Calcineurin Inhibitor-free Immunosuppression Research Articles

Calcineurin-inhibitor free immunosuppression after lung transplantation - a single center case-control study in 51 patients converted to Mechanistic Target of Rapamycin (mTOR) inhibitors.

Data on calcineurin-inhibitor (CNI) free immunosuppression after lung transplantation (LTx) are limited. Aim of this study was to investigate CNI-free immunosuppression using mechanistic target of rapamycin (mTOR) inhibitors. This retrospective analysis was performed at a single center. Adult patients after LTx without CNI during the follow-up period were included. Outcome was compared to those LTx patients with malignancy who continued CNI. Among 2,099 patients in follow-up, fifty-one (2.4%) were converted median 6.2 years after LTx to a CNI-free regimen combining mTOR inhibitors with prednisolone and an antimetabolite, two patients were switched to mTOR inhibitors with prednisolone only. In 25 patients, malignancies without curative treatment options were the reason of the conversion, with a 1-year survival of 36%. The remaining patients had a 1-year survival of 100%. Most common non-malignant indication was neurological complications (n = 9). Fifteen patients were re-converted to a CNI-based regimen. The median duration of CNI-free immunosuppression was 338 days. No acute rejections were detected in 7 patients with follow-up biopsies. In multivariate analysis, CNI-free immunosuppression were not associated with improved survival after malignancy. The majority of patients with neurological diseases improved 12 months after conversion. Glomerular filtration rate increased by median 5 (25 and 75% percentiles -6; +18) ml/min/1.73 m2. mTOR inhibitor based CNI-free immunosuppression may be safely performed in selected patients after LTx. This approach was not associated with improved survival in patients with malignancy. Significant functional improvements were observed in patients with neurological diseases.

Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers After Renal Transplantation.

Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio <1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio <1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.

Chromoblastomycosis in a renal allograft recipient on calcineurin inhibitor-free immunosuppression

Superficial cutaneous fungal infections are common in our country in the kidney transplant recipients. However, deep fungal infections involving the skin and subcutaneous tissue are relatively rare. Here, we report a case of chromoblastomycosis in a renal allograft recipient on a calcineurin inhibitor-free immunosuppression. The case highlights the importance of skin biopsy in differentiating various skin lesions in transplant patients and the role of the early institution of appropriate treatment in successfully treating these infections.

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression.

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n=70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n=41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P<.01; P<.001) and maintenance HTx recipients (P<.001; P<.01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P=.021) and 3years (P=.005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.

Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function.

Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus-based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low-intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade-based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor-free immunosuppression.

(933) - Calcineurin Inhibitor Free Immunosuppression in Heart Transplant Recipients Is Associated with Preserved Renal Function and Good Survival: Long Term Follow-Up

(933) - Calcineurin Inhibitor Free Immunosuppression in Heart Transplant Recipients Is Associated with Preserved Renal Function and Good Survival: Long Term Follow-Up

Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection.

The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor-free immunosuppression regimen.

The Effect of ASP2409, a Novel CD86-Selective Variant of CTLA4-Ig, on Renal Allograft Rejection in Nonhuman Primates.

Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients. To address these issues, a novel CTLA4-Ig variant, ASP2409, with improved CD86 binding selectivity and affinity relative to belatacept was created using DNA shuffling directed evolution methods. We evaluated the immunosuppressive effect of ASP2409 on in vitro alloimmune T cell responses, in vivo tetanus toxoid (TTx)-induced immunological responses and renal transplantation in cynomolgus monkeys. ASP2409 had 6.1-fold higher and 2.1-fold lower binding affinity to monkey CD86 and CD80 relative to belatacept, respectively. ASP2409 was 18-fold more potent in suppressing in vitro alloimmune T cell responses relative to belatacept. In a cynomolgus monkey TTx immunization model, ASP2409 inhibited anti-TTx immune responses at a 10-fold lower dose level than belatacept. In a cynomolgus monkey renal transplantation model, subcutaneous injection of 1 mg/kg ASP2409 prevented allograft rejection through complete CD86 and partial CD80 receptor occupancies and dramatically prolonged renal allograft survival in combination with tacrolimus or mycophenolate mofetil/methylprednisolone. These results support the potential of ASP2409 as an improved CTLA4-Ig for maintenance immunosuppression in organ transplantation.

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Heart Transplantation Recipients: Sirolimus as a Primary Immunosuppressive Agent

Purpose Sirolimus may reduce the development of coronary vasculopathy and calcineurin inhibitor (CNI)-induced nephropathy in adult heart transplant patients. We report our experience with sirolimus as a primary immunosuppressive agent in pediatric heart transplant patients. Methods and Materials We retrospectively reviewed records for all pediatric heart transplant patients for whom we attempted conversion to a CNI-free sirolimus-based regimen. Patients were treated routinely with an anti-metabolite medication in addition to sirolimus, with or without steroids. We examined records for demographics, episodes of rejection, and serum measures of renal function. Results We identified 18 patients (mean age at transplant 7.8 years, range 0.1–21 yrs, 45% female) for whom we attempted conversion to a sirolimus-based regimen an average of 39±46 months post transplant. Of these 18, 4 patients had to discontinue sirolimus due to side effects (pneumonitis, aphthous ulcers, proteinuria, and dactylitis). The remaining 14 patients (mean age at transplant 7.6 years, range 0.1–21 yrs, 43% female) were successfully converted over a period of 88±52 days to the CNI-free immunosuppressive protocol. Follow-up was available for an average of 2.7±2.6 years post-conversion. For these 14 patients, there was no significant difference between the rate of rejection while taking CNIs prior to conversion (0.21 rejection episodes per patient-year) compared to post-conversion (0 rejection episodes per patient-year). Serum creatinine was decreased from 1.0±0.6 mg/dL pre-conversion to 0.8±0.4 post-conversion, and 0.8±0.6 at latest follow-up, however this did not reach statistical significance. Conclusions In this small cohort, a CNI-free sirolimus-based immunosuppressive regimen was not associated with an increased rejection rate or change in markers of renal function. The use of sirolimus as a primary agent in pediatric heart transplant patients warrants further evaluation.

Tacrolimus with mycophenolate mofetil or sirolimus compared with calcineurin inhibitor-free immunosuppression (sirolimus/mycophenolate mofetil) after heart transplantation: 5-year results

Despite improvements in immunosuppressive therapy, the most advantageous combination for cardiac transplant recipients has not been established. This randomized controlled trial was performed to evaluate the efficacy and safety of 3 immunosuppressive protocols. Between 2003 and 2005, 78 de novo cardiac transplant recipients were randomized 2:2:1 to receive steroids and tacrolimus plus mycophenolate mofetil (TAC/MMF; n = 34), TAC and sirolimus (TAC/SRL; n = 29), or SRL and MMF (SRL/MMF) plus anti-thymocyte globulin (ATG; n = 15). Steroids were withdrawn after 6 months. The 5-year survival was 85.3% for TAC/MMF, 93.1% for TAC/SRL, and 86.7% for SRL/MMF (p = 0.31 for TAC/MMF vs TAC/SIR; p = 0.47 for TAC/MMF vs SIR/MMF and p = 0.86 for TAC/SIR vs SIR/MMF). Despite the use of ATG, patients in the SRL/MMF group revealed numerically fewer freedom from acute rejection episodes: TAC/MMF, 82.4%; TAC/SRL, 85.2%; SRL/MMF, 73.3% (p = 0.33). Mean creatinine at 5 years revealed preservation of renal function in the SRL/MMF vs the TAC/MMF group (p = 0.045): TAC/MMF, 1.70±0.91 mg/dl; TAC/SRL, 1.44±0.65 mg/dl; and SRL/MMF, 1.25±0.46 mg/dl. Freedom from cardiac allograft vasculopathy was improved in the SRL/MMF group (93.3%) compared with TAC/MMF (73.5%) and TAC/SRL (80.8%) groups, reaching no statistical significance. Freedom from cytomegalovirus infection was TAC/MMF, 72.2%; TAC/SRL, 89.7%; and SRL/MMF, 86.7%. There was a trend toward improved freedom from cytomegalovirus infection with TAC/SRL vs TAC/MMF (p = 0.076). More frequent discontinuations of study medication occurred in SRL-based immunosuppression protocols (TAC/SRL vs TAC/MMF, p = 0.034; SRL/MMF vs TAC/MMF, p = 0.003). The 3 strategies yield no survival advantage at 5 years, with higher numeric rates of rejection and adverse effects in the calcineurin inhibitor-free arm. A trend was observed in favor of freedom from cardiac allograft vasculopathy and preservation of renal function in the calcineurin inhibitor-free arm. However, the clinical relevance on outcomes is unclear because only few patients were receiving the assigned treatment protocols.

Prospective randomized 3-arm trial comparing tacrolimus with mycophenolate mofetil (MMF) or sirolimus with calcineurininhibitor-free immunosuppression (Sirolimus/MMF) after heart transplantation: 5-year results

Prospective randomized 3-arm trial comparing tacrolimus with mycophenolate mofetil (MMF) or sirolimus with calcineurininhibitor-free immunosuppression (Sirolimus/MMF) after heart transplantation: 5-year results

Monitoring of CD4+CD25highIL-7Rαhigh activated T Cells in Kidney Transplant Recipients

In humans, circulating CD4(+)CD25(high) T cells contain mainly regulatory T cells (Treg; FoxP3(+)IL-7Rα(low)), but a small subset is represented by activated effector T cells (Tact; FoxP3(-)IL-7Rα(high)). The balance between Tact and Treg may be important after transplantation. The aim of this study was first to analyze and correlate CD4(+)CD25(high) Tact and Treg with the clinical status of kidney transplant recipients and second to study prospectively the effect of two immunosuppressive regimens on Tact/Treg during the first year after transplantation. CD4(+)CD25(high) Tact and Treg were analyzed by flow cytometry, either retrospectively in 90 patients greater than 1 year after kidney transplantation (cross-sectional analysis) or prospectively in 35 patients receiving two immunosuppressive regimens after kidney transplantation (prospective analysis). A higher proportion of Tact and a lower proportion of Treg were found in the majority of kidney recipients. In chronic humoral rejection, a strikingly higher proportion of Tact was present. A subgroup of stable recipients receiving calcineurin inhibitor-free immunosuppression (mycophenolate mofetil, azathioprine, or sirolimus) had Tact values that were similar to healthy individuals. In the prospective analysis, the proportion of Tact significantly increased in both immunosuppression groups during the first year after transplantation. These data highlight distinct patterns in the proportion of circulating Tact depending on the clinical status of kidney recipients. Moreover, the prospective analysis demonstrated an increase in the proportion of Tact, regardless of the immunosuppressive regimen. The measurement of Tact, in addition to Treg, may become a useful immune monitoring tool after kidney transplantation.

Increased Incidence of Acute Graft Rejection on Calcineurin Inhibitor–Free Immunosuppression After Heart Transplantation

Background Calcineurin inhibitor (CNI)–free immunosuppression is used increasingly after heart transplantation to avoid CNI toxicity, but in the absence of a randomized trial, concerns remain over an increased rejection risk. Methods We studied the incidence of graft rejection episodes among all cardiac graft recipients, beginning with the first introduction of CNI-free protocols. We compared events during CNI-free and CNI-containing immunosuppression among 231 transplant recipients of overall mean age 55.2 ± 11.8 years, from a mean 5.2 ± 5.4 years after transplantation through a mean follow-up of 3.1 ± 1.4 years. We considered as acute rejection episodes requiring treatment those of International Society for Heart and Lung Transplantation. Results During the total follow-up of 685 patient years (CNI-containing, 563; CNI-free, 122), we performed 1,374 biopsies which diagnosed 78 rejection episodes. More biopsies were performed in CNI-free patients: biopsies/patient-month of CNI-containing, 0.13 versus CNI-free, 0.22 ( P < .05). The incidence of rejection episodes per patient-month was significantly higher on CNI-free compared with CNI therapy, among patients switched both early and later after heart transplantation, namely, within 1 year, 0.119 versus 0.035 ( P = .02); beyond 1 year, 0.011 versus 0.004 ( P = .007); beyond 2 years, 0.007 versus 0.003 ( P = .04); and beyond 5 years: 0.00578 versus 0.00173 ( P = .04). Conclusions Rejection incidence during CNI-free immunosuppression protocols after heart transplantation was significantly increased in both early and later postoperative periods. Given the potentially long delay to rejection occurrence, patients should be monitored closely for several months after a switch to CNI-free immunosuppressive protocols.

Calcineurin Inhibitor-free Immunosuppression Using Everolimus (Certican) after Heart Transplantation: 2 years' Follow-up from the University Hospital Münster

Background Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)–free immunosuppression using everolimus. Methods After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. Results After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 ( P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)]. Conclusion CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.

The Histology of Solitary Renal Allografts at 1 and 5 Years After Transplantation

Previous studies suggest that the majority of renal allografts are affected by progressive, severe chronic histologic injury, yet studies using current protocols are lacking. The goal of this study was to examine the prevalence and progression of histologic changes using protocol allograft biopsies at 1 and 5 years after solitary kidney transplantation in patients transplanted between 1998 and 2004. Chronic histologic changes generally were mild at both 1 and 5 years and were similar in deceased and living donor kidneys. The overall prevalence of moderate or severe fibrosis was 13% (60/447) at 1 year and 17% (60/343) at 5 years. In a subgroup of 296 patients who underwent both 1- and 5-year biopsies, mild fibrosis present at 1 year progressed to more severe forms at 5 years in 23% of allografts. The prevalence of moderate or severe arteriolar hyalinosis was similar in tacrolimus and calcineurin inhibitor-free immunosuppression. These results in the recent era of transplantation demonstrate fewer, less severe and less progressive chronic histologic changes in the first 5 years after transplantation than previously reported.

Five‐year experience using sirolimus‐based, calcineurin inhibitor‐free immunosuppression in pediatric renal transplantation

From December 2003 to December 2008, we employed a protocol for withdrawing TAC and converting to SRL in a cohort of low-risk renal pediatric transplant recipients. We report our experience in these children with respect to graft survival, AR episodes, renal function, and adverse events. All patients received basiliximab induction and TAC, MMF, and prednisone. Criteria for conversion to SRL included first transplants without histologic evidence for AR on three-month surveillance biopsies. Patient exclusion criteria included AR prior to or before surveillance biopsies, polyoma (BK) virus nephropathy, a history of nephrotic syndrome, or multiple organ transplants. Fifty-one of 137 patients who received transplants from December 2003 to December 2008 met criteria for withdrawal of TAC and were converted to SRL. SRL was discontinued in 11 children because of adverse events within 12 months after conversion. Among the remaining 40 patients, actuarial graft survival was 91% at five yr. AR occurred in 13% of patients within one yr after conversion. Complications from SRL included aphthous ulcers (30%); viremia with BK virus (20%), EBV (13%), and CMV (3%); proteinuria (7%); elevated cholesterol (7%); diabetes mellitus (2%); thrombocytopenia (2%); erectile dysfunction (2%); and lymph edema (2%). SRL was discontinued in 20%, predominantly for aphthous ulcers. Our experience with SRL-based immunosuppression demonstrates that a CNI-free regimen can be successful in lower-risk patients meeting our selection criteria. Aphthous ulcers and BK virus viremia were the most prevalent adverse events.

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.

De-novo calcineurininhibitor-free immunosuppression with sirolimus, mycophenolate Mofetil and ATG after heart transplantation: 5-year results

Objectives: Despite improvements in immunosuppressive therapy chronic rejection, renal toxicity and malignancy are major obstacles for long-term success after heart transplantation. Therefore we performed the worldwide first pilot-trial to evaluate the efficacy and safety of a de-novo CNI-free immunosuppressive protocol.

Sotrastaurin, a Novel Small Molecule Inhibiting Protein Kinase C: First Clinical Results in Renal‐Transplant Recipients

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

Acute Rejection Features in Dual Kidney Transplant Recipients from Elderly Donors: Comparison of Calcineurin Inhibitor-Based and Calcineurin Inhibitor-Free Immunosuppressive Protocols

Features of acute rejection in dual kidney transplant have not been studied. The aim of this study is to compare acute rejections in dual kidney transplant recipients from elderly donors on different immunosuppressive protocols. Sixty-nine patients were evaluated: 28 received calcineurin inhibitor-based (group 1) and 41 received calcineurin inhibitor-free immunosuppression (group 2). Histology of all donor kidneys was evaluated before implantation. All rejections showed tubulitis in both groups, and were classified as T-cell mediated acute rejections. Incidence and Banff grade of rejections in the two groups were not significantly different. Late rejections however, were observed in group 1 (P < 0.01) whereas steroid-resistant rejections occurred in group 2 (P < 0.03). C4d deposition was only observed in group 2. Occurrence of acute rejection was significantly associated with graft loss due to interstitial fibrosis/tubular atrophy in both groups. In group 1 mean serum creatinine levels of patients with rejections at six months and one year were higher than those of patients without rejections (P < 0.03 and P < 0.009, respectively). In group 2 they were higher at six months (P < 0.01) but not at one year. In addition, graft loss due to interstitial fibrosis/tubular atrophy occurred in 3/28 patients in group 1 (10.7%, OR= 1.95, 95%CI 1.02-3.71), and in 1/41 patients in group 2 (2.4%, OR= 0.41, 95%CI 0.07-2.24). Taken together these results suggest better renal function in patients on calcineurin inhibitor-free immunosuppression. In conclusion, acute rejections were detrimental irrespective of the type of immunosuppression, but different features were observed with each therapy. A tailored approach should be advantageous for prevention and treatment of acute rejections.