Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized‐Controlled MECANO Trial

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open‐label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor‐specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.     

mTOR inhibitors in pediatric kidney transplantation

The mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly being used in pediatric kidney transplantation in different combinations and doses. Several studies have shown beneficial effects of using mTOR inhibitors in children after pediatric renal transplantation. A switch to a low-dose calcineurin inhibitor (CNI) and mTOR inhibitor has been proven to stabilize the glomerular filtration rate. Additionally, de novo studies using a low-dose CNI and an mTOR inhibitor have shown good graft survival and a low number of rejections. Side effects of mTOR inhibitors, such as hyperlipidemia, wound healing problems, and proteinuria, mainly occur if high doses are given and if treatment is not combined with a CNI. Lower doses of mTOR inhibitors do not result in growth impairment or reduced testosterone levels. Treatment with mTOR inhibitors is also associated with a lower number of viral infections, especially cytomegalovirus. Due to their antiproliferative effect, mTOR inhibitors could theoretically reduce the risk of post-transplant lymphoproliferative disease. mTOR inhibitors, especially in combination with low-dose CNIs, can safely be used in children after kidney transplantation as de novo therapy or for conversion from CNI- and mycophenolate mofetil-based regimens.     

Calcineurin-inhibitor-sparing immunosuppressive protocols

Calcineurin inhibitors (CNI) have played an important role in improving graft survival. However, the balance between preventing immunologic allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. There are three major CNI-sparing strategies. CNI MINIMIZATION: The advent of mycophenolate mofetil (MMF) allows cyclosporine (CsA) reduction to ameliorate renal function in patients with chronic renal allograft dysfunction, without increasing acute rejection rates. In combination with mTOR inhibitors, very low CNI levels may be sufficient to prevent acute rejection. However, in this association, CNI nephrotoxicity is magnified by pharmacokinetic interaction. CNI WITHDRAWAL: CNI withdrawal has been attempted in regimens containing MMF or sirolimus (SRL). Introduction of MMF in patients with chronic allograft nephropathy (CAN) followed by CNI withdrawal resulted in stabilization or improvement of renal function and hypertension profile, although there is some risk of acute rejection. In regimes based on SRL, CNI withdrawal is a safety strategy, achieving a sustained improvement of renal function, histology, and graft survival. There is not consensus at all whether MMF should be added or not in patients converted from CNI to mTOR inhibitor. CNI AVOIDANCE: Polyclonal-based regimens with MMF and steroids have shown acceptable acute rejection rates, but high rates of cytomegalovirus (CMV) and opportunistic infections. Conversely, anti-IL-2R in combination with MMF and steroids resulted in 50% incidence of acute rejection, thus suggesting that CNI avoidance is not feasible in a regimen based on MMF. Alternatively, a protocol based on anti-IL-2R induction therapy combined with SRL, MMF, and prednisone has shown an efficient prevention of acute rejection, higher creatinine clearance and lower rate of CAN in comparison with a group treated with CNI. New strategies using costimulation blockade may help in the development of safe CNI-free regimens. In summary, in renal transplantation the new immunosuppressive medications have made feasible old aspirations such as minimization, withdrawal, or even avoidance of CNI.     

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.     

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation

Early conversion to a calcineurin‐inhibitor (CNI)‐free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1‐year renal function as compared with a cyclosporine (CsA)‐based regimen (SMART core‐study). This observational follow‐up describes 132 patients followed up within the SMART study framework for 36 months. At 36 months, renal function continued to be superior in SRL‐treated patients [ITT‐eGFR_@36m: 60.88 vs. 53.72 (CsA) ml/min/1.73 m², P = 0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36 months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA‐treated patients. In a multivariate analysis, donor age >60 years, S‐creatinine at conversion >2 mg/dl, CMV naïve(‐) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36 months. Early conversion to a CNI‐free SRL‐based immunosuppression is associated with a sustained improvement of renal function up to 36 months after transplantation. Patient selection will be key to derive long‐term benefit and avoid treatment failure using this mTOR‐inhibitor‐based immunosuppressive regimen.     

Belatacept and Sirolimus Prolong Nonhuman Primate Renal Allograft Survival Without a Requirement for Memory T Cell Depletion

Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, nonlymphocyte depleting, belatacept‐based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC‐mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade‐resistant rejection, some animals also received CD2 blockade with alefacept (LFA3‐Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept‐treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, nondepleting, CNI‐free, steroid‐sparing immunomodulatory regimen that promotes sustained rejection‐free allograft survival after renal transplantation.     

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.     

De novo sirolimus-based regimen in Thai renal transplant recipients

BACKGROUND: Calcineurin inhibitor (CNI) toxicity is a common cause of chronic allograft nephropathy. Although de novo sirolimus (SRL) with CNI minimization may provide better graft function, studies in Asian recipients are lacking. AIM: We sought to determine the 1-year outcomes of renal transplant patients who received a de novo SRL-based regimen with CNI minimization. PATIENTS AND METHODS: A single-center, prospective study of de novo SRL-based, reduced-dose cyclosporine regimen was performed from 2004 to 2007. The control group was a historical cohort of a cyclosporine-based regimen (cyclosporine, prednisolone, and mycophenolate mofetil). The 1-year outcome parameters included renal function, rate of acute rejection, biopsy-proven CNI toxicity, graft and patient survivals. RESULTS: The SRL-based regimen achieved 100% 1-year graft and patient survivals. The renal function was comparable between the SRL-based and CNI-based regimens (serum creatinine 1.32 +/- 0.45 and 1.45 +/- 0.43 mg/dL; P = .27). The rate of biopsy-proven acute rejection was comparable (9.5% and 13%; P = .68). The SRL-based regimen had a higher rate of biopsy-proven CNI toxicity (28.5% and 9.7%; P = .03). CONCLUSIONS: De novo SRL-based regimen with CNI minimization provides excellent transplant outcomes. The strategy to minimize or withdraw CNIs may achieve excellent graft function. A prospective study targeting lower CNI trough levels in Asian transplant recipients is required.     

Everolimus with early withdrawal or reduced‐dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta‐analysis

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal‐sparing effect. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75‐17.8). EVR use was not associated with an increased risk of biopsy‐proven acute rejection (RR 0.68, 95% CI: 0.31‐1.46), graft loss (RR 1.60, 95% CI: 0.51‐5.00), or mortality (RR 1.34, 95% CI 0.62‐2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10‐1.91).     

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.     

Conversion From Cyclosporine to Everolimus at 4.5 Months Posttransplant: 3‐Year Results From the Randomized ZEUS Study

The long‐term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12‐month, open‐label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m², 95%CI 4.3, 11.0 mL/min/1.73 m²; p < 0.001) and month 36 (7.5 mL/min/1.73 m², 95%CI 3.6, 11.4 mL/min/1.73 m²; p < 0.001). The incidence of biopsy‐proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.     

Chronic Calcineurin Inhibitor Nephrotoxicity—Lest We Forget

Calcineurin inhibitor (CNI) nephrotoxicity was recognized in Cambridge in the late 1970s. The vasoconstrictor impact of cyclosporine (CsA) and to a lesser extent tacrolimus, in both acute and chronic settings, results from a decrease in vasodilators and increase in vasconconstrictors while direct tubular toxicity results from blockade of mitochondrial permeability transition pores and inhibition of prolyl isomerase. A biopsy of native kidneys of recipients of CNIs reveals nephrotoxicity as the most common pathological diagnosis with chronic CNI toxicity and hypertension the primary problems. A long‐term study of randomized clinical trials with up to 20 years of follow‐up shows inferiority of both renal function and graft survival for continuous CsA compared to either CsA withdrawal or continuous azathioprine and prednisolone. Pathological hallmarks of chronic CNI nephrotoxicity include stripped interstitial fibrosis, arteriolar hyalinosis and glomerular sclerosis, but with the exception of nodular arteriolar hyalinosis the findings are non specific. The model for chronic renal allograft loss must be multifactorial with both immune and nonimmune factors operating dependent upon an individual's risk factors for cell and/or antibody‐mediated rejection, CNI nephrotoxicity and recurrent disease. Better outcomes will require early diagnosis and individualization of therapy dependent upon the dominant mechanisms impacting each patient. The revisionist view put forward by some senior, experienced and thoughtful individuals, challenges the concept of chronic CNI nephrotoxicity as an important clinical entity. By implication, the view that appears to be promoted is as follows: we need not fear‐prolonged exposure to CNIs, and in seeking better long‐term solutions for transplant recipients, we have forgotten alloimmunity. It is thus apparent that we must revisit the data and again question the basis for chronic CNI nephrotoxicity in current clinical practice. This contribution to the debate will focus on the evidence that CNIs are nephrotoxic and that their impact needs to be limited if we are to improve long‐term outcomes after transplantation, leaving others to promote the contrary perspective and perhaps also to reflect on the largely unproven impact of the steroid avoidance and other minimization strategies so prevalent today.     

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.     

Challenges and considerations in diagnosing the kidney disease in deteriorating graft function

Despite significant reductions in acute‐rejection rates with the introduction of calcineurin inhibitor (CNI)‐based immunosuppressive therapy, improvements in long‐term graft survival in renal transplantation have been mixed. Improving long‐term graft survival continues to present a major challenge in the management of kidney‐transplant patients. CNIs are a key component of immunosuppressive therapy, and chronic CNI toxicity has been widely thought to be a major factor in late graft failure. However, recent studies examining the causes of late graft failure in detail have challenged this view, highlighting the importance of antibody‐mediated rejection and other factors. In addition, the diagnosis of CNI nephrotoxicity represents a challenge to clinicians, with the potential for over‐diagnosis and an inappropriate reduction in immunosuppressive therapy. When graft function is deteriorating, accurately determining the cause of the kidney disease is essential for effective long‐term management of the patient. Diagnosis requires a thorough clinical investigation, and in the majority of cases a specific cause can be identified.     

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.     

Results of 4-year analysis of conversion from calcineurin inhibitors to mTOR inhibitors in renal transplant patients: single-center experience

In this retrospective study, 83 patients were accepted. Mammalian target of rapamycin (mTOR) group consisting of 37 patients were converted from calcineurin inhibitors (CNI), and the control group included 46 patients (initially CNI-receiving patients). As a control-match of each mTOR inhibitor patient, the succeeding patient with transplantation who continued CNI therapy was chosen. All patients received CNI, MMF, and prednisolone as an immunosuppressive therapy initially. In comparison of two groups, there was no significant difference between sex, donor organ source, donor organ ischemia time, or mismatches. However, mean age between groups was significantly different (mTOR group: 48.3 ± 12, CNI group: 38.6 ± 11, p < 0.001). Decision of conversion to mTOR inhibitors in 30 patients was made by biopsy. The reasons for conversion were determined as CNI nephrotoxicity in 15 patients, chronic allograft nephropathy in 15 patients, malignancy in 6 patients, and renal artery stenosis in 1 patient. Basal glomerular filtration rates (GFRs) were markedly lower in mTOR group than in CNI group (38.8 mL/min vs. 72.7 mL/min). At the end of 48-month follow-ups, GFR increased from 38 mL/min to 54 mL/min in mTOR group; however, it decreased to 53 mL/min from 72 mL/min in CNI group. There was no difference left between the two groups in GFR after 4-year follow-up. Hyperlipidemia was higher in mTOR group. Acute rejection rates were similar. Cytomegalovirus (CMV) disease was more prevalent in CNI group. Graft failure developed due to secondary reasons, causing mortality in both groups. We suggest that conversion to mTOR inhibitors maintains and improves graft functions well.     

Conversion to Belatacept-Based Immunosuppression Therapy in Renal Transplant Patients

Belatacept, a fusion protein that prevents stimulation of the CD28 receptor, does not have the adverse renal, cardiovascular, and metabolic adverse effects associated with calcineurin inhibitors (CNIs). We present data on 8 renal transplant patients with graft dysfunction who were switched from CNI-based immunosuppressive therapy to belatacept in response to patients' specific needs. In patients 1 through 5, the belatacept regimen comprised 5-mg/kg doses on days 1, 15, 28, 43, and 57, then every 28 days with a decrease in the CNI dose. The CNI dose was tapered: 100% on day 1, 60% on day 15, 30% on day 23, and discontinued on day 29. In patients 6, 7, and 8, belatacept was administered at 10 mg/kg on days 1, 5, 15, 28, 60, and 90, and then at 5 mg/kg every 28 days. CNIs were withdrawn completely on day 1. Reasons for switching were intolerance to CNI, CNI toxicity, vascular lesions, interstitial fibrosis/tubular atrophy, or arterial hypertension. Renal function improved in all cases. Belatacept is approved to be used de novo; the uniqueness of our cases is that it was used in conversion and in patients with renal dysfunction. In the short term, patients did not present with any serious adverse events related to belatacept or cellular or humoral acute rejection episodes.     

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.     

Usefulness of Sirolimus as Rescue Therapy in Heart Transplant Recipients With Renal Failure: Analysis of the Spanish Multicenter Observational Study (RAPACOR)

Background

Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity.

Methods

We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min.

Results

Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events.

Conclusions

Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.