Use Of Proliferation Signal Inhibitors Research Articles

(768) - Proliferation Signal Inhibitors Prevent Donor-Specific Antibody Production in Sensitized Patients after Heart Transplantation

Everolimus and sirolimus are proliferation signal inhibitors (PSI) reported to decrease incidence and progression of transplant coronary artery disease, incidence of cardiac rejection, and development of de novo circulating antibodies (Abs) in the 1st year after heart transplant (Htx). Donor-specific Abs (DSA) appear to be a main factor associated with poor outcome in sensitized patients post-Htx. It is not established whether PSIs affect development of DSA in sensitized patients after Htx. Between 2010 and 2014, we evaluated 78 Htx patients (pts) with circulating Abs after Htx. Several were switched from mycophenolate mofetil (MMF) to PSI including everolimus (n=19) or sirolimus (n=11) in combination with a calcineurin inhibitor (CNI). Pts with pre-existing DSA were excluded. Pts were divided into 2 groups: maintenance of MMF use ≥1-year (Group A), and PSI use ≥ 1-year (Group B). Maintenance MMF group was matched to the switch-to-PSI group for time from Htx. Assessment of circulating Abs, including development of de novo DSA at 12 months after initiation of PSI was performed. In addition, 1-year subsequent survival and freedom from subsequent DSA development, cellular rejection, antibody-mediated rejection (AMR) were recorded. Reduction of PRA over 1 year was recorded for both groups. The PSI group compared to the MMF group had significantly greater freedom from de novo DSA development over the course of 1 year (see table). There was no significant difference between study groups in 1-year subsequent survival and 1-year subsequent freedom from cellular rejection and AMR. There was no significant difference with treatment of PSIs for subsequent 12-month Class I Abs levels %PRA (38 ± 37 vs. 33 ± 34, P=0.58) or Class II Abs levels %PRA (19 ± 29 vs. 20 ± 28, p=0.81). The use of PSIs in sensitized Htx pts appears to lower de novo development of subsequent DSA compared to maintenance MMF. Further study is warranted with a larger population.Tabled 1EndpointsGroup A Mycophenolate ≥ 1-Year (N=48)Group B PSI ≥ 1-Year (N=30)P-Value1-Year Subsequent Survival after PSI or MMF Initiation100.0%100.0%1.0001-Year Subsequent Freedom from De Novo Antibody Development after PSI or MMF Initiation86.9%100.0%0.0421-Year Subsequent Freedom from Any Treated Rejection93.8%96.7%0.5721-Year Subsequent Freedom from Acute Cellular Rejection97.9%96.7%0.7431-Year Subsequent Freedom from Antibody-Mediated Rejection97.9%93.2%0.3061-Year Subsequent Freedom from Biopsy Negative Rejection97.9%100.0%0.429 Open table in a new tab

Abstract 15858: Does Switching to Proliferation Signal Inhibitors Decrease the Risk of Developing Subsequent Malignancies in Heart Transplant Patients?

Introduction: Malignancy is vast approaching as the leading cause of death late after heart transplantation. It is known that the current immunosuppression regimen consisting of tacrolimus/cyclosporine and mycophenolate is associated with increased risk of cancers. The use of proliferation signal inhibitors (PSI) has been associated with less cancer development particularly in specific tumors. We sought to determine if there is an association of the use of PSI in decreasing overall cancer risk. Methods: Between 2004 and 2008 we assessed 16 heart transplant patients who were placed on PSI and compared cancer development based on conditional survival in the ensuing 5 years to those not on PSI (n=16). Patients were matched according to age, sex, time from transplant, and era. Results: Patients were switched to PSI on an average of 0.9 ± 0.9 years after transplant. Those patients that were placed on PSI had a higher subsequent 5-year actuarial freedom from cancer development compared to those patients not on PSI (100.0% vs 77.7%, p=0.049). These specific cancers included: skin cancer (2), squamous cell cancer (2), auricular carcinoma (1), prostate cancer (1), and cranial meningioma (1). There was no difference in 5-year actuarial freedom from cardiac allograft vasculopathy (CAV) development between the CNI + MMF/AZA and CNI + PSI groups (81.3% vs 72.2%,p=0.683). Conclusions: The use of PSI after heart transplantation appears to confer a protective effect against the development of malignancy. Larger number of patients are needed to confirm these observations.

Abstract 16941: Questioning the efficacy of Proliferation Signal Inhibitors for established Coronary Artery Disease after Heart Transplant

Purpose: Cardiac Allograft Vasculopathy (CAV) is one of the major factors limiting long term survival after heart transplantat (HTx). The use of proliferation signal inhibitors (PSIs) such as everolimus and sirolimus has been found to be effective in the prevention of CAV in multicenter studies. There has been 1 study (Mancini et al) that has suggested the use of Sirolimus can decrease the progression of CAV in patients (Pts) long term after Htx. It is not been evaluated in the current era of Tacrolimus (TAC)/Mycophenolate Mofetil (MMF) whether a switch from MMF to PSIs has such an advantage. Methods: Between 1998 and 2010, we evaluated 26 HTx Pts who had developed CAV according to the new ISHLT CAV nomenclature (CAV1, CAV2, CAV3) and were subsequently switched from TAC/MMF to TAC/PSIs. Pts who were maintained on TAC/MMF were served as 1:1 controls. Outcomes for these Pts included worsening of CAV by category at 3 year, subsequent 3-year survival and subsequent 3-year freedom from non-fatal major adverse cardiac events (NF-MACE: Myocardial Infarction, Congestive Heart Failure, angioplasty, pacemaker/ICD and stroke). Results: There were 26 patients in the switched to PSIs group and 23 patients in the maintained on MMF group. All patients were either CAV 1 or CAV 2 at baseline. The average time to switch to PSIs was 5.3 ± 3.3 years. At 3 year follow up, the percentage of patients who had worsened CAV by category were comparable among the two groups. Subsequent 3-year survival and 3-year freedom from NF-MACE were also comparable among the two groups (see Table). Conclusions: In the current era of TAC/MMF, switch from MMF to PSI for patients with established CAV does not appear to be beneficial in preventing progression of disease. A larger number of patients are needed to confirm this finding.

Use of Proliferation Signal Inhibitors in Cardiac Transplantation

Cardiac transplantation remains the definitive and most highly successful therapy for patients with advanced heart failure who have failed all other therapies. Long-term survival is limited by cardiac allograft vasculopathy, the transplant coronary artery disease, and malignancy. Standard, traditional immunosuppressive agents such as calcineurin inhibitors, anti-proliferative agents, and corticosteroids do little to attenuate cardiac allograft vasculopathy, which, because of its diffuse nature, is usually not amenable to percutaneous or surgical revascularization approaches, and may potentiate the developments of malignancies after cardiac transplantation. Proliferation signal inhibitors block the mammalian target of rapamycin, a critical protein involved in cell proliferation, and inhibit lymphocyte and smooth muscle cell proliferation. This results in inhibition of the alloimmune response and acute cellular rejection, even in the setting of low calcineurin levels. More significantly, they have been shown in several clinical trials to attenuate the progression of cardiac allograft vasculopathy when compared to mycophenolate or azathioprine regimens.

Chronic renal insufficiency in heart transplant recipients: risk factors and management options.

Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage.

Early introduction of everolimus immunosuppressive regimen in liver transplantation with extra-anatomic aortoiliac-hepatic arterial graft anastomosis.

Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

Renal Function Improvement After Conversion to Proliferation Signal Inhibitors During Long-Term Follow-up in Heart Transplant Recipients

IntroductionThe use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function. MethodsThis prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion. ResultsNinety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04). ConclusionDespite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

Management of children undergoing cardiac transplantation with high Panel Reactive Antibodies

Highly sensitised children in need of cardiac transplantation have overall poor outcomes because of increased risk for dysfunction of the cardiac allograft, acute cellular and antibody-mediated rejection, and vasculopathy of the cardiac allograft. Cardiopulmonary bypass and the frequent use of blood products in the operating room and cardiac intensive care unit, as well as the frequent use of homografts, have predisposed potential recipients of transplants to allosensitisation. The expansion in the use of ventricular assist devices and extracorporeal membrane oxygenation has also contributed to increasing rates of allosensitisation in candidates for cardiac transplantation. Antibodies to Human Leukocyte Antigen can be detected before transplantation using several different techniques, the most common being the "complement-dependent lymphocytotoxicity assays". "Solid-phase assays", particularly the "Luminex® single antigen bead method", offer improved specificity and more detailed information regarding specificities of antibodies, leading to improved matching of donors with recipients. Allosensitisation prolongs the time on the waiting list for potential recipients of transplantation and increases the risk of complications and death after transplantation. Aggressive reduction of antibodies to Human Leukocyte Antigen in these high-risk patients is therefore of vital importance for long-term survival of the patient and cardiac allograft. Strategies to decrease Panel Reactive Antibody or percent reactive antibody before transplantation include plasmapheresis, intravenous administration of immunoglobulin, and specific treatment to reduce B-cells, particularly Rituximab. These strategies have resulted in varying degrees of success. Antibody-mediated rejection and cardiac allograft vasculopathy are two of the most important complications of transplantation in patients with high Panel Reactive Antibody. The treatment of antibody-mediated rejection in recipients of cardiac transplants is largely empirical and includes the use of high-dose corticosteroids, plasmapheresis, intravenous administration of immunoglobulins, anti-thymocyte globulin, and Rituximab. Cardiac allograft vasculopathy is believed to be secondary to chronic complement-mediated endothelial injury and chronic vascular rejection. The use of proliferation signal inhibitors, such as sirolimus and everolimus, has been shown to delay the progression of cardiac allograft vasculopathy. In some non-sensitised recipients of cardiac transplants, the de novo formation of antibodies to Human Leukocyte Antigen after transplantation may increase the likelihood of adverse clinical outcomes. The use of serial testing for donor-specific antibodies after cardiac transplantation may be advisable in patients with frequent episodes of rejection and patients with history of sensitisation. Allosensitisation before transplantation can negatively influence outcomes after transplantation. A high incidence of antibody-mediated rejection and graft vasculopathy can result in graft failure and decreased survival. Current strategies to decrease allosensitisation have helped to expand the pool of donors, improve times on the waiting list, and decrease mortality. Centres of transplantation offering desensitisation are currently using plasmapheresis to remove circulating antibodies; intravenous immunoglobulin to inactivate antibodies; cyclophosphamide to suppress B-cell proliferation; and Rituximab to deplete B-lymphocytes. Similar approaches are also used to treat antibody-mediated rejection after transplantation with promising results.

Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation

The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation. This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009. In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42). In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents.

Everolimus for Cardiac Allograft Vasculopathy—Every Patient, at any Time?

In this issue, Arora et al. (1) attempt to address the question of whether the addition of everolimus to a calcineurin-based immunosuppression regimen can attenuate the progression of cardiac allograft vasculopathy (CAV) years after heart transplantation. Currently, CAV remains one of the most important factors limiting long-term survival in heart transplant patients. Despite significant advances in immunosuppression and posttransplant care resulting in a progressive decline in allograft rejection and improved survival, the incidence of CAV has changed little, with 30% of patients developing the disease within 5 years of transplantation. A major advance in the management of CAV came with the availability of proliferation signal inhibitors (PSIs), sirolimus and everolimus. These agents are a class of antiproliferative agents shown to inhibit smooth muscle cell proliferation, a key component in the development of CAV. In a study by Keogh et al. (2), the use of sirolimus in 136 de novo heart transplant patients was associated with decreased development of CAV at 2 years compared with patients receiving azathioprine. In a subsequent sentinel multicenter study by Eisen et al. (3), more than 600 patients were randomized to everolimus or azathioprine (both in combination with cyclosporine) within 72 hr of transplantation. Intravascular ultrasonography (IVUS) showed that the average increase in maximal intimal thickness at 12 months was significantly smaller with everolimus compared with azathioprine. This finding was important as it has been demonstrated that a significant increase in maximal intimal thickness at 1 year is associated with higher posttransplant mortality at 5 years (4). Although the benefit of early use of PSIs in heart transplantation seems established, it is unclear whether they provide any benefit to prevent or slow the progression of CAV when initiated later after heart transplantation. In a small study by Mancini et al. (5), 46 patients with severe CAV at a mean 4.3 years after transplantation were randomly assigned to sirolimus or continued on maintenance therapy with mycophenolate mofetil (MMF) or azathioprine (all groups with continued cyclosporine therapy). Patients treated with sirolimus demonstrated slowed angiographic disease progression and improved clinical outcomes. However, to date, no randomized study using IVUS has assessed late immunosuppression change to slow the development of CAV. In this study, to address the aforementioned point, Arora et al. randomized 111 patients on calcineurin inhibitor (CNI) and azathioprine or MMF who were more than 5 years from transplant to the addition of everolimus with reduced-dose CNI or continuing CNI with azathioprine or MMF. All study patients underwent IVUS at study entry and 12 months later. This study represented a subpopulation of the Nordic Certican Trial in Heart and Lung Transplantation randomized trial, a study investigating the efficacy of everolimus with reduced-dose CNI in reducing renal dysfunction in heart and lung transplant recipients. The authors found that the addition of everolimus and reduced CNI at a mean 5.8 years after transplant did not influence CAV progression by IVUS. However, in the subgroup of patients receiving everolimus, reduced-dose CNI, and concomitant azathioprine therapy, CAV progression and a number of inflammatory markers implicated in CAV were attenuated compared with the control CNI group. To the contrary, the subgroup of patients receiving everolimus, reduced-dose CNI, and MMF was associated with accelerated CAV and a parallel increase in inflammatory markers. Although these results are of great interest, the applicability of these findings to the contemporary management of heart transplant recipients remains in question. Unique to this study, the design of the protocol allowed addition of everolimus to preexisting therapy with MMF or azathioprine both in combination with cyclosporine. In clinical practice, most clinicians switch antiproliferative medications as opposed to adding them. The discordant effects of everolimus and azathioprine to everolimus and MMF (both with continued cyclosporine therapy) raise the question of a yet unidentified adverse drug interaction in which MMF may abrogate the effects of everolimus. The findings are certainly hypothesis generating and merit further investigation. The study also includes predominantly cyclosporine-treated patients. In the current era, most heart transplant programs use tacrolimus-based immunosuppression. The three-arm study (6) suggested that patients on tacrolimus with sirolimus and tacrolimus with MMF benefited from lower rates of rejection when compared with cyclosporine with MMF with respect to lower rates of rejection. Although this study raises some important questions, the results should be kept in perspective. The evidence to date suggests benefit for the use of PSI for prevention of CAV when used early after heart transplantation. Confirmation of the results of this study would require adequately powered studies to evaluate the use of combination antiproliferative agents and CNI, with appropriate predefined endpoints, and mechanistic studies to elucidate potential drug interaction.

Temporal Trends in the Use of Proliferation Signal Inhibitors in Maintenance Heart Transplantation: A Spanish Multicenter Study

Proliferation signal inhibitors (PSI; sirolimus, everolimus) are being increasingly used in heart transplantation. We performed an observational, retrospective, multicenter study in 9 Spanish centers seeking to describe the clinical context in which a PSI was used among maintenance heart recipients and its evolution over time. We collected a cohort of 548 patients in whom a PSI was prescribed from October 2001 to March 2009. The group was divided into 3 time periods. The use of PSI steeply increased in the 2005–2006 period, remaining stable thereafter. There were no significant differences over time with regard to age, gender, or time from transplantation to the introduction of the PSI. Everolimus usage overtook sirolimus from 2005 on; currently, >90% of the subjects with PSI indications are prescribed everolimus. Compared with earlier periods, patients in the more recent period (October 2006–March 2009) showed less vascular graft disease and better basal renal function, irrespective of the primary indication for the PSI prescription. Also, skin cancer overtook solid cancer as the main type of neoplasm in patients for whom malignancy was the primary indication for the use of the PSI. The actuarial incidence of PSI withdrawal owing to adverse effects did not change significantly over time.

The use of proliferation signal inhibitors in the prevention and treatment of allograft vasculopathy in heart transplantation

Cardiac allograft vasculopathy (CAV) currently represents one of the most important causes of long-term morbidity and mortality in the heart transplant population. In well-designed studies with de novo patients, the use of proliferation signal inhibitors (PSIs; everolimus and sirolimus) has been shown to significantly prevent the intimal growth of graft coronary arteries in comparison to other immunosuppressive regimens, reducing the incidence of vasculopathy at 12 and 24 months. In addition, conversion to PSIs in maintenance patients with established CAV has also shown promising results in the reduction of the progression of the disease and its clinical consequences. For these reasons the interest shown by various transplantation units in the potential role of PSIs in this field is growing. The aim of the present article is to review the information obtained to date on the use of PSIs in heart transplant recipients, both in the prevention and the treatment of CAV. The principal published recommendations on the introduction and appropriate management of these drugs in clinical practice are also collected, as well as certain recommendations given by the authors based on their experience.

Multidisciplinary Insights on Clinical Guidance for the Use of Proliferation Signal Inhibitors in Heart Transplantation

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance

Increasing success in renal transplantation and longer patient survival has meant that post-transplant malignancies are having an increasing impact on long-term graft and patient survival. Choice of the immunosuppressive agents provides one of the controllable risk factors for the development of malignancies in this population. Calcineurin inhibitors (CNIs) are associated with an increased incidence of cancers, whereas the proliferation signal inhibitors (PSIs), everolimus and sirolimus have demonstrated anti-oncogenic effects in pre-clinical models and are currently being investigated as anti-cancer agents in clinical trials. There is increasing evidence demonstrating a lower incidence of post-transplant malignancies in renal transplant recipients receiving PSI-based immunosuppression compared with those receiving CNIs. Conversion from CNIs to PSIs has been shown to lead to the regression of Kaposi's sarcoma in renal transplant recipients and is now part of accepted standard care for this tumour in this setting. The anti-cancer properties of PSI-based regimens have the potential to combine the dual benefits of immunosuppression without the use of CNIs and the direct anti-oncogenic effects through their inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. In the absence of formal clinical trial evidence on the best way to use PSIs in this setting, a workshop was held to provide practical guidance on immunosuppressive strategies in the context of malignancy, given the current state of knowledge.

Post-transplant lymphoproliferative disorder--the potential of proliferation signal inhibitors

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by abnormal lymphoid proliferation following transplantation. These lymphomas, in particular, have been shown to have a higher incidence in renal transplant recipients compared with the general age-matched population. The effect of different immunosuppressive regimens on the incidence of PTLD has been assessed in a number of studies. Although there are conflicting data on the role of calcineurin inhibitors (CNIs) in promoting the development of PTLD, an increase in risk is described in most studies and is usually related to the aggressiveness of immunosuppression. The proliferation signal inhibitors (PSIs), everolimus and sirolimus, have both immunosuppressive and antiproliferative actions and pre-clinical data suggest that everolimus has an inhibitory effect on the growth of PTLD-derived cell lines. There is currently limited clinical data on the use of PSIs in the management of PTLD, therefore, clinical experience from nine European Transplant centres has been pooled and analysed to assess their potential. Conversion to PSIs and subsequent minimization or withdrawal of CNIs was analysed in 19 renal transplant recipients with PTLD and remission was observed in 15 patients. These data suggest that PSIs may assist with the management of PTLD following renal transplantation.

Kaposi's sarcoma in renal transplant recipients--the impact of proliferation signal inhibitors

The incidence of Kaposi's sarcoma (KS) is greatly increased in renal transplant recipients compared with the general population, with particular prevalence in certain ethnic groups where it can occur in up to 5% of transplant recipients. The increased incidence of disease in transplant populations may, in part, be attributed to the choice of immunosuppressive regimen, with calcineurin inhibitor (CNI)-based immunosuppression being associated with the development of the tumour. A number of small studies have recently demonstrated that conversion to proliferation signal inhibitors (PSIs) along with the concomitant withdrawal of CNIs leads to a rapid resolution of both cutaneous and visceral Kaposi's lesions. In agreement with these data the abrupt onset of KS has been observed following the withdrawal of PSIs. Histological examination of lesions from patients with KS supports data from animal models which suggests that PSIs inhibit tumour angiogenesis through impaired vascular endothelium growth factor production, a key element in the development of the tumour. Previously unpublished data on renal transplant recipients from a number of European and Australian centres have been pooled to provide further insight into the use of PSIs in the management of post-transplant KS. Both members of the PSI class, everolimus and sirolimus, along with CNI withdrawal lead to regression of KS lesions in 11 out of 12 patients. Conversion to PSIs was generally well tolerated with stable renal function maintained in most patients and no episodes of acute rejection recorded. PSIs provide a potential treatment option in the management of post-transplant KS and should be considered for use in renal transplant recipients who develop the disease.

Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation

Non-melanoma skin cancer (NMSC) affects a large proportion of renal transplant recipients, with estimates suggesting that at least half of white-skinned transplant recipients will develop NMSC following transplantation. Squamous-cell carcinoma is the most frequent NMSC following transplantation occurring at a 100-times greater risk than in the general population, while the incidence of basal cell carcinoma is increased 10-fold over the general population. The most important risk factor for the development of NMSC in renal transplant recipients is prior exposure to ultraviolet radiation, therefore, geographical location and skin type highly influence the risk of NMSC. However, both the intensity and type of immuno-suppressive therapy have been associated with an increased risk of NMSC. Given the potential anti-cancer actions of the proliferation signal inhibitors (PSIs), everolimus and sirolimus, demonstrated in both pre-clinical and clinical studies, we have analysed the effect of conversion to PSIs in 53 renal transplant recipients developing NMSC after transplantation. Remission of NMSC was observed in 37 patients and was generally well tolerated with minimal adverse events reported. Fifteen patients developed new lesions following conversion, two of these were receiving low-dose calcineurin inhibitors (CNIs) as part of their immuno-suppressive regimen suggesting that there was insufficient reduction of CNIs. PSI blood levels did not seem to affect the outcomes of conversion. These data, along with published clinical trial data suggest that conversion from CNIs to PSIs may be useful in the management of NMSC following renal transplantation.

Editorial Comment: Heart Transplantation, Cardiac Allograft Vasculopathy and Proliferation Signal Inhibitors

Editorial Comment: Heart Transplantation, Cardiac Allograft Vasculopathy and Proliferation Signal Inhibitors