© 2013 John Wiley & Sons A/S.
Clin Transplant 2013: 27 (Suppl. 25): 16–29 DOI: 10.1111/ctr.12156
Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients Nashan B. Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients. Abstract: Use of induction therapy with mTOR inhibitor maintenance immunosuppression to facilitate reduced calcineurin inhibitor (CNI) exposure in de novo kidney transplant patients has been explored in a series of randomized trials. These studies have typically employed interleukin-2 receptor antagonist (IL-2RA) induction, in low or standard immunological risk recipients. Although no study has directly compared mTOR inhibition plus reduced CNI exposure with or without induction, inclusion of IL-2RA induction appears to permit a substantial reduction in CNI exposure without the need for high mTOR inhibitor dosing. IL2RA induction with an mTOR inhibitor and steroids has consistently shown similar efficacy to standard-exposure CNI with mycophenolic acid and steroids and may improve renal function among patients who remain on the mTOR inhibitor-based regimen. With modern mTOR inhibitor dosing, wound healing complications are of less concern and may be no more frequent than in mycophenolic acid-based regimens. The incidence of cytomegalovirus infection appears lower in patients receiving de novo mTOR inhibition. The available evidence demonstrates that IL-2RA induction with an mTOR inhibitor can successfully reduce CNI exposure by at least half without a penalty in terms of rejection in low- or moderate-risk de novo transplant recipients and may offer renal and antiviral benefits.
A key clinical priority in kidney transplantation is to minimize exposure to calcineurin inhibitors (CNIs). While their efficacy is unquestioned, maintenance CNI therapy is associated with a series of complications including cardiovascular risk factors such as hypertension, dyslipidemia, new-onset diabetes mellitus and hyperglycemia (1), malignancy (2, 3), and nephrotoxicity characterized by interstitial fibrosis/tubular atrophy and arteriolar hyalinosis (4). Minimizing exposure to CNI agents long term can improve graft function and may reduce the risk of new-onset diabetes and hypertension (5–7). The early post-transplant period, in which CNI exposure has historically been required due to the increased risk of acute graft rejection, is of particular concern due to the dose-dependent nature of CNI-related nephrotoxicity (4). Use of induction therapy to provide intensive immunoprophylaxis during the first few weeks posttransplant is clearly a rational component of regimens that attempt to ameliorate CNI-related graft damage. Induction therapy was historically
16
€ rn Nashan Bjo Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf, Hamburg, Germany Key words: antithymocyte globulin – basiliximab – calcineurin inhibitors – daclizumab – everolimus – induction – kidney transplantation – minimization – mTOR inhibitors – sirolimus €rn Nashan, MD, Corresponding author: Bjo PhD, FACS, FRCSC, FEBS, Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 40 7410 56136; Fax: +49 40 7410 43431; e-mail: [email protected] Conflict of interest: None. Accepted for publication 12 February 2013
administered as an adjunct to standard CNI-based regimens in order to reduce rejection rates, but the availability of new immunosuppressants increasingly means that the role of induction is now to facilitate CNI minimization. The introduction of mycophenolic acid (MPA) in the mid-1990s, with its increased immunosuppressive potency vs. the previous antimetabolite azathioprine (8–10), provided the first major opportunity to reduce CNI intensity. Initially, complete CNI avoidance with induction therapy, steroids, and MPA was explored, but rejection rates were found to be unacceptably high (11). More recently, an analysis of data from the United Network for Organ Sharing (UNOS) database confirmed that CNI-free regimens with mycophenolate mofetil (MMF) and steroids using the induction agent alemtuzumab were associated with higher rejection rates and graft loss than CNI-based therapy (12). It appears that induction therapy with MPA and steroids provides inadequate immunosuppression in the immediate
Induction therapy and mTOR inhibition post-transplant period, and other CNI minimization strategies have been assessed. Delayed introduction of CNIs in the presence of MMF, steroids, and induction with antithymocyte globulin (ATG) (13) or an interleukin-2 receptor antagonist (IL-2RA) (14) can be achieved without a penalty in terms of rejection, but does not overcome the risks associated with chronic CNI exposure. Potentially more interesting are results from the CAESAR study, which showed that a regimen of IL-2RA induction with MMF and reduced-exposure cyclosporine (CsA) offers similar efficacy to MMF with standard CsA in the absence of induction (15). Similarly, the large SYMPHONY study demonstrated that in the presence of IL-2RA induction, low-dose CsA was associated with a similar incidence of acute rejection to standard-dose CsA, both with MMF and steroids (16). In neither trial, however, was a renal benefit observed with CsA reduction at month 12 post-transplant, possibly because trough CsA concentrations fell no lower than approximately 100 ng/mL throughout the first year posttransplant (15, 16). For de novo kidney transplant patients, a larger evidence base is available from studies in which CNI exposure is reduced using induction therapy with an mTOR inhibitor-based regimen, although it should be noted that in most cases the duration of such studies was relatively short. Such an approach capitalizes on the synergistic mode of action of mTOR inhibitors and CNIs, which permits CNI reduction without loss of efficacy (17). This study considers the available data and the potential role for such regimens in the de novo kidney transplant population. Current induction therapies
The induction market currently consists of ATG preparations, the monoclonal antibody alemtuzumab, and the IL-2RA agent basiliximab. ATG is a non-specific lymphocyte-depleting agent with a wide range of antibody specificities, including immune response antigens, adhesion molecules, and cell trafficking molecules (18). Its administration results in extensive depletion of T-lymphocytes including B-lymphocytes and other immune cells and modulates the leukocyte–endothelial interactions that contribute to ischemia–reperfusion injury (18). Alemtuzumab also exerts a profound, long-lasting depletion of T-lymphocytes and, to a lesser extent, B-lymphocytes (19). IL-2RA agents, in contrast, are non-depleting and act in a targeted manner against the CD25 subunit of the high-affinity IL-2 receptor expressed by
activated T-lymphocytes, such that resting T-lymphocytes are largely unaffected (20). Inhibiting IL-2 stimulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway restricts proliferation, expansion, and migration of T-lymphocytes (21–23). The modes of action for IL-2RA agents and mTOR inhibitors are inter-related because mTOR is an important gatekeeper in the PI3K/Akt pathway. It acts downstream from the IL-2 receptor to regulate the synthesis of proteins required for cell-cycle progression (24) and thus inhibits cytokine-dependent T-lymphocyte proliferation. A series of randomized trials has compared the efficacy of ATG preparations vs. IL-2RA induction in kidney transplantation (13, 25–32). All such studies that have been undertaken in patients at standard or low immunological risk have reported similar rates of acute rejection with either type of induction (13, 27–30, 32). In patients at high immunological risk receiving standard CNI immunosuppression, MPA, and steroids, however, ATG appears to offer superior efficacy to IL-2RA agents (25, 26, 31). There is limited evidence that use of ATG might reduce the risk of delayed graft function (DGF) (26, 30) but conflicting data exist (26– 29). The primary safety concerns with induction therapy are infection and malignancies. Placebo-controlled randomized studies of the IL-2RA agents basiliximab (33, 34) and daclizumab (35, 36) found no increase in the rates of infection vs. placebo. With ATG, lymphocyte depletion and delayed immunological reconstitution, especially in older patients (37) may be associated with significantly higher rates of infection overall (26) with ATG vs. IL-2RA, although bacterial infections appear to be similar (25). Among randomized trials comparing ATG vs. IL-2RA induction with a standard regimen of CNI therapy and MPA with corticosteroids (13, 25, 27) or delayed initiation of CNI therapy (13, 28, 29), there has been either a numerically (25, 27, 28, 31) or significantly (13, 29) higher incidence of cytomegalovirus (CMV) infection in the ATG arm, although exceptions have been reported (26, 30). Prolonged antiviral prophylaxis may be required in patients with delayed immune recovery following ATG administration. Obtaining robust data concerning the risk of malignancy with induction agents is challenging. The large population sizes required to identify an effect on carcinogenesis necessitate a reliance on long-duration singlecenter observational studies and registry analyses, both of which are handicapped by changes in dosing over time, inclusion of non-randomized populations, and variations in concomitant
17
Nashan
medication. These considerations notwithstanding, large-scale registry analyses have consistently shown IL-2RA induction agents to have no effect on malignancy risk (38–40). Registry analyses from the 1980s and 1990s found an increase in nonHodgkin lymphoma with lymphocyte-depleting induction agents (38), but interpretation is challenging particularly in light of reduced ATG dosing in recent years. Clinical experience with induction and mTOR inhibition
Complete CNI avoidance from the time of transplant has been explored in a number of trials of mTOR inhibition with induction therapy and can improve renal function if the regimen is tolerated (40–42), but high mTOR inhibitor doses are required to prevent rejection (41–43) and frequently result in high rates of adverse events and study drug discontinuation (8, 41, 43). The SYMPHONY study included a treatment arm comprising lowexposure sirolimus (4–8 ng/mL) with MMF, steroids, and daclizumab induction and observed a high rate of biopsy-proven acute rejection (BPAR) (35.3% at month 6) with an increased rate of serious adverse events compared with the CNI-based treatment arms (16). Lower mTOR inhibitor exposure thus appears inadequate to prevent rejection in the absence of CNI therapy. If complete CNI avoidance is attempted, ATG appears preferable to IL-2RA in maintaining immunosuppressive potency. Studies in which ATG was used with an mTOR inhibitor found similar efficacy using a CNI-free regimen vs. standard-exposure tacrolimus (41, 44, 45) or low-exposure tacrolimus (46). Generally, however, complete avoidance of CNI therapy with an mTOR inhibitor has been superseded by the use of low-exposure CNI regimens. Low-exposure CNI regimens
The majority of randomized trials of mTOR inhibitor-based immunosuppression with reduced CNI exposure in de novo kidney transplant patients have employed induction, in the form of IL-2RA agents (Tables 1 and 2). These have typically been undertaken in low- or standard-risk kidney transplant patients (47–51, 56, 57) such that ATG, with its associated increase in infection risk, has not been considered necessary. Indeed, a randomized trial in which 721 heart transplant patients received everolimus in one of two target groups (3–8 or 6– 12 ng/mL) with reduced-exposure CsA and steroids using either basiliximab or ATG induction recently showed an increased incidence of serious
18
infections (including fatal infections) within the first three months after transplantation in the subgroup of patients who had received ATG (58). As a result, the label for everolimus was amended to advise strict caution for the use of ATG (Thymoglobulinâ, Genzyme Corporation, Cambridge, MA, USA) in combination with everolimus, CsA, and steroids (59). The use of alemtuzumab within mTOR inhibitor and reduced-exposure CNI regimens has not yet been investigated. The first indication that IL-2RA induction with mTOR inhibitor maintenance immunosuppression could facilitate CNI reduction in de novo kidney transplant patients came from an early trial of 111 patients receiving a fixed-dose everolimus regimen (3 mg/d), basiliximab, and steroids randomized to standard- or reduced-exposure CsA (56). The primary efficacy endpoint (BPAR, death, graft loss, or loss to follow-up) was significantly less frequent in the reduced-exposure CNI group, a difference largely accounted for by a lower rate of BPAR (6.9% vs. 17.0% at one yr), which was sustained to three yr (12.1% vs. 18.9%). Renal function (serum creatinine) was numerically superior in the reduced CsA cohort. Indeed, lowering the CsA dose further to minimize nephrotoxicity after a protocol amendment improved renal function further without loss of efficacy. A later trial (B201) confirmed the importance of adequate reductions in CsA exposure to optimize renal function (60). Subsequent trials have generally employed concentration-controlled mTOR inhibitor therapy, and a more recent comparison of IL-2RA induction, everolimus, and steroids with reduced-exposure tacrolimus has confirmed that CNI minimization in this setting can be achieved from the time of transplant without an increase in allograft rejection (57). No study has directly compared mTOR inhibition plus reduced CNI exposure in de novo kidney transplant patients with or without induction therapy. However, two large trials (A2306 and A2307) used similar protocols other than use of IL-2R induction with lower CsA target ranges in one trial, and no induction with higher CsA exposure targets in the other study (61). The incidence of BPAR was lower in the patients receiving IL-2RA induction despite lower CsA exposure (Table 1). The value of induction in facilitating lower CNI exposure was indirectly demonstrated in a recent trial by Van Gurp et al. (61), in which 634 de novo moderate-risk kidney transplant patients were randomized to sirolimus (loading dose 6 mg, followed by fixed dosing of 1–2 mg) with reduced tacrolimus or to MMF with standard tacrolimus. Both groups received steroids but no induction therapy. At
Open label Multicenter 12 months
Open label Multicenter 12 months
Open label Single center 24 months
Open label Single center 12 months Open label Multicenter 6 months
Open label Multicenter 6 months
Open label Sirolimus 6 months
Tedesco Silva et al. (A2309) (47)
Salvadori et al. (EVEREST) (48)
Kandaswamy et al. (49)
Ferreira et al. (50)
Vitko et al. (A2307) (51)
Lo et al. (46)
39
256
237
70
Primary tx
Primary tx Functioning graft within 24 h Primary tx
African
None
239b
285
Primary tx No non-heart beating donors Donors ≤60 yr CIT ≤40 h PRA ≤20% PRA
Clin Transplant 2013: 27 (Suppl. 25): 16–29 DOI: 10.1111/ctr.12156
Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients Nashan B. Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients. Abstract: Use of induction therapy with mTOR inhibitor maintenance immunosuppression to facilitate reduced calcineurin inhibitor (CNI) exposure in de novo kidney transplant patients has been explored in a series of randomized trials. These studies have typically employed interleukin-2 receptor antagonist (IL-2RA) induction, in low or standard immunological risk recipients. Although no study has directly compared mTOR inhibition plus reduced CNI exposure with or without induction, inclusion of IL-2RA induction appears to permit a substantial reduction in CNI exposure without the need for high mTOR inhibitor dosing. IL2RA induction with an mTOR inhibitor and steroids has consistently shown similar efficacy to standard-exposure CNI with mycophenolic acid and steroids and may improve renal function among patients who remain on the mTOR inhibitor-based regimen. With modern mTOR inhibitor dosing, wound healing complications are of less concern and may be no more frequent than in mycophenolic acid-based regimens. The incidence of cytomegalovirus infection appears lower in patients receiving de novo mTOR inhibition. The available evidence demonstrates that IL-2RA induction with an mTOR inhibitor can successfully reduce CNI exposure by at least half without a penalty in terms of rejection in low- or moderate-risk de novo transplant recipients and may offer renal and antiviral benefits.
A key clinical priority in kidney transplantation is to minimize exposure to calcineurin inhibitors (CNIs). While their efficacy is unquestioned, maintenance CNI therapy is associated with a series of complications including cardiovascular risk factors such as hypertension, dyslipidemia, new-onset diabetes mellitus and hyperglycemia (1), malignancy (2, 3), and nephrotoxicity characterized by interstitial fibrosis/tubular atrophy and arteriolar hyalinosis (4). Minimizing exposure to CNI agents long term can improve graft function and may reduce the risk of new-onset diabetes and hypertension (5–7). The early post-transplant period, in which CNI exposure has historically been required due to the increased risk of acute graft rejection, is of particular concern due to the dose-dependent nature of CNI-related nephrotoxicity (4). Use of induction therapy to provide intensive immunoprophylaxis during the first few weeks posttransplant is clearly a rational component of regimens that attempt to ameliorate CNI-related graft damage. Induction therapy was historically
16
€ rn Nashan Bjo Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf, Hamburg, Germany Key words: antithymocyte globulin – basiliximab – calcineurin inhibitors – daclizumab – everolimus – induction – kidney transplantation – minimization – mTOR inhibitors – sirolimus €rn Nashan, MD, Corresponding author: Bjo PhD, FACS, FRCSC, FEBS, Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: +49 40 7410 56136; Fax: +49 40 7410 43431; e-mail: [email protected] Conflict of interest: None. Accepted for publication 12 February 2013
administered as an adjunct to standard CNI-based regimens in order to reduce rejection rates, but the availability of new immunosuppressants increasingly means that the role of induction is now to facilitate CNI minimization. The introduction of mycophenolic acid (MPA) in the mid-1990s, with its increased immunosuppressive potency vs. the previous antimetabolite azathioprine (8–10), provided the first major opportunity to reduce CNI intensity. Initially, complete CNI avoidance with induction therapy, steroids, and MPA was explored, but rejection rates were found to be unacceptably high (11). More recently, an analysis of data from the United Network for Organ Sharing (UNOS) database confirmed that CNI-free regimens with mycophenolate mofetil (MMF) and steroids using the induction agent alemtuzumab were associated with higher rejection rates and graft loss than CNI-based therapy (12). It appears that induction therapy with MPA and steroids provides inadequate immunosuppression in the immediate
Induction therapy and mTOR inhibition post-transplant period, and other CNI minimization strategies have been assessed. Delayed introduction of CNIs in the presence of MMF, steroids, and induction with antithymocyte globulin (ATG) (13) or an interleukin-2 receptor antagonist (IL-2RA) (14) can be achieved without a penalty in terms of rejection, but does not overcome the risks associated with chronic CNI exposure. Potentially more interesting are results from the CAESAR study, which showed that a regimen of IL-2RA induction with MMF and reduced-exposure cyclosporine (CsA) offers similar efficacy to MMF with standard CsA in the absence of induction (15). Similarly, the large SYMPHONY study demonstrated that in the presence of IL-2RA induction, low-dose CsA was associated with a similar incidence of acute rejection to standard-dose CsA, both with MMF and steroids (16). In neither trial, however, was a renal benefit observed with CsA reduction at month 12 post-transplant, possibly because trough CsA concentrations fell no lower than approximately 100 ng/mL throughout the first year posttransplant (15, 16). For de novo kidney transplant patients, a larger evidence base is available from studies in which CNI exposure is reduced using induction therapy with an mTOR inhibitor-based regimen, although it should be noted that in most cases the duration of such studies was relatively short. Such an approach capitalizes on the synergistic mode of action of mTOR inhibitors and CNIs, which permits CNI reduction without loss of efficacy (17). This study considers the available data and the potential role for such regimens in the de novo kidney transplant population. Current induction therapies
The induction market currently consists of ATG preparations, the monoclonal antibody alemtuzumab, and the IL-2RA agent basiliximab. ATG is a non-specific lymphocyte-depleting agent with a wide range of antibody specificities, including immune response antigens, adhesion molecules, and cell trafficking molecules (18). Its administration results in extensive depletion of T-lymphocytes including B-lymphocytes and other immune cells and modulates the leukocyte–endothelial interactions that contribute to ischemia–reperfusion injury (18). Alemtuzumab also exerts a profound, long-lasting depletion of T-lymphocytes and, to a lesser extent, B-lymphocytes (19). IL-2RA agents, in contrast, are non-depleting and act in a targeted manner against the CD25 subunit of the high-affinity IL-2 receptor expressed by
activated T-lymphocytes, such that resting T-lymphocytes are largely unaffected (20). Inhibiting IL-2 stimulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway restricts proliferation, expansion, and migration of T-lymphocytes (21–23). The modes of action for IL-2RA agents and mTOR inhibitors are inter-related because mTOR is an important gatekeeper in the PI3K/Akt pathway. It acts downstream from the IL-2 receptor to regulate the synthesis of proteins required for cell-cycle progression (24) and thus inhibits cytokine-dependent T-lymphocyte proliferation. A series of randomized trials has compared the efficacy of ATG preparations vs. IL-2RA induction in kidney transplantation (13, 25–32). All such studies that have been undertaken in patients at standard or low immunological risk have reported similar rates of acute rejection with either type of induction (13, 27–30, 32). In patients at high immunological risk receiving standard CNI immunosuppression, MPA, and steroids, however, ATG appears to offer superior efficacy to IL-2RA agents (25, 26, 31). There is limited evidence that use of ATG might reduce the risk of delayed graft function (DGF) (26, 30) but conflicting data exist (26– 29). The primary safety concerns with induction therapy are infection and malignancies. Placebo-controlled randomized studies of the IL-2RA agents basiliximab (33, 34) and daclizumab (35, 36) found no increase in the rates of infection vs. placebo. With ATG, lymphocyte depletion and delayed immunological reconstitution, especially in older patients (37) may be associated with significantly higher rates of infection overall (26) with ATG vs. IL-2RA, although bacterial infections appear to be similar (25). Among randomized trials comparing ATG vs. IL-2RA induction with a standard regimen of CNI therapy and MPA with corticosteroids (13, 25, 27) or delayed initiation of CNI therapy (13, 28, 29), there has been either a numerically (25, 27, 28, 31) or significantly (13, 29) higher incidence of cytomegalovirus (CMV) infection in the ATG arm, although exceptions have been reported (26, 30). Prolonged antiviral prophylaxis may be required in patients with delayed immune recovery following ATG administration. Obtaining robust data concerning the risk of malignancy with induction agents is challenging. The large population sizes required to identify an effect on carcinogenesis necessitate a reliance on long-duration singlecenter observational studies and registry analyses, both of which are handicapped by changes in dosing over time, inclusion of non-randomized populations, and variations in concomitant
17
Nashan
medication. These considerations notwithstanding, large-scale registry analyses have consistently shown IL-2RA induction agents to have no effect on malignancy risk (38–40). Registry analyses from the 1980s and 1990s found an increase in nonHodgkin lymphoma with lymphocyte-depleting induction agents (38), but interpretation is challenging particularly in light of reduced ATG dosing in recent years. Clinical experience with induction and mTOR inhibition
Complete CNI avoidance from the time of transplant has been explored in a number of trials of mTOR inhibition with induction therapy and can improve renal function if the regimen is tolerated (40–42), but high mTOR inhibitor doses are required to prevent rejection (41–43) and frequently result in high rates of adverse events and study drug discontinuation (8, 41, 43). The SYMPHONY study included a treatment arm comprising lowexposure sirolimus (4–8 ng/mL) with MMF, steroids, and daclizumab induction and observed a high rate of biopsy-proven acute rejection (BPAR) (35.3% at month 6) with an increased rate of serious adverse events compared with the CNI-based treatment arms (16). Lower mTOR inhibitor exposure thus appears inadequate to prevent rejection in the absence of CNI therapy. If complete CNI avoidance is attempted, ATG appears preferable to IL-2RA in maintaining immunosuppressive potency. Studies in which ATG was used with an mTOR inhibitor found similar efficacy using a CNI-free regimen vs. standard-exposure tacrolimus (41, 44, 45) or low-exposure tacrolimus (46). Generally, however, complete avoidance of CNI therapy with an mTOR inhibitor has been superseded by the use of low-exposure CNI regimens. Low-exposure CNI regimens
The majority of randomized trials of mTOR inhibitor-based immunosuppression with reduced CNI exposure in de novo kidney transplant patients have employed induction, in the form of IL-2RA agents (Tables 1 and 2). These have typically been undertaken in low- or standard-risk kidney transplant patients (47–51, 56, 57) such that ATG, with its associated increase in infection risk, has not been considered necessary. Indeed, a randomized trial in which 721 heart transplant patients received everolimus in one of two target groups (3–8 or 6– 12 ng/mL) with reduced-exposure CsA and steroids using either basiliximab or ATG induction recently showed an increased incidence of serious
18
infections (including fatal infections) within the first three months after transplantation in the subgroup of patients who had received ATG (58). As a result, the label for everolimus was amended to advise strict caution for the use of ATG (Thymoglobulinâ, Genzyme Corporation, Cambridge, MA, USA) in combination with everolimus, CsA, and steroids (59). The use of alemtuzumab within mTOR inhibitor and reduced-exposure CNI regimens has not yet been investigated. The first indication that IL-2RA induction with mTOR inhibitor maintenance immunosuppression could facilitate CNI reduction in de novo kidney transplant patients came from an early trial of 111 patients receiving a fixed-dose everolimus regimen (3 mg/d), basiliximab, and steroids randomized to standard- or reduced-exposure CsA (56). The primary efficacy endpoint (BPAR, death, graft loss, or loss to follow-up) was significantly less frequent in the reduced-exposure CNI group, a difference largely accounted for by a lower rate of BPAR (6.9% vs. 17.0% at one yr), which was sustained to three yr (12.1% vs. 18.9%). Renal function (serum creatinine) was numerically superior in the reduced CsA cohort. Indeed, lowering the CsA dose further to minimize nephrotoxicity after a protocol amendment improved renal function further without loss of efficacy. A later trial (B201) confirmed the importance of adequate reductions in CsA exposure to optimize renal function (60). Subsequent trials have generally employed concentration-controlled mTOR inhibitor therapy, and a more recent comparison of IL-2RA induction, everolimus, and steroids with reduced-exposure tacrolimus has confirmed that CNI minimization in this setting can be achieved from the time of transplant without an increase in allograft rejection (57). No study has directly compared mTOR inhibition plus reduced CNI exposure in de novo kidney transplant patients with or without induction therapy. However, two large trials (A2306 and A2307) used similar protocols other than use of IL-2R induction with lower CsA target ranges in one trial, and no induction with higher CsA exposure targets in the other study (61). The incidence of BPAR was lower in the patients receiving IL-2RA induction despite lower CsA exposure (Table 1). The value of induction in facilitating lower CNI exposure was indirectly demonstrated in a recent trial by Van Gurp et al. (61), in which 634 de novo moderate-risk kidney transplant patients were randomized to sirolimus (loading dose 6 mg, followed by fixed dosing of 1–2 mg) with reduced tacrolimus or to MMF with standard tacrolimus. Both groups received steroids but no induction therapy. At
Open label Multicenter 12 months
Open label Multicenter 12 months
Open label Single center 24 months
Open label Single center 12 months Open label Multicenter 6 months
Open label Multicenter 6 months
Open label Sirolimus 6 months
Tedesco Silva et al. (A2309) (47)
Salvadori et al. (EVEREST) (48)
Kandaswamy et al. (49)
Ferreira et al. (50)
Vitko et al. (A2307) (51)
Lo et al. (46)
39
256
237
70
Primary tx
Primary tx Functioning graft within 24 h Primary tx
African
None
239b
285
Primary tx No non-heart beating donors Donors ≤60 yr CIT ≤40 h PRA ≤20% PRA
