 2001 and 2006 were retrospectively studied. Patients received a test dose of 750 mg/m² at the first month followed by six cycles of monthly cyclophosphamide (IVCY) at a dose of 1 g/m² (maximum 1 g) as induction therapy. Responsiveness to treatment, defined as urinary protein to creatinine ratio of less than 0.3 with normalization of C3 level and clinical remission, was assessed at the end of the induction period. Gender, age at onset, duration of disease before treatment, hypertension, clinical nephrotic syndrome, amount of proteinuria, serum creatinine, creatinine clearance, serum C3 level and crescentic formation were compared between responsive and nonresponsive groups. Maintenance therapy with quarterly pulse IVCY or Azathioprine or Mycophenolate mofetil was given for 18–24 months after remission. Results: Twenty nine patients with a mean age of 10.3 ± 2.6 years were studied. Hypertension, microscopic haematuria and nephrotic‐range proteinuria were seen in 66%, 86% and 60% of the patients, respectively. Forty‐one per cent of biopsies showed cellular or fibrocellular crescents. Twenty patients (69%) achieved remission at the end of induction therapy. There were no significant differences in all parameters studied between responsive and nonresponsive groups. The relapse rate after maintenance therapy was 58.8%. Conclusion: Our results show that pulse cyclophosphamide is an effective regimen for induction therapy in children with diffuse proliferative glomerulonephritis. No definite predictor for unresponsiveness was detected in this study.     

狼疮性肾炎94例的治疗总结

目的:探讨中西医结合治疗狼疮性肾炎(IN)的疗效。方法:随机设置中西医组和西医组,分别为94例、84例,两组进行有效率、复发率、副作用的比较。结果:西医组总有效率80.9％,复发率21.4％,副作用发生率77.1％;中西医组总有效率94.6％,复发率4.2％,副作用发生率38.0％,中西医组总有效率高于西医组(P<0.05)。结论:中西医结合治疗在提高疗效,减少复发及减轻副作用均显著优于西医组。     

Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: A case report

Epithelioid angiomyolipoma has malignant potential; however, no effective therapy has been established for advanced cases. A 50‐year‐old woman with a history of right nephrectomy for epithelioid angiomyolipoma was referred to our institution. Computed tomography and magnetic resonance imaging showed multiple tumors in her lung, liver and pelvic cavity. The liver and pelvic tumor specimens obtained by needle biopsy confirmed the diagnosis of epithelioid angiomyolipoma recurrence. The patient was treated with everolimus (10 mg/day). Three months later, pulmonary lesions disappeared; liver and pelvic tumors significantly shrank in size, but the pelvic tumor gradually enlarged again. We carried out surgical resection of the residual liver and pelvic cavity tumors. Although the mammalian target of rapamycin inhibitor seems to be effective for treating epithelioid angiomyolipoma, its long‐term effects remain unknown. Thus, aggressive administration of a multidisciplinary treatment including molecular target therapy and surgical resection is required to improve the prognosis of epithelioid angiomyolipoma.