Conversion to Everolimus in Kidney Transplant Recipients With Calcineurin Inhibitor-Induced Nephropathy: 3 Case Reports

BackgroundCalcineurin inhibitors (CNIs), which remain the most important immunosuppressants in kidney transplant recipients, are a major cause of renal dysfunction due to CNI-induced nephropathy. However, a safe and effective CNI-sparing protocol is yet to be established. Herein, we report a case series of kidney transplant recipients experiencing CNI nephropathy, whose renal function is improved after conversion from CNIs to everolimus.CasesThe 3 kidney transplant recipients included in this study were diagnosed with CNI arteriolopathy by episode biopsy between 9 months and 11 years after transplantation. All patients received triple immunosuppressive therapy consisting of CNI (tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. All allografts were transplanted from elderly living donors to ABO-compatible and donor-specific antibody-negative recipients. All allograft biopsy specimens exhibited CNI arteriolopathy with alternative quantitative criteria for hyaline arteriolar thickening (aah score: 2 or 3), according to the Banff classification; however, histopathologic assessment did not show any evidence of allograft rejection. Conversely, total dose and blood concentrations of CNIs were within appropriate ranges. After conversion from CNIs to everolimus (1.5 mg/day, twice daily; trough level, 3–5 ng/mL), serum creatinine levels returned to baseline levels measured before the diagnosis of CNI arteriolopathy. In all patients, renal allograft function remained stable, with no evidence of donor-specific antibodies, 1 year after conversion from CNIs to everolimus.ConclusionConversion from CNIs to everolimus can safely and effectively improve renal function in kidney transplant recipients experiencing CNI-induced nephropathy.     

Calcineurin Inhibitors in Renal Transplantation Still Needed but in Reduced Doses: A Review

Despite their contribution in the success of organ transplantation, calcineurin inhibitors (CNIs) may be responsible for frequent and severe side effects that can affect graft survival and life expectancy. In this article, we have reviewed registry studies and randomized controlled trials (RCTs) that seek to avoid, withdraw, or minimize CNIs in renal transplant recipients. Attempts to completely avoid CNIs by administering mycophenolate mofetil (MMF) and/or sirolimus (SRL) have resulted in increased risks of rejection and side effects, with small advantage to improve renal graft function. Early withdrawal of CNIs after transplantation using administration of MMF can improve graft function but may be associated with a greater risk of acute or chronic rejection and graft failure. RCTs in which CNIs were replaced a few months after transplantation by SRL reported improved graft function among SRL-treated patients, but such a treatment was complicated by iatrogenic toxicity. Late replacement of CNIs with SRL did not produce a particular advantage and again was complicated by more frequent side effects. On the basis of these trials, it seems that CNI elimination can trigger rejection or side effects. Recent RCTs showed that minimization of CNI doses in association with everolimus does not increase the risk of rejection, allows one to obtain good graft function, and is well tolerated. Such an approach seems therefore preferable to complete elimination of CNIs with substitution of the current immunosuppressive drugs.     

Clinical recommendations for the use of everolimus in heart transplantation

Proliferation signal inhibitors (PSIs), everolimus (EVL), and sirolimus are a group of immunosuppressor agents indicated for the prevention of acute rejection in adult heart transplant recipients. Proliferation signal inhibitors have a mechanism of action with both immunosuppressive and antiproliferative effects, representing an especially interesting treatment option for the prevention and management of some specific conditions in heart transplant population, such as graft vasculopathy or malignancies. Proliferation signal inhibitors have been observed to work synergistically with calcineurin inhibitors (CNIs). Data from clinical trials and from the growing clinical experience show that when administered concomitantly with CNIs, PSIs allow significant dose reductions of the latter without loss of efficacy, a fact that has been associated with stabilization or significant improvement in renal function in patients with CNI-induced nephrotoxicity. The purpose of this article was to review the current knowledge of the role of PSIs in heart transplantation to provide recommendations for the proper use of EVL in cardiac transplant recipients, including indications, treatment regimens, monitoring, and management of the adverse events.     

Conversion from calcineurin inhibitor–based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients

The calcineurin inhibitors (CNIs) remain the standard of care for maintenance immunosuppression following renal transplantation. CNIs have demonstrated their effectiveness in reducing acute cellular rejection; however, some evidence suggests that these compounds negatively affect native renal function and are associated with allograft injury in renal transplant recipients. CNIs have also been linked with hypertension, new‐onset diabetes after transplantation, tremor, and thrombotic microangiopathy, which have significant consequences for long‐term allograft function and patient health overall. Thus, converting patients to a non‐CNI‐based regimen may improve renal function and also provide extrarenal benefits. A number of studies have been conducted that explore CNI conversion strategies in renal transplant recipients in an effort to improve long‐term allograft function and survival. These include converting to alternative, non‐nephrotoxic, maintenance immunosuppressants, such as the mammalian target of rapamycin inhibitors (sirolimus and everolimus) and the costimulation blocker belatacept. In this review of literature, evidence for the potential renal and extrarenal benefits of conversion to these non‐CNI‐based regimens is evaluated. Clinical challenges, including the adverse event profiles of non‐CNI‐based regimens and the selection of candidates for conversion, are also examined.     

Everolimus (Certican) in renal transplantation: a review of clinical trial data,current usage,and future directions

The efficacy and tolerability of everolimus have been demonstrated in a number of clinical trials, and there is also an increasing body of clinical experience. The efficacy of everolimus after renal transplantation is at least equivalent to that of mycophenolate mofetil. Studies combining everolimus with full- or reduced-dose cyclosporine (CsA) have shown that CsA exposure can be minimized, without increasing the risk of acute rejection, particularly when combined with therapeutic drug monitoring. A role for everolimus in regimens involving elimination of calcineurin inhibitors is currently being investigated. Everolimus with significantly reduced-dose CsA has not been shown to enhance CsA-related nephrotoxicity. Adverse events seen in trials of everolimus are generally class-specific and include edema, arthralgia, dyslipidemia, impaired wound healing, and proteinuria. A low incidence of malignancy has been observed with everolimus, and studies are ongoing to examine its antitumor effects in the treatment of certain malignancies. It seems likely that everolimus will continue to play a role in the development of reduced-exposure calcineurin inhibitor regimens and has considerable potential to improve outcomes for transplant recipients, focused perhaps on “old-for-old” transplant recipients and patients at high risk of poor graft function or malignancy. This review considers the available data on the clinical application of everolimus and identifies current and future strategies for improving outcomes after renal transplantation.     

Everolimus Represents an Advance in Immunosuppression for Patients Who Have Developed Cancer After Renal Transplantation

Renal transplantation provides the best quality of life for the patients with chronic end-stage renal failure. However, the immunosuppression necessary for graft survival may give rise to infectious complications, an increased risk of cardiovascular and neoplastic diseases, all of which can shorten the patient's survival. The objective of this study was to evaluate the efficacy and safety of the proliferation signal inhibitor immunosuppressant drugs everolimus among patients who develop neoplasms after renal transplantation. This retrospective study included 25 patients (mean age −56.5 ± 14.1 years) who were diagnosed with posttransplant neoplastic disease and immunosuppressed with calcineurin inhibitors (CNIs). Treatment was initiated with everolimus with or without CNIs. During the follow-up, the renal function (initial serum creatinine 1.4 mg/dL vs final serum creatinine 1.3 mg/dL) and proteinuria levels (initial 0.3 g/d vs final 0.4 g/d) remained stable. There was a low percentage of patients with relapse of their tumor. One patient had a relapse of bladder cancer with tumor progression at 3 years; another patient with melanoma developed lymph node invasion. There were neither acute rejection episodes nor cardiovascular complications. The results suggested that tumor relapse was low. The results suggested that immunosuppression with everolimus combined with low doses of CNIs or in single-drug therapy is safe immunosuppression for patients who develop posttransplant malignant diseases.     

Rapamycin in lung transplantation: preliminary results

INTRODUCTION: Rapamycin is a potent immunosuppressive agent with a different mechanism of action and different adverse effects from those of calcineurin inhibitors (CNIs). OBJECTIVE: To analyze our experience with rapamycin in patients undergoing lung transplantation and heart-lung transplantation in our center. PATIENTS AND METHODS: Patients were treated with rapamycin when showing chronic rejection and/or toxicity associated with the CNI after lung transplantation or heartlung transplantation. Patients with chronic rejection were administered rapamycin in combination with CNIs, whereas the CNIs were eliminated in patients with toxicity. RESULTS: Since October 2001, 7 patients (4 women), of mean age 45+/-15 years, received treatment with rapamycin (heart-lung transplantation, 2 cases; lung transplantation, 5 cases). The indications were chronic rejection in 4 patients and CMIs toxicity in 3 patients (kidney failure in 2 cases and optic neuropathy in 1 case). Pulmonary function stabilization was observed in 3 of 4 patients receiving rapamycin for chronic rejection. In the 3 patients with CNIs toxicity elimination of these drugs did not result in pulmonary functional deterioration. Patients with kidney failure showed an improvement in creatinine levels; visual acuity improved in the patient with optic neuropathy. We observed 2 infectious complications (pneumococcal pneumonia and pulmonary aspergillosis), which resolved with treatment. CONCLUSION: Rapamycin is an alternative for lung-transplant recipients who develop chronic rejection and/or CNIs toxicity.     

De Novo Everolimus-Based Therapy in Renal Transplant Recipients: Effect on Proteinuria and Renal Prognosis

Background

In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation.

Methods

We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation.

Results

The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 ± 0.5, 0.5 ± 0.3, 0.47 ± 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 ± 24 vs 73.04 ± 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 ± 29 mL/min).

Conclusion

EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.     

Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.     

Incidence of donor‐specific antibodies in kidney transplant patients following conversion to an everolimus‐based calcineurin inhibitor‐free regimen

Scarce data exist regarding the incidence of donor‐specific antibodies (DSAs) in kidney transplant patients receiving everolimus‐based immunosuppression without calcineurin inhibitors (CNIs). The aim of this retrospective case–control study was to compare the incidence of de novo DSAs in patients converted to an everolimus‐based regimen without CNIs with that seen in patients maintained on CNIs. Sixty‐one DSA‐free kidney transplant patients who had been converted to an everolimus‐based regimen (everolimus group) were compared to 61 other patients maintained on CNIs‐based regimen (control group). Patients were matched according to age, gender, induction therapy, date of transplantation, and being DSA‐free at baseline. At last follow‐up, the incidence of DSAs was 9.8% in the everolimus group and 5% in the control group (p = ns). In the everolimus group, the increased incidence of DSAs between baseline and last follow‐up was statistically significant. Antibody‐mediated rejection occurred in 6.5% in the everolimus group and 0% in the CNIs group. The incidence of DSAs is numerically increased in kidney transplant patients treated with an everolimus‐based without CNIs. A study including a larger number of patients is required to determine whether a CNI‐free everolimus‐based immunosuppression significantly increases DSAs formation.     

Calcineurin inhibitors affect circulating regulatory T cells in stable renal transplant recipients

INTRODUCTION: Immunosuppression, although crucial for short-term management, has been described in renal transplantation to be a major hurdle for long-term graft survival. Efforts have been directed at achieving a true state of allotolerance, thereby reducing the load of immunosuppression. Recently, increased frequencies of CD4(+)CD25(high) regulatory T cells (Tregs) have been described as an additional mechanism to induce alloimmune tolerance. MATERIALS AND METHODS: We assessed 64 renal transplant recipients with stable renal function for at least 1 year, divided into two groups: one composed of patients receiving rapamycin but not calcineurin inhibitors (CNIs), and another, of those receiving CNIs but not rapamycin. RESULTS: We demonstrated that T cells with a regulatory phenotype were decreased in peripheral blood of renal transplant recipients under CNI therapy compared to those who were CNI-free. The Tregs in our patients showed a modest association with renal function as measured by the delta serum creatinine, which was not significant. CONCLUSIONS: CNIs, but not rapamycin, reduce the frequencies of circulating Tregs in renal transplant recipients. The use of rapamycin might be further exploited in strategies reducing immunosuppression in renal transplantation. Furthermore, quantification of blood Tregs may be a suitable tool to identify those recipients who are candidates for reducing immunosuppression.     

Calcineurin inhibitor sparing regimens using m‐target of rapamycin inhibitors: an opportunity to improve cardiovascular risk following kidney transplantation?

Maintenance therapy with calcineurin inhibitors (CNIs) increases cardiovascular risk. Use of the m‐TOR inhibitors everolimus or sirolimus to minimize CNI exposure is usually undertaken to preserve renal function following kidney transplantation, but may also improve cardiovascular risk status. Recent studies of early conversion from CNI to m‐TOR inhibitors have shown a numerical improvement in the incidence of hypertension, but results are not clear‐cut. Dyslipidaemia, in contrast, is more frequent under m‐TORs than with CNI‐based immunosuppression. New‐onset diabetes is rare (≤5%) using modern m‐TOR regimens, for example, everolimus and reduced‐exposure CNI. Renal function improvement with m‐TOR inhibitor regimens versus CNIs would also be expected to improve cardiovascular risk. Moreover, m‐TOR‐based CNI‐minimization regimens are not associated with proteinuria, a known cardiovascular risk factor, with the possible exception of late conversion in patients with poor renal function. Interestingly, m‐TOR inhibitors may also exert cardioprotective effects. Animal data suggest that m‐TORs may restrict the pathogenesis of atherosclerosis, consistent with preliminary clinical data that conversion from CNIs to everolimus can stabilize markers for arterial stiffness. In conclusion, use of m‐TORs has the potential to lessen the toll of cardiovascular disease following kidney transplantation – an opportunity that merits further exploration.     

Conversion from calcineurin inhibitors to everolimus with low-dose cyclosporine in renal transplant recipients with squamous cell carcinoma of the skin

Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in renal transplant recipients. Conversion to mammalian target of rapamycin inhibitors after diagnosis of SCC may reduce the incidence of recurrence of skin cancer. This retrospective study evaluated the outcome of renal transplant recipients followed by the Renal Unit with posttransplant diagnosis of SCC treated with conversion from calcineurin inhibitors (CNIs) to Everolimus (EVR) associated with low-dose cyclosporine. Eleven patients developed SCC at a median time from renal transplantation of 107 months (range 36-264). Five patients with creatinine clearance (CCl) below 40 mL/min before conversion developed end stage renal disease (two cases) or further deterioration of renal function (two cases); only one patient in this group maintained a stable renal function. The remaining six patients with a CC1 greater than 40 mL/min and proteinuria below 0.8 g/24 hours maintained a stable renal function after conversion to EVR at a median follow-up of 22 months (range 15-75). Conversion from CNIs to EVR has been proven safe, effective, and associated with low recurrence of SCC in patients with a CCl >40 mL/min. In the case of preexisting deterioration of renal function or significant proteinuria, conversion to EVR should be carefully evaluated.     

Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results.

Everolimus is a macrolide immunosuppressive agent with known consistent absorption. In this double-blind study, we examined the safety and tolerability of everolimus vs. placebo in de novo liver transplant recipients. One hundred and nineteen liver allograft recipients were randomized to 1 of 4 groups: everolimus 0.5 mg bid, everolimus 1.0 mg bid, everolimus 2 mg bid, or placebo. Patients received oral cyclosporine to achieve a target trough level of 150-400 ng/mL in combination with prednisone. Primary and secondary endpoints of safety, tolerability, and efficacy were determined at 12 months, and patients were followed through 36 months. There was a trend toward fewer treated acute rejections in the everolimus group than in the placebo group: everolimus 0.5 mg: 39.3%; everolimus 1.0 mg: 30.0%; everolimus 2 mg: 29.0%; placebo: 40.0% (P = not significant). Adverse events were higher in everolimus-treated patients especially at the 4-mg/day dose, but there was no difference in the incidence of thrombocytopenia or leukopenia between all groups and renal function as determined by serum creatinine, and creatinine clearance remained stable to 36 months in everolimus-treated patients. Mean cholesterol and triglycerides increased from baseline in all treatment groups, and maximum levels were seen at 6 months. In conclusion, this study demonstrates that everolimus in combination with oral cyclosporine had an acceptable safety and tolerability profile, paving the way for additional studies in this transplant indication.     

Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review

Calcineurin inhibitors (CNIs) have been associated in a dose‐dependent fashion with an increased risk of post‐transplant hepatocellular carcinoma (HCC) recurrence. The mammalian target of rapamycin inhibitors (mTORi) (sirolimus/everolimus) might represent an alternative immunosuppressive regimen with antineoplastic effect. In the present systematic review, the association between mTORi and HCC recurrence after liver transplantation (LT) was evaluated and compared against that of CNIs‐treated patients. In total, 3666 HCC liver transplant recipients from 42 studies met the inclusion criteria. Patients under CNIs developed HCC recurrence significantly more frequently, compared with patients under mTORi (448/3227 or 13.8% vs. 35/439 or 8%, P < 0.001), although patients treated with CNIs had a higher proportion of HCC within Milan criteria (74% vs. 69%) and lower rates of microvascular invasion, compared with mTORi‐treated patients (22% vs. 44%) (P < 0.05). Patients on everolimus had significantly lower recurrence rates of HCC, compared with those on sirolimus or CNIs (4.1% vs. 10.5% vs. 13.8%, respectively, P < 0.05), but everolimus‐treated recipients had shorter follow‐up period (13 vs. 30 vs. 43.2 months, respectively) and more frequently been transplanted for HCC within Milan criteria (84% vs. 60.5% vs. 74%, respectively, P < 0.05). Our findings favor the use of mTORi instead of CNIs to control HCC recurrence after LT, but comparative studies with longer follow‐up are needed for final conclusions.     

The clinical impact of chronic transplant glomerulopathy in cyclosporine era

BACKGROUND: The clinical impact of chronic transplant glomerulopathy (CTG) on the outcome of kidney allograft receiving calcineurin inhibitors (CNIs) remains uncertain. A retrospective study of renal transplant recipients at Ospedale Maggiore of Milan was undertaken to evaluate the clinical outcome of patients with CTG. METHODS: Among 666 biopsies taken at least 6 months after transplantation (Tx) in 498 transplant patients treated with CNIs, 28 cases (5.6%) of chronic transplant glomerulopathy (CTG) were identified and their clinical features at Tx, at follow-up and graft survival were compared with those of 56 controls transplanted in the same period and with kidney functioning 12 months after Tx. Clinical characteristics at biopsy and at 1 year after Tx were similar in the two groups. RESULTS: After diagnosis graft function deteriorated in 22 patients (78.5%), while it remained stable in 6. Graft loss developed in 92 % of patients with proteinuria >2.5 g/day and in 33 % of those with lower proteinuria (P<0.005). In cases with more severe CTG the rate of graft loss was higher, though not significantly. Graft survival at 10 years was 48% in patients with CTG and 88% in controls (P<0.0001). CONCLUSIONS: The incidence and clinical course of CTG do not seem to be modified by CNI-based immunosuppression. The evolution is unpredictable but the severity of glomerulopathy and proteinuria at follow-up are associated with progression to graft failure. Patients with CTG have a graft survival significantly worse than that of the general population of transplanted patients.     

An Atypical Presentation of Thrombotic Microangiopathy After Lung Transplant: A Case Report

Thrombotic microangiopathy (TMA) is a pathologic condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to microvascular endothelial lesions and thrombosis. It occurs in a variety of diseases and, unless recognized and treated, leads to severe morbidity and mortality. We present the case of a 48-year-old woman who underwent lung transplantation, initially under tacrolimus, mycophenolate mofetil (MMF), and prednisolone. Several complications emerged in the following months, including abdominal aortic and left renal artery thrombosis and cutaneous infections, although her renal function remained normal. Six months after transplant, her renal function began to deteriorate, which was assumed to be due to elevated tacrolimus levels and doses were adjusted. Due to leukopenia, MMF was changed to everolimus. One year after, she was admitted with fatigue, anemia, and renal dysfunction. Complementary exams revealed only iron deficiency, leukopenia, normal platelets, and elevated lactate dehydrogenase; her renal ultrasound was normal. A renal biopsy was performed and thrombotic microangiopathy was subsequently identified as the main cause of the renal dysfunction. Tacrolimus was therefore discontinued and MMF restarted with slow improvement of renal function. Only when everolimus was stopped did the patient's renal function show incremental improvement. TMA may be a serious complication after lung transplantation and the risk is higher when a combination of tacrolimus and everolimus is used. Renal biopsy findings are essential to confirm the final diagnosis of TMA, allowing for a change in immunosuppression to prevent permanent and severe renal damage.     

Experience of Using Everolimus in the Early Stage of Living Donor Liver Transplantation

Objectives

The aim of our study was to review the experience of early use of everolimus for recipients after adult-to-adult living donor liver transplantation.

Methods

From February 2012 to December 2012, 80 recipients underwent living donor liver transplantation. Forty-three of them used everolimus as an adjunct to the calcineurin inhibitors (CNIs) in the early postoperative period. Thirty-nine patients had hepatocellular carcinoma (HCC) and poor renal function was noted in 9 patients. Ten of them were females and 33 were males. The age varied from 39 to 75 years old. The starting date of use was within 1 week in 33 patients, 2 weeks in 9 patients, and 1 patient was administered on postoperative day 20. The initial doses of everolimus were 0.25 mg every 12 hours and increased to 0.5 mg every 12 hours to target the level at 3–5 ng/mL. Doppler ultrasound was performed regularly postoperative days 1, 4, and 14.

Results

The mean time between liver transplantation and everolimus treatment was 12 ± 8 days. The maximum dose of everolimus used was 1 mg/d with a target trough level between 3 and 5 ng/mL. At 3 months, a target trough level of 3 ng/mL was achieved. Six of 9 renal failure patients showed significant recovery of renal function, whereas 3 of them showed further deterioration and 1 required hemodialysis. During the follow-up period of 9 ± 6 months, all showed good patency of hepatic artery without thrombosis. Three patients (7%) developed HCC recurrence, whereas 1 patient died at the 10th month postoperative due to sepsis. Elevation of lipid profile was noted in 5 patients. Stomatitis was the most frequent side effect and occurred in 15 patients.

Conclusions

The early use of everolimus was safe and feasible. Also, it can be safely used in patients with prior renal failure while reducing the doses of CNIs. Although the recurrence rate of HCC was reduced, further study is ongoing to evaluate the long-term impact of everolimus on prevention of HCC recurrence.     

Possible role of everolimus in improving renal function in long-term heart transplantation

Patient survival after heart transplantation has improved dramatically since the availability of calcineurine inhibitor (CNIs); the number of long-term patients is progressively increasing. However, in these patients, nephrotoxicity of CNIs has been largely responsible for the progressive development of renal dysfunction. Since impaired renal function is an important issue that reduces long-term patient survival, it is important to develop strategies to improve renal function while maintaining immunologic safety to preserve graft function. Everolimus is an mTOR inhibitor sirolimus analogue, that has proved, to be highly efficacious to prevent acute myocardial rejection and reduce the severity of cardiac allograft vasculopathy in de novo HTx patients. There is reasonable evidence that, in long term heart transplanted patients, renal function may improve when everolimus is administered associated with a progressive reduction of CNIs. So far there is no evidence to identify which patient may benefit from this therapeutic approach. Indeed everolimus alone may be equally effective to prevent rejection and improve renal function when CNIs are completely discontinued, but data are still lacking on the risks, dosages and side effects of this type of immunosuppression. Ongoing clinical studies will provide further guidance about the possibility to halt or reduce the progression of renal impairment in long term heart transplant patients.