Calcineurin inhibitor-free immunosuppression in kidney transplantation

The introduction of calcineurin inhibitors (CNI) revolutionized kidney transplantation (KTx). Exceptionally low acute rejection rates and excellent graft survival could be achieved with CNI-based (cyclosporine and tacrolimus) immunosuppressive protocols. However, despite short-term success, long-term graft attrition continues to be a significant problem, thus leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may be contributing to long-term damage in transplant kidneys. Therefore, newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs altogether. Protocols exploring these options have gained greater attention over the last few years. Herein, we review studies addressing either CNI withdrawal or CNI avoidance strategies as well as discuss the risks versus benefits of these protocols. Given the accumulated experience to date, in our opinion, the use of CNIs as a part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI withdrawal and avoidance strategies need to be further validated in controlled clinical trials.     

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

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

Calcineurin inhibitor sparing in renal transplantation

Although calcineurin inhibitors (CNIs) are effective at preventing acute rejection, their long-term use is associated with nephrotoxicity that may compromise long-term renal allograft survival. Consequently, there is considerable interest in identifying immunosuppressive regimens that permit reduced exposure to CNIs while maintaining adequate immunosuppression. Introducing such strategies early after transplantation may mean that the development of CNI-associated nephrotoxicity could be minimized or prevented. Several CNI-sparing regimens have shown at least comparable efficacy with standard-dose CNI regimens. In particular, a regimen of mycophenolate mofetil (MMF), corticosteroids, interleukin-2 receptor antagonist induction, and low-dose tacrolimus from the time of transplantation provided superior renal function and a lower acute rejection rate than the same regimen but with low-dose cyclosporine or low-dose sirolimus, or standard-dose cyclosporine, MMF, and corticosteroids. The use of low-dose cyclosporine does not seem to eliminate nephrotoxicity in de novo renal transplant recipients. The early withdrawal of CNIs from MMF-based regimens generally improves renal function but has been associated with an increased risk of acute rejection, in particular when the levels of mycophenolic acid were not adjusted to maintain the same total level of immunosuppression. Research aiming to achieve the "best" balance of efficacy and toxicity of available immunosuppressive regimens continues.     

Calcineurin-inhibitor minimization protocols in heart transplantation

Cardiac transplantation has become an established method for end-stage heart disease. A calcineurin-inhibitor (CNI)-based regimen is the cornerstone of immunosuppressive therapy after cardiac transplantation. CNIs have reduced acute rejection and infection and markedly increased survival of cardiac transplantation patients. However, the dose- and time-dependent nephrotoxic effects of CNIs can limit long-term survival, and chronic renal failure is a major cause of morbidity and mortality in long-term cardiac transplant patients. Early experience on withdrawal of CNIs (and maintenance of patients on azathioprine and steroids) in patients, who developed chronic renal dysfunction, resulted in rejection episodes with, sometimes, fatal outcome. The introduction of newer immunosuppressive drugs, like thymoglobulin, anti CD-25 monoclonal antibodies, mycophenolate mofetil, everolimus or sirolimus into clinical practice, has given transplant physicians new tools to adapt immunosuppression to patients' needs. Changes of immunosuppressive protocols by using new drugs early and late after transplantation and simultaneous reduction or weaning of CNIs have become attractive options. The aim of this article is to review strategies to delay, reduce or prevent CNIs after cardiac transplantation as means to improve short- and long-term outcome mainly by protecting 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.     

Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.     

Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity

Abstract: Background: The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation. Materials and methods: A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors’ personal files were reviewed. Results: Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization. Conclusions: Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.     

Minimization of immunosuppression in kidney transplantation

PURPOSE OF REVIEW: In an effort to reduce the long-term toxicities of immunosuppressant drugs, corticosteroid and calcineurin inhibitor-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. This article focuses on outcomes of these strategies described in recently published trials. RECENT FINDINGS: The use of induction antibody therapy and potent residual immunosuppressants has increased the safety of steroid-free regimens, resulting in a paradigm shift towards earlier elimination of steroids after kidney transplantation. Even in the modern era, results of randomized trials generally indicate that steroid elimination increases the risk of rejection compared with maintenance steroid therapy. Among calcineurin inhibitor-sparing strategies, withdrawal of these agents after their initial use in stable patients, or conversion to either mycophenolate mofetil or sirolimus in patients with early renal dysfunction appears to yield the greatest benefit in preserving renal function. The outcomes of calcineurin inhibitor avoidance protocols have been mixed and have fallen into disfavor. SUMMARY: The benefits of minimizing immunosuppression in kidney transplant recipients must be weighed against the risks of precipitating acute rejection or chronic allograft dysfunction. Additional research is needed to identify clinical and immune parameters that will enable selection of patients for whom the benefits outweigh the risks.     

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

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

Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long‐term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient‐years) was significantly higher than that observed on CNI therapy in the pre‐conversion period (2.2 per 100 patient‐years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post‐conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow‐up. Conversion to a CNI‐free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post‐conversion rejection could help to refine the current PSI conversion strategies.     

抗体类免疫诱导剂在实体器官移植中的应用现状

器官移植是治疗终末期器官衰竭的首选有效治疗方法,然而器官移植术后早期急性排斥反应往往是导致移植失败的重要因素。为了减少器官移植后排斥反应的发生,往往需要在移植前或移植中加用强效免疫抑制剂对受体免疫系统进行抑制性诱导治疗。抗体类免疫诱导剂作为器官移植早期实施覆盖性免疫抑制治疗的常用方法,可显著减少器官移植术后早期急性排斥...     

HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies

BACKGROUND: New immunosuppressive drugs such as anti-interleukin-2 receptor antibodies (aIL2R) and mycophenolate mofetil (MMF) have reduced the incidence of acute rejection after renal transplantation. Whether matching donor and recipient human leukocyte antigen (HLA) antigens is still relevant in patients receiving modern immunosuppression has been questioned. METHODS: We retrospectively analyzed the incidence and risk factors of acute rejection during the first posttransplant year and the impact of acute rejection on long-term graft survival in a cohort of 208 renal transplant patients treated with aIL2R (basiliximab, n=166; daclizumab, n=42), calcineurin inhibitors (tacrolimus, n=180; cyclosporin, n=28), mycophenolate mofetil, and steroids. Graft and patient survival were calculated by the Kaplan-Meier method. Risk factors for acute rejection were analyzed by logistic regression modeling. RESULTS: Twenty-seven patients were treated for acute rejection (26 biopsy-proven) during the first posttransplant year. The Kaplan-Meier estimate of first-year acute rejection was 13.2%. The number of HLA mismatches (odds ratio [OR] 1.65 per HLA mismatch) and long periods of dialysis before transplantation (OR 3.1 for more than 4 years of dialysis) were the only independent risk factors for first-year acute rejection. First-year acute rejection was associated with a significant reduction in overall and death-censored graft survival at 5 years after transplantation. CONCLUSIONS: Although infrequent in patients receiving modern immunosuppressive drugs, acute rejection remains an important risk factor for graft loss after renal transplantation. Our results suggest that better HLA matching and shorter periods of dialysis before transplantation could reduce acute rejection rates and further improve outcomes under current immunosuppressive regimens.     

Is acute rejection the key predictor for long-term outcomes after renal transplantation when comparing calcineurin inhibitors?

In the context of modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. The type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage. Randomized clinical trials in renal transplant patients have generally shown that there are fewer acute rejection episodes with tacrolimus compared with cyclosporine, although with contemporary regimens, including mycophenolate acid, this difference is less marked than previously. In randomized trials, kidney graft survival rates with cyclosporine and tacrolimus have proven similar. Large-scale registry analyses have consistently shown no graft survival benefit with tacrolimus vs cyclosporine, and indeed, 2 such analyses have reported significantly higher graft survival with cyclosporine-based immunosuppression compared with tacrolimus in living-donor kidney transplant patients receiving mycophenolate mofetil. There are no reports of improved patient survival with either calcineurin inhibitor after kidney transplantation. In conclusion, the perception of better efficacy with tacrolimus vs cyclosporine based on the incidence of acute rejection is not supported by a difference in graft or patient survival after kidney transplantation.     

Hot-topic debate on kidney function: renal-sparing approaches are ineffective

Key Points: 1. Both acute kidney injury and chronic renal disease are common in patients undergoing liver transplantation. The etiologies are mixed. 2. The incidence of chronic renal failure after liver transplantation is unacceptable, and it has a significant impact on long-term outcomes after liver transplantation. 3. The role of calcineurin inhibitors (CNIs) in the development of posttransplant chronic renal failure is likely overrated. 4. The use of CNIs in the early posttransplant period is currently essential. 5. Whether new agents will be able to provide effective immunosuppression as primary immunosuppressives remains to be proven.     

Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a cardiac transplant patient with chronic renal failure.

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.     

Renal transplantation with early steroid withdrawal

Steroids are effective immunosuppressants in renal transplantation but are associated with significant adverse effects. As a result, there has been increased interest in protocols utilizing steroid minimization. Initial trials stopped steroids at approximately 3 months, when the highest risk phase for acute rejection was over. As two randomized trials using cyclosporine and mycophenolate mofetil without induction therapy showed an unacceptably high acute rejection rate, more recent interest has focused on the cessation of steroids very early, usually within the first week after transplantation. Most protocols have used antibody induction combined with calcineurin inhibitors and mycophenolic acid derivatives. Uncontrolled studies have shown a low rate of acute rejection, but the most recent randomized controlled trials have demonstrated an increased risk of acute rejection. These trials have not shown any consistent difference in short-term patient or graft survival. Cardiovascular risk factors do not appear to be consistently improved by early steroid withdrawal. Most trials lack sufficient follow-up (5 years or more) to assess the impact of the increased acute rejection rate seen with early steroid withdrawal on long-term outcomes. Thus, the use of such protocols remains investigational.     

Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation

BACKGROUND: Calcineurin inhibitors and steroids are standard immunosuppressants in solid organ transplantation, but (long-term) side effects are harmful to the recipient and the graft. The authors present a novel strategy for posttransplant immunosuppression that combines a depleting antibody with an antimetabolite, avoiding calcineurin inhibitors and steroids. METHODS: In a prospective, nonrandomized, observational cohort study, 75 pancreas-kidney and solitary pancreas recipients received alemtuzumab (4 doses for induction and up to 12 doses within the first year) and mycophenolate mofetil (> or = 2 g/day) for induction and maintenance therapy. Minimum follow-up was 6 months. We compared the results with a historical group of 266 consecutive pancreas recipients on Thymoglobulin (induction) and tacrolimus (maintenance). RESULTS: Differences in patient and graft survival rates between the study and control groups at 6 months were not statistically significant. However, the incidence of a first reversible rejection episode was significantly higher for simultaneous pancreas-kidney recipients in the study (vs. control) group. We noted a trend toward higher modification of renal disease levels at 6 months posttransplant in the study (vs. control) groups. CONCLUSIONS: The combination of alemtuzumab and mycophenolate mofetil was associated with an acceptable rejection rate, a good safety profile, and good (graft and native) kidney function; it eliminated undesired calcineurin inhibitor- and steroid-related side effects. Longer follow-up is warranted before expanded application can be recommended.     

Sirolimus in kidney transplantation from marginal donors

Nephrotoxicity caused by calcineurin inhibitors can lead to either delayed graft function or long-term decline of renal function after kidney transplantation. Therefore, recipients of renal transplants from marginal donors require non-nephrotoxic immunosuppression. Eighteen patients received kidney transplants from marginal donors, with a calcineurin inhibitor-free immunosuppressive regimen, based on basiliximab, mycophenolate mofetil, steroids, and sirolimus. Renal graft biopsy was performed in all cases before surgery. Mean follow-up was 11.8 months. We report immediate renal function in 9 patients, delayed graft function in 5 and acute tubular necrosis in 4 patients. One patient was successfully treated for biopsy-proven acute rejection. Hypercholesterolemia and hypertriglyceridemia were the most common adverse effects (n = 13) associated with arthralgia (n = 2) and thrombocytopenia (n = 2). Five patients underwent a switch to tacrolimus, due to sirolimus-induced side effects. Immunosuppression without the use of calcineurin inhibitors is a safe and effective regimen in kidney transplantation, although sirolimus-related side effects still represent a morbidity factor in these patients.     

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

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

Use of IL-2 receptor antagonists to reduce delayed graft function following renal transplantation: a review

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.