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.     

Steroid minimization for sirolimus‐treated renal transplant recipients

Matas AJ, Granger D, Kaufman DB, Sarwal MM, Ferguson RM, Woodle ES, Gill JS. Steroid minimization for sirolimus‐treated renal transplant recipients.
Clin Transplant 2011: 25: 457–467. © 2010 John Wiley & Sons A/S. Abstract: Steroids are associated with a myriad of post‐transplant side effects. Therefore, as new immunosuppressive drugs have been developed, attempts have been made to minimize steroid exposure. Sirolimus (SRL) has been demonstrated to have efficacy in early and late post‐transplant immunosuppression. Accordingly, numerous trials have studied steroid minimization (early and late post‐transplant) in the context of SRL‐containing protocols (either with or without a calcineurin inhibitor). We herein review these trials and show that recent studies have determined that both late steroid withdrawal and early rapid discontinuation can be successful with SRL immunosuppression.     

Steroid and calcineurin inhibitor-sparing protocols in kidney transplantation

Recent improvements in kidney transplantation have been driven largely by lower acute rejection rates attributed to better immunosuppressive agents. In an effort to reduce the long-term toxicities of immunosuppressant drugs, corticosteroid- and calcineurin inhibitor (CNI)-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. Nevertheless, these strategies may increase the risk of acute and chronic allograft injury (CAI) that may worsen the fate of transplant recipients. This article focuses on steroid and CNI sparing protocols to elucidate their safety and efficacy in patients receiving a kidney transplant. Steroid avoidance protocols are rapidly and increasingly being used. Studies have shown that corticosteroids are not essential to achieve excellent short- and intermediate-term results. However, the role of steroid withdrawal is only marginally beneficial and very often benefit overstated. CNI-sparing strategies have been used to help maintain the balance between allograft survival and nephrotoxicity. Trials evaluating CNI minimization have shown reduced incidence of CAI and preservation of allograft function. CNI withdrawal within 3 to 12 months after kidney transplantation improved graft function despite increased risk of acute rejection. This approach may be feasible with adequate exposure and proper usage of mammalian target of rapamacin inhibitors. Late withdrawal or conversion did not show a clear benefit. Timing and degree of renal dysfunction are key determining factors. With regards to CNI avoidance, earlier trials, such as the Symphony study, did not support the use of a CNI-free regimen of low-dose sirolimus as initial immunosuppression. However, recent studies using costimulatory blockade-based immusouppression showed that CNI avoidance is possible. The best maintenance immunosuppressive with CNI- or steroid-sparing is a work in progress and awaits longer term follow-up. The availability of newer biologics for costimulatory blockade and new immunosuppressive agents with novel mechanisms of action have the potential of using CNI- and steroid-sparing protocols to minimize the incidence of CAI and improve long-term outcomes in kidney transplant recipients.     

Calcineurin Inhibitor Minimization,Conversion, Withdrawal,and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta‐Analysis

Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta‐analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate‐ to high‐strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard‐dose regimens; moderate‐strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate‐ to high‐strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine‐based strategies and low‐risk populations. Additional research is needed with tacrolimus‐based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient‐centered outcomes.     

The role of Thymoglobulin induction in kidney transplantation: an update

The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte‐depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T‐cell surface antigens as well as natural killer‐cell antigens, B‐cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long‐lasting T‐cell depletion. Randomized studies have established the anti‐rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6–7.5 mg/kg, with vigilant short‐ and long‐term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high‐risk patients, in those at increased risk of DGF and to maintain efficacy in low‐risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance.     

Strategies to prevent chronic allograft nephropathy in kidney transplantation: focus on calcineurin inhibitors

Chronic allograft nephropathy is one of the leading causes of long-term graft failure in kidney transplant recipients. The etiology of this condition is multifactorial, but administration of calcineurin inhibitors is often implicated. With the introduction of newer immunosuppressive agents, strategies for calcineurin inhibitor minimization, avoidance, and withdrawal have been emerging in the literature. These strategies may improve long-term kidney allograft function, but are not without risks. Results from recent clinical trials evaluating the safety and efficacy of these strategies to prevent chronic allograft nephropathy in kidney transplant recipients are summarized and reviewed. Patients who had never received a calcineurin inhibitor or who had cyclosporine withdrawn from their regimens had better kidney function than patients who received or kept receiving a calcineurin inhibitor. The impact of the improvement in kidney function on long-term graft survival remains to be determined. In addition, the benefit in renal function must be weighed against the bone marrow toxicities and/or metabolic complications associated with these regimens.     

Corticosteroid avoidance in pediatric renal transplantation

Corticosteroids have played a central role in the evolution of renal transplant as the modality of choice for renal replacement in end stage kidney disease. Their use is associated with significant, dose related morbidity including osseous, cardiovascular, metabolic complications, body disfigurement and growth retardation in children. The strategies that have been employed to minimize these side effects include reduction in the daily administered dose of steroids, use of alternate day dosing regimens, steroid withdrawal post-transplantation and complete steroid avoidance. Steroid dose minimization has been associated with increased rates of acute rejection, though introduction of newer and more potent immunosuppressives has helped reduce the incidence of this complication. Steroid minimization will benefit patient morbidity due to cataracts, cardiovascular and osseous complications, but may offer little benefit towards improving linear growth. Alternate day steroid therapy may have a greater impact on growth improvement, but may be troubled by regimen non-adherence. Steroid withdrawal post-transplant, the ultimate target, is successful in a cohort of patients, but overall, has been historically associated with unacceptably high rates of clinical acute rejection, and has thus been used sparingly in adults and even less so in children. Complete corticosteroid avoidance, using newer induction and immunosuppressive agents, has been associated with an 8–23% incidence of acute rejection in pediatric renal transplant patients, significant catch-up growth post-transplant, improvements in post-transplant hypertension and hyperlipidemia, and a high safety profile at current follow-up. Newer induction protocols may allow complete steroid-free immunosuppression thus offering significant advantages in preventing the above-mentioned steroid related morbidity, which could also possibly be applicable to other areas of solid organ transplantation in all age groups.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Effects of steroid avoidance and novel protocols on growth in paediatric renal transplant patients

The vast majority of kidney transplant recipients undergo triple maintenance immunosuppression that includes the use of steroids. Irrespective of their long history in organ transplantation and proven efficacy in preventing acute graft rejection, steroids exhibit an unfavourable toxicity profile, including growth retardation in children. Given these negative effects, therapeutic approaches that will substantially decrease patients’ exposure to steroids have been considered. The planned approaches included alternate day administration, rapid or late steroid withdrawal at the pre-scheduled time after transplantation and complete steroid avoidance. All three of these strategies have been tested in single- or multicentre studies and shown to have distinct clinical advantages in terms of decreasing the incidence and severity of specific adverse events. However, the safety of these protocols could not be universally proven. The Stanford study showed that a complete steroid avoidance under the “cover” of tacrolimus, mycophenolate mofetil and extended daclizumab induction is a very effective regimen for obtaining an improvement in post-transplantation growth. The recently reported international randomized TWIST trial demonstrated growth improvement as early as 6 months post-transplantation. These protocols may potentially enable paediatric renal graft recipients to safely avoid steroid exposure.     

Immunosuppression: does one regimen fit all?

There has been considerable interest in the individualization of immunosuppressive regimens in an attempt to avoid side effects and improve long-term outcomes. Most available studies have addressed steroid and calcineurin inhibitor minimization in an attempt to prevent the development of chronic allograft dysfunction and cardiovascular mortality. Herein, we evaluate the available evidence for incorporation of these novel strategies in standard clinical care of kidney transplant recipients. Protocol biopsies, pharmacogenetics, and other assays have been developed to guide tailoring of immunosuppression; however, although promising results have been obtained, trials showing their ability to improve long-term outcome are lacking and urgently needed.     

Steroid withdrawal in renal transplantation

Over the last decade, steroid minimization became one of the major goals in pediatric renal transplantation. Different protocols have been used by individual centers and multicenter study groups, including early and late steroid withdrawal or even complete avoidance. The timing of steroid withdrawal determines if antibodies are used, as avoidance and early withdrawal require antibody induction, while late withdrawal typically does not. A monoclonal antibody was used in most protocols during an early steroid withdrawal together with tacrolimus and mycophenolate mofetil in low immunological risk patients. Polyclonal induction was reported as effective in high-risk patients. Cyclosporine A and mycophenolate mofetil were used in late steroid withdrawal with no induction. All described protocols were effective in terms of preventing acute rejection and preserving renal graft function. There was no superiority of any specific protocol in terms of clinical benefits of steroid withdrawal. Pre-puberty determined growth benefit while other clinical advantages, including better control of glycemia, lipids, and blood pressure, were age independent. It is not clear whether the steroid withdrawal increases the risk of recurrence of primary glomerular diseases post-transplant, however it cannot be excluded. There is no evidence to date for a higher risk of anti-HLA production in steroid-free children after renal transplantation. Key summary points - Current strategies to minimize the steroid-related adverse effects in pediatric renal graft recipients include steroid withdrawal, early or late after transplantation, or complete steroid avoidance - Early steroid withdrawal or avoidance is generally used following the induction therapy with mono- or polyclonal antibodies, while in late steroid withdrawal induction therapy was generally not used - Elimination of steroids (early or late) does not increase the risk of acute rejection and does not deteriorate long-term renal graft function - Early steroid withdrawal is possible in patients at high immunological risk using a combination of polyclonal antibody induction, tacrolimus, and mycophenolate mofetil - All protocols of steroid minimization showed relevant clinical benefits, however the growth-related benefit was limited to pre-pubertal patients in all but one of the studies - Adverse events of steroid withdrawal occurred in a higher incidence of post-transplant bone marrow suppression Key research points - There is no clear evidence of the impact of steroid withdrawal on the risk of recurrence of primary glomerulonephritis after renal transplantation in children, therefore further evaluation of this important issue should be performed in prospective trials - There is limited pediatric data on the risk of anti-HLA/donor-specific antibody production in steroid-free patients after renal transplantation. It is not clear whether the selection of the type of induction antibody (lymphocyte depleting versus short, two-dose administration of anti-IL2R inhibitor) is important in this term. The production of anti-HLA antibodies should then be monitored on a regular basis and analyzed in prospective trials.     

Minimization of steroids in kidney transplantation

The goal of steroid minimization trials has been to minimize or eliminate steroid-related side-effects while simultaneously not increasing the rate of acute rejection (AR) and chronic graft loss. Early trials of late steroid withdrawal (≥3 months post-transplant) were associated with significantly increased AR rates and late graft loss. More recent trials of rapid discontinuation of prednisone (RDP) (≤7 days post-transplant) have been associated with little or no increase in AR rates and no difference in graft survival (versus maintenance prednisone). Of note, induction therapy appears to be important for success; however, it is not clear if any single maintenance protocol is superior. Intermediate-term follow-up (5–7 years) is now available for some randomized and nonrandomized trials; graft survival and renal function remain excellent. Most of these trials have been done in low immunologic risk recipients, but there are reports of success of RDP in children, black recipients, sensitized recipients, recipients with potentially recurring disease, and kidney–pancreas recipients. Of critical importance, steroid-related side-effects have been minimized. Steroid minimization protocols can clearly be recommended for low-risk patients; additional trials are necessary for those at higher risk. Additional research is also necessary on integrating calcineurin inhibitor minimization with steroid minimization.     

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

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

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

Background  

Immunosuppression 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.     

Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients

Kidney transplant recipients administered belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept-based maintenance regimens. Steroid-sparing, belatacept-based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept-based regimen for minimizing early cellular AR occurrence.     

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.     

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 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.     

Impact of Calcineurin‐Inhibitor Conversion to mTOR Inhibitor on Renal Allograft Function in a Prednisone‐Free Regimen

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone‐free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow‐up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy‐proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone‐free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.