Rescue Therapy in Adults

The efficacy of tacrolimus in kidney transplantation was first shown in recipients with refractory rejection. Refractory rejection episodes in cyclosporine-treated patients were reversed by replacing cyclosporine with tacrolimus as the maintenance immunosuppressive agent. In contrast to antilymphocyte antibody preparations (e.g., OKT3 and polyclonal antibody preparations) that induce long-term suppression of T cell responses, the immunosuppressive effects of tacrolimus could be titrated on a daily basis by following drug levels.

An early large experience with tacrolimus in treating refractory acute renal allograft rejection in 77 patients receiving cyclosporine-based immunosuppressive therapy was reported from Pittsburgh. Several conclusions were drawn from this study, as follows: (1) tacrolimus provided effective therapy for acute renal allograft rejection; (2) tacrolimus often provided effective therapy for vascular rejection in kidney transplants; and (3) the success of tacrolimus therapy for refractory acute renal allograft rejection was related to the severity and duration of rejection.

The 5-year follow-up of the Pittsburgh experience showed good long-term renal allograft function in patients undergoing tacrolimus rescue therapy. A total of 169 patients were converted from cyclosporine to tacrolimus for refractory rejection, with a 74% success rate and a mean serum creatinine value of 2.3 ± 1.1 mg/dL (202 μmol/L). A prospective randomized multicenter comparative trial confirmed the efficacy of tacrolimus-based rescue therapy in patients with acute renal transplant rejection. Rescue therapy with tacrolimus-based regimens reduced the incidence of recurrent acute rejection to 8.8% versus 34.1% ( P = 0.002) in patients who remained on cyclosporine-based immunosuppression.

In a large European study on tacrolimus conversion for cyclosporine-induced toxicities, 73% of patients with cyclosporine-induced gingival hyperplasia ( n = 32) showed significant resolution of hyperplasia, and recipients with cyclosporine-induced hypertrichosis ( n = 116) showed marked improvement. The mean serum low-density lipoprotein (LDL) level decreased from 138 to 120 mg/dL, and the high-density lipoprotein levels remained unchanged in patients with cyclosporine-induced hyperlipidemia ( n = 78). Finally, hypertension markedly or completely resolved in 25% of patients ( n = 75). A randomized study in which patients were either converted to tacrolimus ( n = 27) or remained on cyclosporine-based immunosuppression ( n = 30) demonstrated a significant reduction in cholesterol from 255 to 206 mg/dL in the patients randomized to tacrolimus.

Antibody-Mediated Rejection

Antibody-mediated rejection often occurs within the first 2 weeks after transplantation and is associated with oliguria, graft tenderness, fever, leukocytosis, and circulating donor-specific antibodies. Before the introduction of tacrolimus, combinations of bolus corticosteroids, plasmapheresis, and antilymphocyte antibody preparations were used to treat acute humoral rejection, with inconsistent and unsatisfactory response rates. Tacrolimus-based regimens were developed for acute humoral rejection in renal transplant recipients, based on clinical experiences with tacrolimus in treating liver and heart transplants with acute humoral rejection. Experimental evidence also supported the potential of tacrolimus in limiting antibody responses.

The studies of tacrolimus in acute humoral rejection preceded the development of plasmapheresis and intravenous immunoglobulin regimens in the management of humoral rejection and highly sensitized patients (see Chapter 20 ), and more recent work with bortezomib and eculizumab. Thus conversion to tacrolimus for antibody-mediated rejection is not currently a primary treatment modality, although it may accompany antibody-specific therapy.

Maintenance Immunosuppression

The outcomes of kidney transplantation have improved with the advent of CNIs as part of highly effective immunosuppressive regimens. Several studies have addressed short-term outcomes of immunosuppression, including rates of acute rejection and patient and graft survival. Studies also have addressed medium- and long-term outcomes with CNI-based immunosuppression, including 10-year patient and graft survival, renal function, cardiovascular events, and posttransplant diabetes mellitus (PTDM).

Comparison of Tacrolimus-Based and Cyclosporine-Based Regimens

The phase III US multicenter clinical trial compared the efficacy and safety of tacrolimus with that of the original formulation of cyclosporine. At 1 year posttransplantation, 30.7% of tacrolimus-treated patients had experienced acute rejection compared with 46.4% of cyclosporine-treated patients ( P = 0.001). The incidence of moderate to severe rejection was 10.8% in the tacrolimus-treated group compared with 26.5% in the cyclosporine-treated group. The intent-to-treat analysis showed no significant differences in 5-year patient or graft survival between the tacrolimus-treated and the cyclosporine-treated patients. When crossover because of rejection was counted as graft failure, a statistically significant increase in graft survival was found in the tacrolimus group at 5 years (63.8% vs. 53.8%; P = 0.014). The patients treated with tacrolimus had a lower incidence of hirsutism and gingival hyperplasia, but a higher incidence of alopecia, than patients treated with cyclosporine.

Racial differences were also evaluated for acute rejection in the US phase III multicenter clinical trial. Among African Americans, 23.2% of patients in the tacrolimus-treated group developed acute rejection compared with 47.9% of patients in the cyclosporine-treated group ( P = 0.012). When crossover because of rejection was counted as graft failure, there was a significant increase in the 5-year graft survival in African American patients in the tacrolimus-treated group (65.4% vs. 42.6%; P = 0.013) compared with the cyclosporine-treated group.

The US multicenter study that compared the efficacy and tolerability of tacrolimus versus cyclosporine also revealed that significantly fewer kidney transplant recipients required antihypertensive treatment in the tacrolimus-treated group compared with the cyclosporine-treated group. The projected graft half-life evaluated by the European Multicenter Renal Transplant Study also favored tacrolimus over cyclosporine (15.8 vs. 10.8 years).

A multicenter trial evaluated the effect of tacrolimus as secondary intervention in patients being treated with cyclosporine for 3 or more months after transplantation who had one of the following risk factors for chronic renal allograft failure: serum creatinine 2 mg/dL or greater for men and 1.7 mg/dL or greater for women, or a greater than 30% increase in the nadir posttransplant serum creatinine level. The trial randomly assigned 197 patients to convert to tacrolimus or remain on cyclosporine. At 24 months, 56.8% of the patients in the tacrolimus-treated group and 87.5% in the cyclosporine-treated group had a serum creatinine level 2 mg/dL or greater ( P = 0.002). Significantly fewer patients who were converted from cyclosporine to tacrolimus experienced a cardiovascular event compared with patients who continued treatment with cyclosporine (5.6% vs. 24.3%; P = 0.002). Median serum cholesterol and LDL cholesterol levels were significantly lower in the tacrolimus-treated group compared with the cyclosporine-treated group. Therapeutic intervention with tacrolimus resulted in improved renal function, better lipid profiles, and fewer cardiovascular events in patients who were at risk for developing chronic renal allograft failure.

Comparison of Calcineurin Inhibitor/Azathioprine and Tacrolimus/Mycophenolate Mofetil Regimens

A randomized prospective three-arm study compared the effect of immunosuppressive protocols using tacrolimus/azathioprine ( n = 76), tacrolimus/mycophenolate mofetil (MMF) ( n = 72), and cyclosporine microemulsion/MMF ( n = 75). At 1 year, although there were no significant differences in overall rejection rates, there were significant differences in the total number of patients who required antilymphocyte antibody treatment (4.2% in the tacrolimus/MMF arm compared with 10.7% in the cyclosporine/MMF arm and 11.8% in the tacrolimus/azathioprine arm; P = 0.05). There were no significant differences among the three groups in patient or graft survival at 1, 2, and 3 years. A 2012 single-institution, prospective, open-labeled, randomized controlled trial comparing cyclosporine/azathioprine ( n = 146) versus tacrolimus/MMF ( n = 143) in 289 kidney transplant recipients treated with antithymocyte globulin (ATG) and prednisone showed equal patient and graft survivals at 1 year; however, the tacrolimus/MMF group had better estimated glomerular filtration rates (GFR; cyclosporine/azathioprine 48 ± 1 vs. tacrolimus/MMF 53 ± 1 mL/min/1.73 m ² , P = 0.007), and a trend toward lower rates of biopsy-proven acute rejection (BPAR), cyclosporine/azathioprine (14.4%) versus 11 (7.7%) with tacrolimus/MMF ( P = 0.07).

Comparison of Tacrolimus/Mycophenolate Mofetil and Calcineurin Inhibitor/Sirolimus Regimens

A randomized study comparing the combination of sirolimus or MMF with tacrolimus-based immunosuppression showed no significant differences in the incidence of biopsy-confirmed acute rejection (BCAR; 13% tacrolimus/sirolimus ( n = 185) versus 11.4% tacrolimus/MMF ( n = 176; P = 0.64). Graft survival and patient survival were not significantly different between the groups at 6 months after transplantation. The combination of tacrolimus and MMF was superior to tacrolimus and sirolimus in terms of improved renal function and a lower risk of hypertension and hyperlipidemia. The incidence of acute rejection was significantly higher in the tacrolimus/sirolimus arm (30% vs. 2% for cyclosporine/sirolimus and 12% for tacrolimus/MMF) at 36 months in a randomized trial comparing these three regimens in renal transplantation. There was not, however, a significant difference in actuarial graft survival at 8 years posttransplant among the groups.

These optimistic findings were countered by an analysis of 44,915 adult renal transplants in the Scientific Renal Transplant Registry from 2000 to 2004. A total of 3524 (7.8%) patients received a baseline immunosuppressive regimen of tacrolimus/sirolimus, with an inferior overall survival ( P < 0.001) and death-censored graft survival ( P < 0.001) compared with tacrolimus/MMF ( n = 27,007). Six-month acute rejection rates were low and did not differ among groups. These data have to be interpreted in the context of the limitations of any retrospective database analysis.

A steroid-free randomized trial comparing sirolimus/tacrolimus, sirolimus/mycophenolate, and tacrolimus/mycophenolate showed higher than expected BCAR in the sirolimus/mycophenolate arm. The BCAR and graft survival at 2 years for the sirolimus/tacrolimus group was 17.4% and 88.5% respectively, and for the tacrolimus/mycophenolate group 12.3% and 95.4%. Among the side effects, the sirolimus group had a higher incidence of delayed wound healing and hyperlipidemia.

Comparison of Tacrolimus-Based Dual Versus Triple Immunosuppression Therapy

Dual immunosuppression therapy refers to the use of tacrolimus with a second agent, such as a corticosteroid. Triple immunosuppression therapy refers to the use of tacrolimus and a corticosteroid with a third agent, such as azathioprine or MMF.

Dual therapy with tacrolimus-based immunosuppression provided similar efficacy to tacrolimus-based triple therapy for 36 months. At 12 months, patient survival rates in the dual-therapy groups were ≥96% compared with ≥94% with triple therapy, with graft survival rates of ≥90% (dual-therapy groups) and ≥91% (triple-therapy groups). Three-year follow-up data are available from the Italian and Spanish trials, and graft survival was 87% in dual-therapy and triple-therapy groups. A similar percentage of patients experienced an acute rejection episode with dual-therapy or triple-therapy tacrolimus-based immunosuppressive regimens. Most of these episodes occurred in the first year after transplantation, with a 10- to 15-fold reduction in the incidence of rejection over the next 2 years. In one study, the addition of MMF to tacrolimus plus corticosteroid therapy significantly ( P = 0.007) reduced the incidence of rejection at 9 months.

In another prospective randomized trial the combination of tacrolimus and prednisone was compared with tacrolimus, MMF, and prednisone in renal transplant recipients without induction therapy. The combination of tacrolimus, steroids, and MMF was associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids. Currently, most centers utilize a triple immunosuppression regimen, consistent with the 2009 Kidney Disease: Improving Global Outcomes guidelines.

Induction Therapies with Calcineurin Inhibitor Regimens

Margreiter et al. studied the efficacy of alemtuzumab induction followed by tacrolimus monotherapy ( n = 65) compared with a control group of tacrolimus, MMF, and steroids ( n = 66). At 12 months the biopsy-proven rejection rate was 20% in the study group and 32% in the control group ( P = 0.09). Patient survival at 1 year was 98% for both groups. Graft survival was 96% for the study group versus 90% for the control group ( P = 0.18). A similar study compared alemtuzumab induction with tacrolimus monotherapy against daclizumab, tacrolimus, and mycophenolate therapy. The alemtuzumab and tacrolimus arm showed a survival with a functioning graft at 1 year of 97.6% versus 95.1% in the daclizumab arm and at 2 years of 92.6% versus 95.1% in the daclizumab group. These results suggest that alemtuzumab induction together with tacrolimus monotherapy is at least as efficient as the daclizumab, tacrolimus, and mycophenolate or a tacrolimus, mycophenolate, and steroids regimen. The use of alemtuzumab induction with tacrolimus monotherapy was evaluated in 200 living donor kidney transplant recipients. The actuarial 3-year patient and graft survival in this study was 96.4% and 86.3%, respectively. The cumulative incidence of acute cellular rejection (ACR) at 3 years was 24%, about 88.7% of the ACR episodes were Banff 1, and of those, 82% were steroid-sensitive. The mean serum creatinine (mg/dL) and GFR (mL/min/1.73 m ² ) at 3 years were 1.5 ± 0.7 and 54.9 ± 20.9, respectively. The alemtuzumab/tacrolimus treatment was also evaluated in high immunologic risk patients, as defined by a prior failed renal transplant, prior history of sensitization, or panel-reactive antibodies >20%. Patients were randomized to receive single-dose alemtuzumab before graft reperfusion, with tacrolimus monotherapy, or four doses of thymoglobulin with tacrolimus, mycophenolate, and steroids. One-year cumulative graft survival was 85.7% for the alemtuzumab group and 87.5% for the thymoglobulin group. A similar study was done comparing the efficacy of alemtuzumab versus conventional induction therapy (basiliximab or rabbit [rATG]). In this trial patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or African American ethnicity. There were 139 high-risk patients, of whom 70 received alemtuzumab and 69 received rATG. The 335 low-risk patients were randomized to alemtuzumab (164 patients) or basiliximab (171 patients). All patients received tacrolimus and MMF and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. By the first year after transplantation, BCAR was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early BCAR was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rATG had similar efficacy.

In another study, alemtuzumab ( n = 113) or rATG ( n = 109) induction was compared in 180 (81%) kidney transplants alone, 38 (17%) simultaneous pancreas–kidney (SPK), and 4 (2%) pancreas after kidney (PAK) transplants. Survival, initial length of stay, and maintenance immunosuppression (including early steroid elimination) were similar between alemtuzumab and rATG groups, but BPAR episodes occurred in 16 (14%) alemtuzumab patients compared with 28 (26%) rATG patients ( P = 0.02). Late BPAR (>12 months after transplant) occurred in one (8%) alemtuzumab patient and three (11%) rATG patients ( P = not significant [NS]). Infections and malignancy were similar between the two induction arms. The results of this study showed that alemtuzumab and rATG induction therapies were equally safe, but alemtuzumab was associated with less BPAR.

Role of Calcineurin Inhibitors and Corticosteroids in the Development of Hypertension and Hyperglycemia

Although both CNIs and steroids have been associated with posttransplant hypertension and hyperglycemia, steroid dosing may have a major part in the development of these complications after transplantation (see Chapter 16 ). In one study, patients were evaluated 4 months after kidney transplantation; twice as many patients treated with tacrolimus and high-dose prednisone developed hypertension compared with patients treated with tacrolimus and low-dose prednisone (63% vs. 32%, P < 0.05).

Corticosteroids may promote the development of PTDM by inducing insulin resistance, decreasing insulin receptor number and affinity, impairing endogenous glucose production, and impairing glucose uptake by muscle.

A study was done to assess the relative role of tacrolimus and corticosteroids in the development of glucose metabolic disorders. Corticosteroid withdrawal in patients receiving tacrolimus-based immunosuppression led to a 22% decrease in fasting C-peptide levels ( P = 0.0009). Fasting insulin levels and the insulin-to-glucose ratio also decreased but not significantly ( P = NS). Steroid withdrawal also led to a reduction in lipid levels. Tacrolimus trough level reduction from 9.5 to 6.4 ng/mL resulted in a 36% increase in pancreatic beta-cell secretion ( P = 0.04), and insulin secretion increased by a similar rate. Hemoglobin A _1c improved from 5.9% to 5.3% ( P = 0.002), although lipid levels did not change after trough level reduction. Corticosteroid withdrawal resulted in a decrease in insulin resistance and a reduction in lipid levels; reduction of tacrolimus trough levels also improved glucose metabolism.

A randomized multicenter double-blinded trial was performed to determine whether steroid avoidance reduced the risk of new onset diabetes posttransplant in the setting of CNI therapy. Patients were randomized 1:1 to either steroid withdrawal ( n = 142) or continuation ( n = 135) on posttransplant day 8 in addition to an immunosuppressive regimen of tacrolimus and MMF. Low-dose prednisone (5 mg/d) was utilized in the steroid continuation arm starting 6 months posttransplant. At 5 years posttransplant, 36.3% of steroid continuation patients and 35.9% of steroid withdrawal patients had developed diabetes ( P = 0.98). The percentage of patients requiring insulin therapy was lower in the steroid withdrawal group compared with the steroid continuation group (3.7% vs. 11.6%, P = 0.049). However, through 5 years posttransplant the proportion of new onset diabetes patients requiring treatment was similar between the withdrawal and continuation group. This study suggests that steroid withdrawal has limited effect in preventing new onset diabetes posttransplant.

Early Corticosteroid Withdrawal Regimens

The safety of early corticosteroid withdrawal (see Chapter 14 ) was evaluated by a prospective randomized multicenter double-blind study of early (7 days posttransplantation) corticosteroid cessation versus long-term maintenance with corticosteroids along with tacrolimus, MMF, and antibody induction in primary renal transplant patients. Patient and graft survivals at 1 year were 98% and 96%, respectively. BPAR occurred in 9.8% of patients, and 4% were treated empirically for rejection. One-year analysis suggested that early withdrawal of corticosteroids was safe, resulting in excellent patient and graft survival, low acute rejection rates, and no graft loss to rejection Five-year results confirmed that early corticosteroid withdrawal provides a similar long-term renal allograft survival and function; however, early corticosteroid withdrawal is associated with a higher incidence of mild, Banff 1A, steroid-sensitive episodes of rejection. Steroid withdrawal provided improvements in cardiovascular risk factors (triglyceride, diabetes, weight gain). A randomized trial comparing cyclosporine versus tacrolimus as long-term immunosuppression regimens after early steroid withdrawal 5 days after renal transplantation showed that tacrolimus was more effective in enabling patients to remain on a steroid-free regimen at 3 years (88% vs. 65%; P < 0.001).

In another study, 101 patients underwent renal transplantation with tacrolimus, MMF, and 7 days of corticosteroids. Anti-CD25 monoclonal antibody was administered to 25 patients at higher immunologic risk. After a median follow-up of 51 months (range 36–62 months), patient survival was 97%, and graft survival was 91%. The incidence of acute rejection at 12 months was 19%. Only three further episodes of rejection occurred beyond 12 months. Graft function was stable during the study, with a mean estimated creatinine clearance of 57 mL/min at the end of follow-up. This steroid avoidance regimen was associated with excellent medium-term patient and graft outcomes and a low incidence of side effects. Most 10-year outcomes were described in a protocol incorporating discontinuation of steroids at postoperative day 7. The 10-year graft survival was 61% for living donor transplant and 51% for deceased donor transplants, comparable to 10-year Scientific Registry of Transplant Recipients national data. The University of Minnesota’s prospective, randomized trial evaluated outcomes of three different maintenance immunosuppression protocols after early steroid withdrawal (6 days posttransplantation) in 440 kidney transplant recipients. Patients were randomized to cyclosporine/MMF ( n = 151), high-dose tacrolimus/low-dose sirolimus ( n = 149), or low-dose tacrolimus/high-dose sirolimus ( n = 140). All patients received thymoglobulin induction. The 10-year graft and patient survival did not differ between the three treatment arms. There were no differences in 10-year rates of BPAR. The rate of new-onset diabetes was highest in the high-dose tacrolimus group at 10 years (19%). The efficacy of early steroid withdrawal compared with chronic steroid maintenance has also been shown to be a reasonable approach in repeat kidney transplant recipients, with results showing similar graft and patient survivals at 1 and 5 years.

The effect on tacrolimus exposure in the setting of early steroid withdrawal was evaluated in a prospective, randomized, multicenter study that included 397 patients. Patients were assigned on posttransplant day 8 to receive either steroid withdrawal ( n = 191) or continuation ( n = 195). Significantly higher tacrolimus trough levels were observed in the steroid withdrawal group compared with the steroid continuation group at 2 weeks posttransplant, although this interaction was not seen in the African American subgroup.

Another randomized multicenter study assessed which induction agent was most effective in allowing rapid steroid withdrawal (day 8 posttransplant). In total, 615 low-immunologic-risk patients were randomly assigned (1:1:1) to basiliximab/steroids ( n = 215), basiliximab/steroid withdrawal ( n = 197), or thymoglobulin/steroid withdrawal ( n = 203), in addition to a maintenance immunosuppression protocol of tacrolimus and MMF. At 1 year, BPAR rates were similar at 9.9% for the thymoglobulin arm, 11.2% for the basiliximab/steroids arm, and 10.6% for the basiliximab/steroid withdrawal arm. Patient and graft survival were comparable and excellent in all treatment groups at 12 months.

Corticosteroid-Free Immunosuppression Regimens

A 6-month open-label multicenter parallel-group study included 538 renal patients randomly assigned (1:1) to a daclizumab/tacrolimus/MMF regimen ( n = 260) or a tacrolimus/MMF/corticosteroid regimen ( n = 278). The incidence of BPAR was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5% in the tacrolimus/MMF/corticosteroids and daclizumab/tacrolimus/ MMF groups ( P = NS). The median serum creatinine level at 6 months and overall safety profile were similar with both regimens.

A single-center, nonrandomized, retrospective sequential study was used to evaluate outcomes in kidney transplant recipients given either alemtuzumab (Campath) ( n = 123) or basiliximab ( n = 155) in combination with a prednisone-free maintenance protocol using tacrolimus and MMF. There was no significant difference in the 3-year graft and patient survival rates between the two groups. A lower rate of early (<3 months) rejection was observed in the alemtuzumab (4.1%) versus the basiliximab (11.6%) group, but rejection rates for both groups were equivalent at 1 year. Patient and graft survival and rejection rates were nearly identical between whites and African Americans receiving alemtuzumab. The quality of renal function and the incidence of infectious complications were similar between the alemtuzumab and basiliximab groups.

Two corticosteroid-free, tacrolimus-based regimens were compared with standard triple therapy in a 6-month phase III open-label parallel-group multicenter study. A total of 451 patients were randomly assigned (1:1:1) to receive tacrolimus/MMF/corticosteroids, tacrolimus/ MMF without induction, or tacrolimus monotherapy with basiliximab induction. The incidences of BPAR were 8.2% (triple therapy), 30.5% (tacrolimus/MMF), and 26.1% (basiliximab/tacrolimus) ( P = 0.001). The incidences of corticosteroid-resistant acute rejection were similar among the groups ( P = NS). Graft and patient survival rates were similar among the groups. Overall safety profiles were similar. Differences were noted for anemia (24.5% vs. 12.6% vs. 14.5%), diarrhea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple-therapy, tacrolimus/MMF, and basiliximab/tacrolimus groups, respectively. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the basiliximab/tacrolimus regimen offering some safety benefits. A prospective randomized trial was done comparing tacrolimus/sirolimus with tacrolimus/mycophenolate in renal transplant recipients using a prednisone-free regimen with more than 8.5 years of follow-up. All patients received anti-IL-2 receptor antagonist (basiliximab). The tacrolimus/MMF group had overall better renal allograft survival (91% vs. 70%, P = 0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/MMF group experienced biopsy-proven ACR ( P = 0.07). By 3 months posttransplant, estimated GFR was significantly lower in the tacrolimus/sirolimus group compared with the tacrolimus/MMF group (47.7 vs. 59.6 mL/min/1.73 m ² ; P = 0.0002), and this trend persisted throughout the follow-up period.

Comparison of Corticosteroid-Sparing Regimens Using Tacrolimus-Based and Cyclosporine-Based Immunosuppression

Studies of corticosteroid-sparing protocols in patients treated with cyclosporine and MMF showed acute rejection rates to be unacceptably high among African American recipients A study examining corticosteroid withdrawal in 52 stable renal transplant recipients treated with tacrolimus and MMF showed a 98% patient survival and 92.3% graft survival. The tacrolimus-based regimen was thought to promote compliance by facilitating steroid withdrawal and reducing cosmetic complications (see Chapter 16 ). A prospective randomized study comparing 5-year outcomes in kidney recipients maintained on four different CNIs based immunosuppression protocols (cyclosporine/MMF, cyclosporine/sirolimus, tacrolimus/MMF, tacrolimus/sirolimus) with basiliximab induction without long-term steroid therapy showed acceptable patient and graft survival at 5 years in all four groups.

Calcineurin Inhibitor Avoidance and Low-Dose Tacrolimus Regimens

Transitioning to an inhibitor of mammalian target of rapamycin (mTOR)-based immunosuppressive regimen is a strategy to avoid nephrotoxicity caused by CNIs. The ELEVATE trial, a multicenter study, compared de novo adult kidney recipients randomized at 10 to 14 weeks to convert to everolimus ( n = 359) or to remain on CNI therapy ( n = 356; 231 tacrolimus; 125 cyclosporine) in addition to MMF and steroids. At 12 months, the primary endpoint of GFR was similar between the two groups and biopsy-proven rejection was more frequent in everolimus-treated patients compared with tacrolimus-treated patients (9.7% vs. 2.6%, P < 0.001). In a similar study, the ZEUS trial, 300 renal transplant recipients were randomized to continue receiving cyclosporine or to convert to everolimus at 4.5 months posttransplant. At 5 years, mean eGFR was 66.2 mL/min/1.73 m ² with everolimus and 60.9 mL/min/1.73 m ² with cyclosporine ( P < 0.001), whereas rates of biopsy-proven rejection were higher with everolimus (13.6% vs. 7.5%, P = 0.095). A meta-analysis of 29 randomized controlled trials investigating conversion of CNI to mTOR inhibitor determined that patients converted to mTOR therapy had a higher GFR and rate of acute rejection at 1 year.

A prospective, randomized trial in renal transplantation compared sirolimus/MMF/prednisone ( n = 81) with tacrolimus/MMF/prednisone ( n = 84). The mean follow-up was 33 months. There was no difference in patient survival, graft survival, or the incidence of clinical acute rejection between the two groups. There was also no difference in the mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 or 2 years. At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular, or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study suggests that many of the promises of CNI-free immunosuppression have perhaps not been achieved with short-term follow-up. The question of improved safety and efficacy in the longer term with CNI-free immunosuppression has to be subjected to longer-term follow-up of the aforementioned study and similar studies. Many previous studies of complete CNI avoidance have used cyclosporine as the comparator drug. The 15-year follow-up data of a multicenter randomized trial of CNI avoidance used cyclosporine in the CNI arm. Renal transplant recipients initially treated with MMF/cyclosporine/steroids were randomized at 6 months posttransplant to MMF/steroids ( n = 63), MMF/cyclosporine ( n = 76), or MMF/cyclosporine/steroids ( n = 73). Fifteen years after conversion to a CNI-free regimen, there was no difference in patient or graft survival between the groups. Patients treated with CNI withdrawal experienced higher rates of acute rejection, and early rejection after CNI withdrawal was associated with decreased graft survival. There was no long-term benefit of CNI withdrawal on the development of comorbidities such as diabetes mellitus, malignancy, or cardiovascular disease.

A meta-analysis of 27 randomized controlled trials with 4105 renal transplant recipients examined both CNI avoidance and withdrawal trials. The analysis concluded CNI avoidance/ withdrawal protocols have better graft function at 1- and 2-year follow-up, however CNI avoidance protocols have rate rates of acute rejection at 1 year, although the rates are similar to CNI groups at 2 years. Overall 1- and 2-year patient and graft survival were similar. A meta-analysis of 19 randomized controlled trials with analysis of 3312 renal transplant recipients with median follow-up of 12 months showed that CNI-sparing strategies with adjunctive mycophenolate can achieve comparable short-term graft function.

A lower tacrolimus exposure regimen was evaluated by Ekberg et al. In this trial, 1645 renal transplant recipients were randomly assigned to receive standard-dose cyclosporine, MMF, and corticosteroids, or daclizumab induction, MMF, and corticosteroids in combination with low-dose cyclosporine (target trough 50–100 ng/mL), low-dose tacrolimus (target trough 3–7 ng/mL), or low-dose sirolimus (target trough 3–7 ng/mL). At 12 months the mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 mL/min) than in the other three groups. The rate of BPAR was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). One-year allograft survival differed significantly among the four groups ( P = 0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). An observational 2-year follow-up to this study showed that the mycophenolate and low-dose tacrolimus (GFR 68.6 ± 23.8 mL/min) arm continued to have the highest GFR compared with standard-dose cyclosporine, low-dose cyclosporine, and low-dose sirolimus (65.9 ± 26.2, 64.0 ± 23.1, and 65.3 ± 26.2 mL/min, respectively), but the difference was not significant ( P = 0.17). The mycophenolate and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. Another trial evaluating low-dose tacrolimus randomized renal transplant recipients to either low-dose tacrolimus/everolimus or standard-dose tacrolimus/MMF with steroids and induction therapy. The rate of BPAR was significantly higher (19.1% vs. 11.2%, P < 0.05) in the low-dose tacrolimus/everolimus group, whereas mean GFR (63.1 vs. 63.1 mL/min) and safety were comparable at 1 year.

The effects of tacrolimus withdrawal were studied in a multicenter prospective randomized trial of immunologically quiescent kidney transplant recipients. Patients 6 months posttransplant without de novo donor-specific antibodies (DSAs) or prior episode of acute rejection were randomized to tacrolimus withdrawal ( n = 14) or continuation ( n = 14) in addition to induction with thymoglobulin, MMF, and steroids. The study was prematurely stopped because of high rates of rejection (4 of 14) and de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. In a similar study, low-immunologic-risk patients at least 4 years posttransplant were randomized to tacrolimus weaning ( n = 5) or continuation ( n = 5). All five patients in the withdrawal group had to be restarted on tacrolimus because of the development of acute rejection or de novo DSAs, whereas all five patients in the control group remained stable. These two trials suggest that even in highly selective stable kidney recipients, tacrolimus withdrawal is to be avoided.

Other Calcineurin Inhibitors and Formulations

One of the major risk factors for graft failure is noncompliance with medication regimens. Advagraf (Tac-OD), a once-daily formulation, was introduced by Astellas in 2008 to potentially improve medication compliance. In phase I and II trials, Advagraf showed equivalent pharmacokinetic parameters (C ₀ and AUC _0–24 ) compared with the twice-daily Prograf formulation (Tac-BID) in healthy controls, de novo kidney transplant recipients, and stable kidney transplant recipients after conversion. In a phase III open-label randomized study, 4-year safety and efficacy profiles were similar among patients receiving Advagraf (Tac-OD) and Tac-BID. The OSAKA trial randomized patients to Tac-BID 0.2 mg/kg per day ( n = 237), Tac-OD 0.2 mg/kg per day ( n = 263), Tac-OD 0.3 mg/kg per day ( n = 246) all with MMF and steroids, or Tac-OD 0.2mg/kg per day ( n = 230) with MMF, basiliximab, and perioperative steroids. The study showed comparable outcomes between Tac-BID and Tac-OD 0.2 mg/kg for its primary, composite endpoint of efficacy failure (42.2% vs. 40.6%). Advagraf was approved for use in the US in 2013. It is currently approved as maintenance immunosuppression with MMF and steroids, with or without basiliximab induction.

Envarsus XR (Tac-ER) is another once-daily formulation introduced by Veloxis to help with posttransplant immunosuppression adherence. Its design allows for improved bioavailability by decreasing the drug’s particle size via MeltDose (Veloxis Pharmaceuticals) technology. It was granted approval by the FDA in 2015 as prophylaxis for rejection in patients converting from twice-daily tacrolimus formulations. Envarsus’ noninferiority was demonstrated in the phase III MELT trial. Stable patients between 3 months and 5 years posttransplant were randomized to either conversion from Tac-BID to Tac-ER ( n = 163) or to remain on Tac-BID ( n = 163). Throughout the study the mean daily dose of Tac-ER was significantly lower than the preconversion dose ( P = 0.0001). The primary endpoint of efficacy failure rate was 2.5% for both arms. Patients receiving Tac-ER experienced more drug discontinuation within 12 months (12% vs. 5%, P = 0.028), although the incidence of adverse events was similar between the two groups. Another phase III multicenter trial evaluated the efficacy and safety of Envarsus in adult de novo kidney transplant recipients by randomizing patients to either Envarsus (Tac-ER; n = 268) or Tac-BID ( n = 275). The overall incidence of treatment failure (death, graft failure, biopsy-proven acute cellular rejection, or lost to follow-up) at 12 months was 18.3% in the Envarsus group and 19.6% in the Tac-BID. This treatment difference was below the 10% noninferiority margin. Overall, patients receiving Envarsus had a cumulative drug dose 14% lower compared with Tac-BID, and target trough levels were achieved faster.

Voclosporin (VCS, ISA247) is a novel CNI in development for organ transplantation. PROMISE was a phase IIb 6-month multicenter randomized open-label study of three ascending concentration-controlled groups of VCS (low, medium, and high) versus tacrolimus in 334 de novo kidney transplant recipients. This 6-month study showed VCS to be as efficacious as tacrolimus in preventing acute rejection (VCS low 10.7%, medium 9.1%, and high 2.3% vs. tacrolimus 5.8%) with similar renal function in the low- and medium-exposure groups.

Sandimmune, the original oil-based formulation of cyclosporine (Sandimmune; Novartis, Basel, Switzerland), was introduced in 1983. Although a significant advance in immunosuppressive therapy, this formulation had numerous problems. Absorption was slow and showed a great deal of intrapatient and interpatient variability, making dosing difficult and increasing the risk of chronic rejection.

In 1995 Neoral (Sandimmune Neoral; Novartis, Basel, Switzerland), a microemulsion formulation of cyclosporine, was approved for use by the FDA. This formulation improved bioavailability with more rapid absorption and less variability in de novo and stable transplant patients. Since its introduction, numerous randomized and nonrandomized studies have showed lower acute rejection rates, although long-term patient and graft survival compared with the Sandimmune formulation are similar.

Pediatric Renal Transplantation

See Chapter 37 for a more detailed discussion of pediatric renal transplantation. The efficacy of tacrolimus as an immunosuppressive agent in pediatric renal transplantation has been shown in single-center experiences and in multicenter trials. A retrospective cohort study of 986 pediatric renal transplant recipients in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database (index renal transplant 1997 through 2000), who were treated with either cyclosporine/MMF/steroids ( n = 766) or tacrolimus/MMF/steroids ( n = 220), was performed to examine differences in outcome between these two groups. In this analysis, tacrolimus and cyclosporine, in combination with MMF and steroids, were associated with similar rejection rates and graft survival in pediatric renal transplant recipients. Tacrolimus was associated with improved graft function at 1 and 2 years after transplantation. A 6-month randomized prospective open parallel-group study with an open extension phase was conducted in 18 centers from nine European countries to compare the efficacy and safety of tacrolimus with cyclosporine in pediatric renal transplant recipients. The study randomly assigned (1:1) 196 pediatric patients (<18 years old) to receive either tacrolimus ( n = 103) or cyclosporine microemulsion ( n = 93), administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. At 1 year, tacrolimus therapy was associated with a significantly lower incidence of acute rejection (36.9%) compared with cyclosporine (59.1%; P = 0.003). At 4 years, patient survival was similar, but graft survival significantly favored tacrolimus over cyclosporine (86% vs. 69%; P = 0.025). At 1, 2, 3, and 4 years, the mean GFR was significantly better in the tacrolimus group than in the cyclosporine group. Three patients in each arm developed posttransplant lymphoproliferative disorder, and the incidence of diabetes mellitus was similar in the two groups. Tacrolimus was significantly more effective than cyclosporine in preventing acute rejection in pediatric renal transplant recipients. Renal function and graft survival also were superior with tacrolimus. The addition of basiliximab to a tacrolimus-based regimen (tacrolimus/azathioprine/steroids) did not show any improved clinical efficacy at 6 months in a pediatric patient population with similar BPAR rates (20.4% without basiliximab vs. 19.2% with basiliximab) and GFR (79.4 without basiliximab vs. 77.6 mL/min/1.73 m ² with basiliximab). According to the 2014 NAPRTCS, less than 3% of patients were being treated with cyclosporine 30 days posttransplant, whereas more than 90% of patients were being treated with tacrolimus.

The effect of corticosteroids on the epiphyseal growth plates is well recognized and results in irreversible growth stunting. Experience with corticosteroid withdrawal under tacrolimus therapy in pediatric patients has been associated with favorable outcomes. Two-thirds of the pediatric kidney transplant recipients were withdrawn successfully from corticosteroids, with a low incidence of graft dysfunction or acute rejection (23%). Many of these patients had remarkable catch-up growth. The Tacrolimus and Withdrawal of Steroids (TWIST) trial was a randomized study evaluating the effect of early steroid withdrawal on posttransplant growth. A total of 196 patients were randomized to either early steroid withdrawal with tacrolimus/MMF/daclizumab or steroid continuation with tacrolimus/MMF. At 1 year, the steroid withdrawal group ( n = 54) grew better than the steroid continuation ( n = 59) cohort (0.25 difference in adjusted mean height change, P = 0.001). Growth was sustained at 2 years in the withdrawal group and significantly better in prepubescent children (0.50 difference in adjusted mean height change, P =. 0.004).

Changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, cytotoxic antibodies, lymphocyte populations, and cytokine response were studied in 14 pediatric renal transplant recipients with chronic rejection who were converted to tacrolimus from cyclosporine. Serum creatinine levels decreased, creatinine clearance increased, and urinary protein excretion decreased after 6 months, and these values were maintained after 2 years under tacrolimus treatment.

In one study eight pediatric renal transplant recipients (median age at transplant 2 years; range 1.2–12.9 years) were converted to tacrolimus- and sirolimus-based immunosuppression as rescue therapy. All patients had biopsy-proven chronic allograft nephropathy. After the addition of sirolimus, the median dose required to keep tacrolimus blood trough concentrations within the target range increased by 71.2% (range 21.9%–245.4%), and the dose-normalized tacrolimus exposure (AUC) decreased to 67.1%. Adding sirolimus to tacrolimus-based immunosuppression in young pediatric renal transplant recipients resulted in a significant decrease in tacrolimus exposure.