Calcineurin Inhibitors In Combination Research Articles

Long-Term Maintenance Therapy With Calcineurin Inhibitors: An Update

Combination therapy with mammalian target of rapamycin (mTOR)-inhibitors and calcineurin inhibitors (CNIs) provides significant immunosuppressive efficacy. If the combination of these agents is not properly optimized, however, important risks for synergistic toxicity and long-term complications may result. The combination of a CNI and an mTOR-inhibitor is a potent immunosuppressive therapy that effectively prevents the incidence of acute rejection, although the potential nephrotoxic impact must be considered in the longer term. The trend has therefore been to use a low-dose CNI in combination with the mTOR-inhibitor sirolimus in order to reduce the risk of nephrotoxicity. Recent studies show that an mTOR-inhibitor/low-dose CNI combination is effective in the short term following transplantation, and over time, consideration should be given to the elimination of the CNI in order to preserve renal function. In the medium to long term, it is also possible to consider the elimination of steroids from such a protocol. Considering CNI dose minimization or elimination is an essential component of this approach, as is the optimal dose and level of both drugs when used in combination.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

BackgroundImmunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation.Methods/DesignA prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT.DiscussionThis prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial.Trial registration numberNCT00890253 (clinicaltrials.gov)

Clinical implications of the type 1/type 2 balance of helper T cells and P-glycoprotein function in peripheral T lymphocytes of myasthenia gravis patients

Myasthenia gravis is an autoimmune disorder mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Imbalances between T helper type 1 and type 2 cytokine production play a key role in the induction and development of several autoimmune diseases. Peripheral T helper type 1 and type 2 cells in 50 myasthenia gravis patients were estimated by intracellular cytokines. The percentage of T helper type 1 cells in CD4(+) cells was higher than that of type 2 or type 0 cells (P<0.0001). There was a significant correlation between T helper type 1/type 2 ratio and the P-glycoprotein function on CD3(+) T cells (P=0.008). In the patients treated with prednisolone alone (n=12), there was a significant correlation negatively between the percentage of change in the T helper type 1/type 2 ratio and the reduction rate of quantitative myasthenia gravis scores after 12 months of treatment (P=0.012). In contrast, all of the patients treated with prednisolone and calcineurin inhibitor in combination saw reductions in the scores. Our data suggest that the T helper type 1/type 2 ratio was involved in the disease activity of the patients treated with prednisolone alone. On the other hand, the patients treated with prednisolone and calcineurin inhibitor in combination had their disease condition improved regardless of the T helper type 1 predominance. Therefore, the data suggest that supplemental calcineurin inhibitors are effective for the myasthenia gravis patients treated with prednisolone alone when their T helper balance shifts toward to type 1.

Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): The TRY study

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Pharmaceutical and Cellular Strategies in Prophylaxis and Treatment of Graft-Versus-Host Disease

Acute and chronic GVHD after allogeneic hematopoetic stem cell transplantation are still associated with significant morbidity and mortality. For prophylaxis of acute GVHD calcineurin inhibitors in combination with an antimetabolite (MTX or MMF) are administered, and these therapies are based on controlled studies. New prophylaxis strategies include mTOR-inhibitors in combination with tacrolimus but require confirmation by controlled trials. First-line treatment of acute GVHD consists mainly of steroids with doses ranging from 1 mg/kg/day prednisone to 3 mg/kg/day methylprednisolone. Second-line treatment of acute GVHD after failure of steroids is less well defined due to the lack of controlled studies. Treatment options are the use of cytotoxic antibodies (ATG, campath), cytokine blocking agents (etanercept, daclizumab), immunomodulating modalities (photopheresis), and antimetabolites (pentostatin, MMF). Recently, cellular approaches were developed, such as the adoptive transfer of mesenchymal stem cells. Nevertheless steroid-resistant acute GVHD is still a main challenge in alloHSCT and associated with high mortality. First-line treatment of chronic GVHD is also based on steroids with 1 mg/kg/day prednisolone or prednisone, which are often combined with calcineurin inhibitors. There is no consensus on second-line treatment of chronic GVHD and most therapies are solely based on phase II trials. Treatment options are the use of immunomodulating modalities (photopheresis, mTOR-inhibitors) and antimetabolites (MMF, MTX, pentostatin). Recent reports showed an efficacy of rituximab in selected patients. Other treatment options are low dose total nodal irradiation or the use of antibodies like ATG. Moreover, successful topical treatment of manifestations of chronic GVHD manifestations has been reported consisting of topical steroids like budesonide, topical calcineurin inhibitors, or PUVA.

Renal impairment after liver transplantation - a pilot trial of calcineurin inhibitor-free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation

ObjectivesChronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function.MethodsThe aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients [GFR 44.9 ± 9.9 mL/min/1.73 m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ± 0.42 mg/dL] were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d.ResultsAt month 12 mean SCr (-0.3 ± 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ± 13.1 mL/min/1.73 m2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ± 22 mmHg (p = 0.03).ConclusionsReduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Calcineurin inhibitor minimization protocols in liver transplantation

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.

Proliferation signal inhibitors and cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is the leading cause of late morbidity and mortality in heart transplant patients and limits long-term survival. Immunosuppression following cardiac transplantation has traditionally comprised a calcineurin inhibitor in combination with mycophenolate mofetil or azathioprine and corticosteroids. This combination provides effective immunosuppression but does not prevent subsequent development of CAV. Proliferation signal inhibitors (such as sirolimus and everolimus), a new class of immunosuppressants, have recently been shown to be effective in attenuating the development of CAV following cardiac transplantation. In addition to immunosuppressive properties, proliferation signal inhibitors have important antiproliferative effects outside the immune system. Several ex-vivo and preclinical studies on animal models have demonstrated control of the vascular manifestations after cardiac transplantation. In clinical trials, proliferation signal inhibitors used as secondary immunosuppressive agents in place of azathioprine or mycophenolate prevented CAV progression and reduced the incidence of clinically significant cardiac events. Proliferation signal inhibitors are also effective as primary immunosuppressants, and, after complete calcineurin inhibitor withdrawal, mitigate the progression of CAV, improve calcineurin inhibitor-induced nephropathy and hypertension. Proliferation signal inhibitors are powerful immunosuppressive agents with antiproliferative properties that attenuate CAV and have the potential to improve long-term survival following cardiac transplantation.

Methicillin‐Resistant Staphylococcus aureus Colonization in Children with Atopic Dermaitis

Children with atopic dermatitis are more frequently colonized with Staphylococcus aureus than children without atopic dermatitis. However, little epidemiological data exist regarding the prevalence of methicillin-resistant S. aureus among children with atopic dermatitis. Recent studies have revealed an increasing prevalence of community-associated methicillin-resistant S. aureus among patients presenting to hospitals with serious bacterial infections, particularly those with cutaneous and soft tissue infections. As many atopic dermatitis patients are treated empirically with antibiotics for secondary skin infections, an understanding of the epidemiology of bacterial colonization and superinfection is essential for directing proper treatment in the atopic patient population. This study investigates the prevalence of risk factors for community-associated, methicillin-resistant S. aureus colonization among pediatric atopic dermatitis patients encountered at an academic pediatric dermatology clinic. An observational cross-sectional study was conducted at the Children's Hospital of Philadelphia in which 54 patients previously diagnosed with atopic dermatitis were enrolled. A detailed patient questionnaire, a complete cutaneous examination, and an evaluation of eczema severity according to the Eczema Area and Severity Index were completed at the time of enrollment. Bacterial cultures from the skin and nares were obtained to determine the frequency of colonization with either methicillin-sensitive S. aureus or methicillin-resistant S. aureus. Although most atopic dermatitis patients studied were colonized with S. aureus (43/54 [80%]), methicillin-resistant S. aureus was isolated from only seven atopic dermatitis patients (7/43 [16%]). Patients colonized with S. aureus were more likely to be male, to have been previously hospitalized, to have used a topical calcineurin inhibitor in combination with a topical steroid, and less likely to have used topical antibiotics. Bivariable analysis, however, revealed that only previous hospitalization was independently associated with an increased risk of methicillin-resistant S. aureus colonization. We observed that 80% of atopic dermatitis patients were colonized with S. aureus, and that of these patients, 16% of colonized patients were colonized with a methicillin-resistant strain. Methicillin-resistant S. aureus colonization was found to be significantly associated with previous hospitalization. Evidence also indicates that topical calcineurin inhibitors used in conjunction with topical steroids is associated with increased S. aureus colonization, while topical antibiotic use appears to decrease S. aureus colonization.

Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation

A nonquantitative summary of the current evidence suggests that calcineurin inhibitor (CNI) minimization and also CNI-free protocols are safe and efficient when used after the initial 3 months post-transplantation. In fact, the largest study so far showed that low-dose CNI in combination with mycophenolate mofetil (MMF) and steroids performed better than standard dose cyclosporine A (CsA). If CsA is used in combination with a mammalian target of rapamycin-Inhibitor (mTOR-I) considerable dose reduction of both drugs is required. A better choice than using both drug groups in lower doses together may be the withdrawal of CsA from this combination after 3-12 months. Later withdrawals or conversions to an mTOR-I failed to show additional benefit in terms of graft function or survival but caused less post-transplant malignancies. With improved short- and medium-term outcomes, this entity will become more of an issue. In fact, in some areas of the world, nowadays malignancies are the leading cause of death.

Komplikationen nach Lungentransplantation

Intestinal perforation after lung transplantation is common in elderly patients with diverticulitis. The distal intestinal obstruction syndrome (DIOS) is a current complication in patients with cystic fibrosis. Myelosuppressive drugs as in most immunosuppressive regimens can cause cytopenia. Thrombotic microangiopathy is often caused by immunosuppressive regimen with a calcineurin-inhibitor in combination with a proliferation signal-inhibitor. Although renal failure and neurological symptoms are often additional side effects of the immunosuppressive therapy there are no reliable data on CNI-free protocols. Studies have shown that administration of statins is associated with improved function and survival of lung allografts.

Malignancies of the colorectum and anus in solid organ recipients

Patients undergoing solid organ transplantation (SOT) are at increased risk for developing malignancies due to the long term immunosuppression. Data on malignancies of the large intestine after various types of SOT are rare. A total of 3595 SOTs were performed between 1986 and 2005 at our center and retrospectively analyzed with regard to the incidence and course of malignancies of the colon, rectum, and anus. Standard immunosuppression consisted of calcineurin inhibitors in combination with azathioprine or mycophenolate mofetil and steroids with or without antithymocyte globulin or IL-2 receptor antagonist induction. A total of 206 patients (5.7%) developed malignancies. Colorectal adenocarcinoma was diagnosed in nine patients (0.25%; mean age at diagnosis 65 years) at a mean of 5.3 years after transplantation. Five patients (55%) died 7.2 years post-transplant due to cardiovascular disease (n = 4) and tumor progression (n = 1). Four patients developed anal neoplasia (0.11%) 7 years post-transplant with 100% 1-year survival. Five patients showed post-transplant lymphoproliferative disorders (PTLD) with intestinal involvement. The incidence of anal but not of colorectal cancers in our transplant recipients differed from that of immunocompetent individuals of corresponding age (0.11% vs. 0.002% and 0.25% vs. 0.3%). PTLD may involve the colon.

Proliferation signal inhibitors in cardiac transplantation

Standard immunosuppression after cardiac transplantation includes a calcineurin inhibitor in combination with mycophenolate mofetil or azathioprine and corticosteroids. These agents have led to excellent outcomes but have shortcomings in terms of efficacy and toxicity. A new class of immunosuppressants, proliferation signal inhibitors, may meet some of these shortcomings. The efficacy of the available proliferation signal inhibitors - sirolimus and its derivative everolimus - has been compared with azathioprine in three randomized clinical trials. Sirolimus or everolimus use was associated with lower rates of acute rejection and reduced development of chronic allograft vasculopathy. Sirolimus was not found to be superior to mycophenolate mofetil in a randomized trial. Proliferation signal inhibitors have been reported to be effective in refractory recurrent acute rejection. Nonrandomized studies have demonstrated that proliferation signal inhibitor-based immunosuppression enables recovery from renal dysfunction secondary to calcineurin inhibitor treatment. Proliferation signal inhibitor-based treatment is associated with a lower risk of malignancy than calcineurin inhibitor-based regimens. Proliferation signal inhibitors have significant adverse effects that may limit widespread use. Proliferation signal inhibitors are important new immunosuppressive agents that have added considerably to the armamentarium allowing further tailored immunosuppression to individualize patient care after heart transplantation.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML.Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS.Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission.Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

Immunotherapy with Tacrolimus (FK506) Does Not Select for Resistance to Calcineurin Inhibitors inCandida albicansIsolates from Liver Transplant Patients

In Candida albicans, calcineurin mediates tolerance to azole antifungal drugs, survival in serum, and virulence. In this study, we examined 24 Candida isolates from liver transplant recipients receiving a calcineurin inhibitor as a component of their immunosuppressive therapy. We were unable to detect a difference in susceptibility to calcineurin inhibitors in combination with fluconazole, serum, or calcium in these isolates.

Prophylaxis and Treatment of Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). The ability to prevent GVHD--the application of successful prophylaxis--is crucial as treatment when prophylaxis fails or remains suboptimal. A calcineurin inhibitor in combination with methotrexate is still the mainstream regimen for prophylaxis of GVHD. Despite a steady increase in the repertoire of available drugs, corticosteroids remain the first-line therapy for patients who fail prevention and develop GVHD. Pan T-cell depletion studies suggest that success in prophylaxis and treatment of GVHD will depend on whether GVHD can be prevented without losing anti-malignancy and anti-infectious effects. Better understanding of the allogeneic response that is responsible for GVHD will facilitate the development of such an approach.

Current and Future Immunosuppressive Strategies in Renal Transplantation

The past decade has witnessed the introduction of several new immunosuppressive agents. The availability of these new pharmacologic offerings has not diminished the challenge of achieving a balance of adequate graft protection while minimizing the consequences of excessive immunosuppression. For renal transplant recipients, maintenance immunosuppression generally consists of a calcineurin inhibitor in combination with an antiproliferative agent and a corticosteroid; more recently, mammalian target of rapamycin inhibitors have been used. Excellent results have been achieved at many transplant centers with combinations of these agents in a variety of protocols. Regimens designed to limit or eliminate calcineurin inhibitor and/or corticosteroid therapy are actively being pursued in the transplant community. Allograft tolerance and xenotransplantation are being studied, and the knowledge gained from the effort may help in the development of innovative strategies and new immunosuppressive agents.