Langenbecks Arch Surg DOI 10.1007/s00423-014-1191-9
REVIEW ARTICLE
Current strategies for immunosuppression following liver transplantation Daniel Nils Gotthardt & Helge Bruns & Karl Heinz Weiss & Peter Schemmer
Received: 26 March 2014 / Accepted: 30 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background New strategies for immunosuppression (IS) after liver transplantation (LTx) are in part responsible for the increased patient and graft survival seen over time. With a few basic exceptions—notably the continued use of steroids and calcineurin inhibitors (CNIs)—IS drugs and regimens being used today are different from those used 30 years ago. While graft loss due to acute or chronic rejection has become rare, the side effect burden of IS drugs exerts a significant toll on patients. Concepts/trends CNIs continue to form the backbone of IS regimens, although their use is hampered by nephrotoxicity and other adverse effects. Consequently, a variety of CNI reduction or withdrawal strategies have formed the basis of clinical trials or entered into clinical practice. These trials have included the use of everolimus, an mTOR inhibitor, and antiinterleukin-2 receptor antibodies. Basiliximab, as well as other lymphocyte nondepleting and depleting agents, have shown benefit in induction regimens. Summary Along with steroid reduction or elimination, current strategies for IS after LTx continue to explore novel combinations of agents, with an aim toward striking a balance between diminution of rejection and the need for avoiding adverse effects of the IS drugs. Long-term maintenance strategies are also discussed in this review, as is development of tolerance and antibody-mediated rejection.
D. N. Gotthardt (*) : K. H. Weiss Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany e-mail: [email protected] H. Bruns : P. Schemmer Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
Keywords Calcineurin minimization . IL-2 . Induction . Operational tolerance . Steroid reduction . Tacrolimus trough levels
Introduction From the triple-drug regimen of azathioprine, prednisone, and antilymphoid globulin used in the early days of liver transplantation (LTx) over 45 years ago [1] to the wealth of drugs and regimens currently available, immunosuppression (IS) for LTx has continued to undergo changes and refinements. This has paralleled the increases in patient and graft survival. According to the European Liver Transplant Registry, 1-year patient survival in 2001 reached 83 % compared to 34 % before 1985 [2]. A landmark study in 4,000 patients who underwent LTx between 1981 and 1998 and were followed until 2000 showed overall patient survival to be 59 % and actuarial 18-year survival to be 48 % [3]. Patient survival was found to be significantly better in children, female recipients, and patients who received transplants after 1990, with a notable improvement in the quality of IS and a significant reduction in acute and chronic rejection-associated losses [3]. Notably, the actuarial patient survival rate at 1 year was 71 % in the era when cyclosporine (CyA) was introduced, which was significantly less than that for the era when tacrolimus (TAC) was introduced (86 %) [3]. Similarly, a 20-year follow-up of 313 LTx patients published in 2013 showed patient and graft survival at 1, 10, and 20 years to be 88.4, 72.7, 52.5, and 83.7, 64.7, and 46.6 %, respectively [4]. Whereas improvements in surgical and medical techniques, patient selection criteria, and donor liver procurement, allocation, and preservation also contributed to these trends [5], the advances made in IS continue to be a driving force in LTx improvements. Because most of the long-term complications of LTx are due to IS drug side effects rather than chronic rejection,
Langenbecks Arch Surg
Fig. 1 Immunosuppression use in adult liver transplant recipients over time in the USA, 1998–2010. One-year posttransplantation data for mTOR inhibitors and steroids limited to patients alive with graft function 1 year posttransplantation. One-year posttransplantation data are not reported for transplant recipients in 1998, as follow-up data were very sparse (Organ Procurement and Transplantation Network/Scientific
Registry of Transplant Recipients (OPTN/SRTR) 2011 Annual Report for the liver, Table 7.4. http://srtr.transplant.hrsa.gov/annual_reports/ 2011/. Accessed 5 January 2014). IL2-RA anti-interleukin-2 receptor monoclonal antibody, mTOR mammalian target of rapamycin, Tx transplantation
treatment strategies center on maintaining a delicate balance between avoiding IS drug toxicity and reducing the risk of acute rejection [6–8]. The focus in LTx today is on minimization of IS [9, 10]. Although successful complete withdrawal of IS has been reported and attempted, clinical operational tolerance involving the lack of need for IS is unreachable in the majority of situations [6, 7]. After introduction of the model for end-stage liver disease (MELD) score-based allocation system in the USA and Eurotransplant area, the average MELD scores at transplantation continued to rise, reaching a mean score of 34 in Germany [11]. This led to higher rates of renal insufficiency at transplantation because impaired renal function contributes to a higher MELD score [12]. This also led to the observation that patients are now “sicker” at the time of transplantation than they were a decade ago. The goal of this review is to discuss current strategies for IS after LTx, focusing on recent evidence for various protocols in the short term (induction) and long term (maintenance). Given that the toolbox of available IS drugs has substantially enlarged during the last two decades, with the number of combinations growing even larger, selecting the optimal protocol for any given patient can be a difficult task for clinicians. The expanded options allow for and indeed make it incumbent upon clinicians to individualize therapy according to patient-specific factors such as comorbidities, age, and rejection history and drug-specific factors such as side effect profile and mechanism of action [13]. Accordingly, this review discusses recent trials of steroid-sparing and calcineurin inhibitor (CNI) reduction (in both the short and long term). Tolerance development and antibody-mediated rejection (AMR) are also briefly discussed.
recipients in the USA received initial IS with TAC and mycophenolate mofetil (MMF) plus steroids; 12.9 % of recipients received this regimen without steroids [14]. At 1 year postLTx, a higher proportion of recipients received steroid-free regimens compared to those used initially, with about a quarter of recipients on TAC monotherapy [14]. Trends over roughly the past decade are shown in Fig. 1 and indicate a rising use of TAC and MMF. Although TAC is frequently used in the USA, CyA continues to be used to a significant degree as the CNI in Europe, as evidenced by the authors’ experience as well as by a large single-center European study on 20-year survival after LTx, which showed CyA to be used in 75 % of cases 6 months after primary LTx [4]. Although not possible to discern from the SRTR data, recent studies and reports have expressed concern that current LTx recipients are being overimmunosuppressed [15, 10]. Much of the rationale behind IS minimization strategies is to avert the infectious and metabolic complications of steroids and the renal toxicity, hepatitis C virus (HCV) reinfection, and tumor-promotion effects of CNIs [13]. Table 1 shows as an example of the treatment stratification approach used at the authors’ institution.
De novo immunosuppression after liver transplantation Recent data reported by the Scientific Registry of Transplant Recipients (SRTRs) indicate that in 2011, 59.3 % of LTx
Induction therapy Induction therapy has been defined as a prophylactic, perioperative course of intensive IS given to prevent acute rejection in the 1st months after LTx when the risk of rejection is highest [16]. Typically, it has been used to delay CNI use or avoid steroid use and/or reduce the rate of acute cellular rejection (ACR) [16]. Using data from the United Network for Organ Sharing registry, Cai et al. identified three eras of induction therapy, the latest era being a high-induction, modern antibody era (2003 to present) with rabbit antithymocyte globulin (rATG), basiliximab, daclizumab, or alemtuzumab
Langenbecks Arch Surg Table 1 Example of a treatment strategy for immunosuppression after liver transplantation (authors’ institution) Group A
Group Ba
Group C
High risk of infection, acceptable risk of High risk of infection, unacceptable risk of Low risk of infection, neither group A nor group B rejection: MELD score at LTx >25 and/or rejection: as group A, but HCV positive hospitalized >3 weeks, retransplantation, HCV negative Induction with basiliximab or ATG. MMF Induction with basiliximab or ATG. MMF MMF 1,000 mg BID from day 1 CyA from day 1. 1,000 mg BID from day 1. CNI from day 7. 1,000 mg BID from day 1. TAC from day 7 HCV positive, PSC, or AIH→TAC (upper trough ST only for 5 days. (upper trough levels). ST only for 5 days. levels). ST according to schedule shown in Table 3 MMF can be exchanged to Everolimus taking into account the special situation of the patient AIH autoimmune hepatitis, ATG antithymocyte globulin, BID twice daily, CNI calcineurin inhibitor, CyA cyclosporine, HCV hepatitis C virus, LTx liver transplantation, MELD model for end-stage liver disease, MMF mycophenolate mofetil, PSC primary sclerosing cholangitis, ST steroids, TAC tacrolimus a
Group B might become unnecessary due to newly developed drugs for treating HCV
[17]. They found that induction recipients had higher graft and patient survival rates compared with nonrecipients in all categories of organ transplant [17]. Indeed, induction therapy use has increased over time (Fig. 1, last panel) and was used in almost 30 % of LTx recipients in 2011 in the USA (Fig. 2) [14]. Induction agents can be classified as lymphocyte depleting or nondepleting. Induction with rATG, a lymphocytedepleting polyclonal antibody, has been reported to be safe in adult LTx recipients, showing excellent survival and low rejection rates without increases in IS-related side effects [18]. This retrospective study of 1,013 adult LTx recipients treated with rATG-based induction also found that rATG could be used in conjunction with rituximab without significant increases in cytomegalovirus (CMV) infection, posttransplant lymphoproliferative disorder (PTLD), fungal infections, or HCV recurrence [18]. Induction with basiliximab, a lymphocyte nondepleting chimeric anti-interleukin-2 receptor monoclonal antibody (IL2-RA), is
commonly used in Germany [19]. In the first large-scale investigation of basiliximab in LTx, basiliximab induction or placebo (both groups also including CyA and steroids) showed a similar incidence of infection and other adverse events, with reduced incidence of acute rejection episodes in the basiliximab group [20]. Another early study found that compared with earlier studies, basiliximab as add-on to CyA, steroids, and azathioprine provided increased efficacy in reducing the incidence of acute rejection episodes, with no clinically significant increase in adverse events [21]. Recently, it was reported that patients who received basiliximab in place of steroids after LTx for hepatocellular carcinoma (HCC) had similar overall and disease-free survival as those who received steroids [22]. A retrospective, nonrandomized study in patients with renal insufficiency found basiliximab induction resulted in similar 30-day and 1-year patient, graft, and renal outcomes as a control group that received standard (nondelayed) CNI-based IS [23]. Daclizumab, another IL2-RA, will not be discussed (except as part of steroid reduction strategies; see below) as it is no longer available outside the USA. Alemtuzumab is a humanized rat monoclonal antibody directed against CD52 on peripheral blood mononuclear cells. It has also been used in induction regimens for LTx [24]. However, its use is questionable because although a controlled study in 55 HCVnegative LTx recipients on alemtuzumab induction found less rejection episodes and no difference in major outcomes compared with standard care with CNIs and steroids, it did find more infections, particularly with CMV, in the alemtuzumab group [24].
CNI reduction strategies Fig. 2 Induction agents used at the time of liver transplantation, adult recipients, in the USA in 2011. Patients transplanted in 2011 and discharged with a functioning graft (Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) 2011 Annual Report for the liver, Table 7.2. http://srtr. transplant.hrsa.gov/annual_reports/2011/. Accessed 5 January 2014). IL2-RA anti-interleukin-2 receptor monoclonal antibody
CNIs have long remained a staple of IS regimens for LTx, but because of their nephrotoxicity and other adverse effects, various CNI reduction or delaying strategies have been tested [19]. Indeed, there is considerable evidence in favor of a lower optimal dose of TAC after LTx than is commonly used. For example, a systematic review and meta-analysis of 64 trials found
Langenbecks Arch Surg
that lower trough concentrations of TAC (6–10 ng/mL during the 4–6 weeks) after LTx did not adversely affect rates of ACR and resulted in less renal impairment compared with higher trough levels [25]. Despite these observations, recent studies using TAC have continued to target higher trough levels of 8–12 ng/mL during the 1st month [26] or until month 4 after LTx [27]. Because of the high levels of infection, new-onset diabetes, and severe cholestatic HCV recurrence in the former study, it was suggested that the patients possibly could have been overimmunosuppressed [28]. Similarly, the overimmunosuppression suggested by the latter study led commentators to propose that the standard-of-care treatment for randomized controlled trials should consist of reduced TAC levels [29]. Table 2 shows the CNI trough levels used at the authors’ institution. A Cochrane review of CNI minimization without substitution with another IS agent found only one ongoing randomized clinical trial and thus did not have enough information to recommend this strategy [30]. A recent single-center study examined a group of patients who received low-dose CNI (TAC baseline levels
REVIEW ARTICLE
Current strategies for immunosuppression following liver transplantation Daniel Nils Gotthardt & Helge Bruns & Karl Heinz Weiss & Peter Schemmer
Received: 26 March 2014 / Accepted: 30 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background New strategies for immunosuppression (IS) after liver transplantation (LTx) are in part responsible for the increased patient and graft survival seen over time. With a few basic exceptions—notably the continued use of steroids and calcineurin inhibitors (CNIs)—IS drugs and regimens being used today are different from those used 30 years ago. While graft loss due to acute or chronic rejection has become rare, the side effect burden of IS drugs exerts a significant toll on patients. Concepts/trends CNIs continue to form the backbone of IS regimens, although their use is hampered by nephrotoxicity and other adverse effects. Consequently, a variety of CNI reduction or withdrawal strategies have formed the basis of clinical trials or entered into clinical practice. These trials have included the use of everolimus, an mTOR inhibitor, and antiinterleukin-2 receptor antibodies. Basiliximab, as well as other lymphocyte nondepleting and depleting agents, have shown benefit in induction regimens. Summary Along with steroid reduction or elimination, current strategies for IS after LTx continue to explore novel combinations of agents, with an aim toward striking a balance between diminution of rejection and the need for avoiding adverse effects of the IS drugs. Long-term maintenance strategies are also discussed in this review, as is development of tolerance and antibody-mediated rejection.
D. N. Gotthardt (*) : K. H. Weiss Department of Internal Medicine IV, University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany e-mail: [email protected] H. Bruns : P. Schemmer Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
Keywords Calcineurin minimization . IL-2 . Induction . Operational tolerance . Steroid reduction . Tacrolimus trough levels
Introduction From the triple-drug regimen of azathioprine, prednisone, and antilymphoid globulin used in the early days of liver transplantation (LTx) over 45 years ago [1] to the wealth of drugs and regimens currently available, immunosuppression (IS) for LTx has continued to undergo changes and refinements. This has paralleled the increases in patient and graft survival. According to the European Liver Transplant Registry, 1-year patient survival in 2001 reached 83 % compared to 34 % before 1985 [2]. A landmark study in 4,000 patients who underwent LTx between 1981 and 1998 and were followed until 2000 showed overall patient survival to be 59 % and actuarial 18-year survival to be 48 % [3]. Patient survival was found to be significantly better in children, female recipients, and patients who received transplants after 1990, with a notable improvement in the quality of IS and a significant reduction in acute and chronic rejection-associated losses [3]. Notably, the actuarial patient survival rate at 1 year was 71 % in the era when cyclosporine (CyA) was introduced, which was significantly less than that for the era when tacrolimus (TAC) was introduced (86 %) [3]. Similarly, a 20-year follow-up of 313 LTx patients published in 2013 showed patient and graft survival at 1, 10, and 20 years to be 88.4, 72.7, 52.5, and 83.7, 64.7, and 46.6 %, respectively [4]. Whereas improvements in surgical and medical techniques, patient selection criteria, and donor liver procurement, allocation, and preservation also contributed to these trends [5], the advances made in IS continue to be a driving force in LTx improvements. Because most of the long-term complications of LTx are due to IS drug side effects rather than chronic rejection,
Langenbecks Arch Surg
Fig. 1 Immunosuppression use in adult liver transplant recipients over time in the USA, 1998–2010. One-year posttransplantation data for mTOR inhibitors and steroids limited to patients alive with graft function 1 year posttransplantation. One-year posttransplantation data are not reported for transplant recipients in 1998, as follow-up data were very sparse (Organ Procurement and Transplantation Network/Scientific
Registry of Transplant Recipients (OPTN/SRTR) 2011 Annual Report for the liver, Table 7.4. http://srtr.transplant.hrsa.gov/annual_reports/ 2011/. Accessed 5 January 2014). IL2-RA anti-interleukin-2 receptor monoclonal antibody, mTOR mammalian target of rapamycin, Tx transplantation
treatment strategies center on maintaining a delicate balance between avoiding IS drug toxicity and reducing the risk of acute rejection [6–8]. The focus in LTx today is on minimization of IS [9, 10]. Although successful complete withdrawal of IS has been reported and attempted, clinical operational tolerance involving the lack of need for IS is unreachable in the majority of situations [6, 7]. After introduction of the model for end-stage liver disease (MELD) score-based allocation system in the USA and Eurotransplant area, the average MELD scores at transplantation continued to rise, reaching a mean score of 34 in Germany [11]. This led to higher rates of renal insufficiency at transplantation because impaired renal function contributes to a higher MELD score [12]. This also led to the observation that patients are now “sicker” at the time of transplantation than they were a decade ago. The goal of this review is to discuss current strategies for IS after LTx, focusing on recent evidence for various protocols in the short term (induction) and long term (maintenance). Given that the toolbox of available IS drugs has substantially enlarged during the last two decades, with the number of combinations growing even larger, selecting the optimal protocol for any given patient can be a difficult task for clinicians. The expanded options allow for and indeed make it incumbent upon clinicians to individualize therapy according to patient-specific factors such as comorbidities, age, and rejection history and drug-specific factors such as side effect profile and mechanism of action [13]. Accordingly, this review discusses recent trials of steroid-sparing and calcineurin inhibitor (CNI) reduction (in both the short and long term). Tolerance development and antibody-mediated rejection (AMR) are also briefly discussed.
recipients in the USA received initial IS with TAC and mycophenolate mofetil (MMF) plus steroids; 12.9 % of recipients received this regimen without steroids [14]. At 1 year postLTx, a higher proportion of recipients received steroid-free regimens compared to those used initially, with about a quarter of recipients on TAC monotherapy [14]. Trends over roughly the past decade are shown in Fig. 1 and indicate a rising use of TAC and MMF. Although TAC is frequently used in the USA, CyA continues to be used to a significant degree as the CNI in Europe, as evidenced by the authors’ experience as well as by a large single-center European study on 20-year survival after LTx, which showed CyA to be used in 75 % of cases 6 months after primary LTx [4]. Although not possible to discern from the SRTR data, recent studies and reports have expressed concern that current LTx recipients are being overimmunosuppressed [15, 10]. Much of the rationale behind IS minimization strategies is to avert the infectious and metabolic complications of steroids and the renal toxicity, hepatitis C virus (HCV) reinfection, and tumor-promotion effects of CNIs [13]. Table 1 shows as an example of the treatment stratification approach used at the authors’ institution.
De novo immunosuppression after liver transplantation Recent data reported by the Scientific Registry of Transplant Recipients (SRTRs) indicate that in 2011, 59.3 % of LTx
Induction therapy Induction therapy has been defined as a prophylactic, perioperative course of intensive IS given to prevent acute rejection in the 1st months after LTx when the risk of rejection is highest [16]. Typically, it has been used to delay CNI use or avoid steroid use and/or reduce the rate of acute cellular rejection (ACR) [16]. Using data from the United Network for Organ Sharing registry, Cai et al. identified three eras of induction therapy, the latest era being a high-induction, modern antibody era (2003 to present) with rabbit antithymocyte globulin (rATG), basiliximab, daclizumab, or alemtuzumab
Langenbecks Arch Surg Table 1 Example of a treatment strategy for immunosuppression after liver transplantation (authors’ institution) Group A
Group Ba
Group C
High risk of infection, acceptable risk of High risk of infection, unacceptable risk of Low risk of infection, neither group A nor group B rejection: MELD score at LTx >25 and/or rejection: as group A, but HCV positive hospitalized >3 weeks, retransplantation, HCV negative Induction with basiliximab or ATG. MMF Induction with basiliximab or ATG. MMF MMF 1,000 mg BID from day 1 CyA from day 1. 1,000 mg BID from day 1. CNI from day 7. 1,000 mg BID from day 1. TAC from day 7 HCV positive, PSC, or AIH→TAC (upper trough ST only for 5 days. (upper trough levels). ST only for 5 days. levels). ST according to schedule shown in Table 3 MMF can be exchanged to Everolimus taking into account the special situation of the patient AIH autoimmune hepatitis, ATG antithymocyte globulin, BID twice daily, CNI calcineurin inhibitor, CyA cyclosporine, HCV hepatitis C virus, LTx liver transplantation, MELD model for end-stage liver disease, MMF mycophenolate mofetil, PSC primary sclerosing cholangitis, ST steroids, TAC tacrolimus a
Group B might become unnecessary due to newly developed drugs for treating HCV
[17]. They found that induction recipients had higher graft and patient survival rates compared with nonrecipients in all categories of organ transplant [17]. Indeed, induction therapy use has increased over time (Fig. 1, last panel) and was used in almost 30 % of LTx recipients in 2011 in the USA (Fig. 2) [14]. Induction agents can be classified as lymphocyte depleting or nondepleting. Induction with rATG, a lymphocytedepleting polyclonal antibody, has been reported to be safe in adult LTx recipients, showing excellent survival and low rejection rates without increases in IS-related side effects [18]. This retrospective study of 1,013 adult LTx recipients treated with rATG-based induction also found that rATG could be used in conjunction with rituximab without significant increases in cytomegalovirus (CMV) infection, posttransplant lymphoproliferative disorder (PTLD), fungal infections, or HCV recurrence [18]. Induction with basiliximab, a lymphocyte nondepleting chimeric anti-interleukin-2 receptor monoclonal antibody (IL2-RA), is
commonly used in Germany [19]. In the first large-scale investigation of basiliximab in LTx, basiliximab induction or placebo (both groups also including CyA and steroids) showed a similar incidence of infection and other adverse events, with reduced incidence of acute rejection episodes in the basiliximab group [20]. Another early study found that compared with earlier studies, basiliximab as add-on to CyA, steroids, and azathioprine provided increased efficacy in reducing the incidence of acute rejection episodes, with no clinically significant increase in adverse events [21]. Recently, it was reported that patients who received basiliximab in place of steroids after LTx for hepatocellular carcinoma (HCC) had similar overall and disease-free survival as those who received steroids [22]. A retrospective, nonrandomized study in patients with renal insufficiency found basiliximab induction resulted in similar 30-day and 1-year patient, graft, and renal outcomes as a control group that received standard (nondelayed) CNI-based IS [23]. Daclizumab, another IL2-RA, will not be discussed (except as part of steroid reduction strategies; see below) as it is no longer available outside the USA. Alemtuzumab is a humanized rat monoclonal antibody directed against CD52 on peripheral blood mononuclear cells. It has also been used in induction regimens for LTx [24]. However, its use is questionable because although a controlled study in 55 HCVnegative LTx recipients on alemtuzumab induction found less rejection episodes and no difference in major outcomes compared with standard care with CNIs and steroids, it did find more infections, particularly with CMV, in the alemtuzumab group [24].
CNI reduction strategies Fig. 2 Induction agents used at the time of liver transplantation, adult recipients, in the USA in 2011. Patients transplanted in 2011 and discharged with a functioning graft (Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) 2011 Annual Report for the liver, Table 7.2. http://srtr. transplant.hrsa.gov/annual_reports/2011/. Accessed 5 January 2014). IL2-RA anti-interleukin-2 receptor monoclonal antibody
CNIs have long remained a staple of IS regimens for LTx, but because of their nephrotoxicity and other adverse effects, various CNI reduction or delaying strategies have been tested [19]. Indeed, there is considerable evidence in favor of a lower optimal dose of TAC after LTx than is commonly used. For example, a systematic review and meta-analysis of 64 trials found
Langenbecks Arch Surg
that lower trough concentrations of TAC (6–10 ng/mL during the 4–6 weeks) after LTx did not adversely affect rates of ACR and resulted in less renal impairment compared with higher trough levels [25]. Despite these observations, recent studies using TAC have continued to target higher trough levels of 8–12 ng/mL during the 1st month [26] or until month 4 after LTx [27]. Because of the high levels of infection, new-onset diabetes, and severe cholestatic HCV recurrence in the former study, it was suggested that the patients possibly could have been overimmunosuppressed [28]. Similarly, the overimmunosuppression suggested by the latter study led commentators to propose that the standard-of-care treatment for randomized controlled trials should consist of reduced TAC levels [29]. Table 2 shows the CNI trough levels used at the authors’ institution. A Cochrane review of CNI minimization without substitution with another IS agent found only one ongoing randomized clinical trial and thus did not have enough information to recommend this strategy [30]. A recent single-center study examined a group of patients who received low-dose CNI (TAC baseline levels
