A recent therapeutic strategy after renal transplantation includes simultaneous use of reduced calcineurin inhibitor dosing, maximized use of a non-nephrotoxic, antiproliferative drug (inosine monophosphate dehydrogenase [IMPDH] or TOR inhibitor), and single-agent, antibody induction (lymphodepleting polyclonal antibody rabbit anti-human thymocyte globulin (ATG), nondepleting human anti-interleukin-2 receptor (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or lymphodepleting humanized anti-CD52 monoclonal antibody alemtuzumab) (1–15). Its goal was to reduce/avoid both calcineurin inhibitor's nephrotoxicity and the incidence of acute/chronic rejection, leading to more favorable longer term patient and graft survival. Standard single-agent induction protocols previously used at our center (5–8, 13–15) include the following: five doses of Dac (1 mg/kg) given once every other week, seven daily doses of ATG (1 mg/kg), and two doses of alemtuzumab (0.3 mg/kg) given during the first week posttransplant, with each single agent started on the day of transplant. Combined with this strategy, early corticosteroid withdrawal (CSWD) has also been used in the attempt to avoid well-known side effects while maintaining favorable patient and graft survival (16–18).
Evidence now suggests that an equally effective induction strategy includes the combined use of more than one induction agent (each with fewer doses than if used alone), with the goal of bringing the kidney transplant recipient even closer (through more effectively timed lymphodepletion) to an optimally immunosuppressed state, perhaps allowing further reduction in long-term maintenance drug dosing (19–25). In fact, we have successfully used dual ATG/Dac induction therapy in both simultaneous kidney-pancreas (19–20) and kidney-alone (23, 24) transplantation, and a recent report shows that the addition of anti-CD25 to ATG more effectively delays the return of peripheral blood CD25+ cells (25). Although ATG contains antibodies to a wide variety of peripheral blood mononuclear cell epitopes, with a possible protective effect on preservation injury and chronic rejection (4, 9, 13–16, 26, 27), it also triggers B-cell and plasma cell apoptosis (28, 29). Alemtuzumab (Campath-1H) (C1H) potently depletes T and B cells along with other lymphoid subsets, perhaps allowing reduced dosing of concurrent maintenance immunosuppressive agents (11–15, 30). C1H and ATG have also shown a greater propensity for the development of regulatory T cells (T-regs) posttransplant (13, 30, 31), whereas Dac allows normal repopulation of T-regs posttransplant (32).
We therefore wanted to determine whether the combination of ATG/C1H (1 dose each) would be effective in achieving the beneficial effects of both agents while allowing reduced maintenance tacrolimus dosing (rTd), one half of the conventional IMPDH inhibitor dosing, and early CSWD. We compared in a prospective, single-center, open-label randomized trial this new induction strategy versus our standard: ATG/Dac (three doses of ATG; two doses of Dac), with rTd, full IMPDH inhibitor dosing, and early CSWD (23, 24). Both dual-induction strategies used fewer doses of each agent compared with the earlier, single-agent induction protocols at our center (5–8, 13–15). Although comparison of dual- versus single-agent induction would be a worthy goal, the main purpose of this study was to compare two distinct dual antibody induction regimens in conjunction with using rTd, an IMPDH inhibitor, and steroid avoidance.
Patient Demographics and Early Outcome
Distributions of baseline demographics and early outcomes for the two study groups (Table 1) show no significant differences. Note that 71% and 76% of patients in groups I and II, respectively, were minorities (non-white). Nineteen patients received expanded criteria donor kidneys (8 in group I; 11 in group II). Two patients received donation after cardiac death kidneys (both in group II).
Two patients received kidneys that never functioned (both in group II), (primary nonfunction in one; arterial thrombosis of pediatric en bloc kidneys in the other). Excluding these two cases, delayed graft function (DGF) was low in both arms: 6% (6 of 100) vs. 2% (2 of 100) in groups I and II, respectively (P=0.16); slow graft function (SGF) was also relatively low.
Immunosuppressive Doses and Trough Levels
Except for one patient in group I who did not receive a second course of Dac (due to infection and subsequent death), all other patients received the planned induction therapy in each study group. Five patients with DGF (four in group I; one in group II) and five additional patients with SGF (three in group I; two in group II) received 3 to 10 and 1 to 4 additional courses of ATG, respectively, before starting rTd therapy.
Mean doses of rTd, enteric-coated mycophenolate sodium (EC-MPS), serum trough concentrations, WBC, percentages having EC-MPS withheld or discontinued, and percentages taking corticosteroids by treatment arm are shown in Table 2. Mean tacrolimus trough levels reached those planned, for example, mean levels at month 12 were 6.04±0.18 in group I vs. 6.21±0.20 in group II (nonsignificant [N.S.]). Although mean tacrolimus trough levels were comparable between study groups, mean tacrolimus doses were consistently lower in group I (significant at month 24), with mean ratio of tacrolimus trough level to dose (bioavailability) being significantly higher in group I at month 24 (P=0.02). Two patients discontinued tacrolimus during the study (1 due to Epstein-Barr virus infection in group I, 1 due to necrotizing fasciitis in group II); both patients were switched to sirolimus.
As planned, mean daily EC-MPS doses were significantly higher in group I versus group II (P<0.001 at each time). Although the percentage of patients ever having EC-MPS withheld or discontinued was 19% (19 of 100) vs. 21% (21 of 100) in groups I and II (median time-to-withholding: 3 months), respectively (P=0.72), a significant difference in reasons for EC-MPS withholding was observed, with EC-MPS withheld/discontinued due to leukopenia, gastrointestinal (GI) symptoms, and infection being 12% (12 of 100), 7% (7 of 100), and 0% (0 of 100) in group I vs. 19% (19 of 100), 0% (0 of 100), and 2% (2 of 100) in group II, respectively (P=0.01). Thus, EC-MPS withholding/discontinuance due to leukopenia or infection was more common in group II, even in the presence of lower EC-MPS dosing. Conversely, EC-MPS was withheld/discontinued due to GI symptoms only in group I. In total, 11 patients discontinued EC-MPS, eight in group I (six due to GI symptoms, two due to leukopenia) versus three in group II (two due to infection, one due to leukopenia); five of these patients were switched to sirolimus.
Percentages of patients remaining on corticosteroids at any month were low (<20% in group I; <15% in group II), with a significant difference in favor of group II only at 12 months (P=0.03). Percentages ever remaining on corticosteroids (during the follow-up period) were 27% (27 of 100) vs. 20% (20 of 100) in groups I and II, respectively (P=0.24). Reasons for remaining on corticosteroids (either continuously or after restarting, depending on the reason) included the following: DGF/SGF (eight in group I; six in group II), development of AR (nine in group I; nine in group II), other (four in group I; three in group II), and unknown (six in group I; two in group II). Except for a significantly lower mean WBC and higher percentage having WBC less than 3500/mL in group II at month 1 (P=0.01 and 0.002), no other major differences in WBC were observed.
There were no differences between groups in the incidence rate of developing biopsy-proven acute rejection (BPAR): 14 of 100 vs. 13 of 100 (including borderline) and 10 of 100 vs. 9 of 100 (excluding borderline) in groups I and II, respectively (P=0.89 and 0.84) (Table 3, Fig. 1a, b); actuarial estimates at 48 months posttransplant (including borderline) were 15%±4% for both groups, respectively. During the first 12 months posttransplant, the incidence rate of developing BPAR (primary endpoint) was 11 of 100 vs. 9 of 100 (including borderline) (8 of 100 vs. 6 of 100 excluding borderline) in groups I and II, respectively (N.S.). In groups I and II, 86% (12 of 14) and 85% (11 of 13) of patients experiencing BPAR were non-white. Fourteen patients (7 of 14 in group I; 7 of 13 in group II) received antilymphocyte therapy in treating the first BPAR. Although only 5.5% (11 of 200) of patients had a first BPAR grade that was IB or higher or C4d+, 6 of 7 and 3 of 4 of these patients in groups I and II, respectively, received antilymphocyte therapy. Thus, steroid-resistant rejection occurred mainly in the higher grade (or C4d+) cases. Five patients, three in group I and two in group II, experienced a 2nd BPAR. Finally, eight patients developed a humoral rejection (C4d+) (five in group I, with 1 occurring as the 2nd BPAR; three in group II).
Comparisons of mean creatinine (Cr) and estimated glomerular filtration rate (eGFR) (Table 4) showed similar and favorable levels in groups I and II over time, with slight trends for renal function among patients with functioning grafts improving in both groups between 1 and 36 months posttransplant. At 36 months posttransplant, the geometric mean*/standard error (SE) serum Cr and arithmetic mean eGFR (±SE) were 1.14*/1.05 and 72.1±3.3 in group I vs. 1.24*/1.05 and 67.5±3.3 in group II (N.S.).
Patient and graft survival ±SE (Table 5, Fig. 1c, d) were similar in the two groups, with actuarial estimates at 48 months posttransplant being 96%±2% and 91%±3% in group I (four deaths, four graft failures) vs. 92%±3% and 83%±5% in group II (seven deaths, six graft failures), respectively (P=0.35 and 0.25). Causes of graft failure were vascular rejection (n=1), Epstein-Barr virus infection/BPAR (n=1), noncompliance (n=1), and pseudoaneurysm (n=1) in group I; primary nonfunction (n=1), arterial thrombosis of pediatric en bloc kidneys (n=1), BPAR (n=2), chronic allograft injury (CAI) (n=1), and cardiovascular disease (n=1) in group II. Excluding the two patients in group II with grafts that never functioned, four graft failures were observed in each group (P=0.98), and actuarial graft survival in group II at 48 months became 85%±5% (P=0.45). Each of the 11 deaths occurred with functioning grafts; proportions of graft failures and deaths occurring during the first 12 months posttransplant were 9 of 10 and 6 of 11, respectively. Causes of death were cardiovascular event (n=1), sepsis (n=1), systemic amyloidosis (n=1), and unknown (n=1) in group I; sepsis (n=2), cardiovascular event (n=2), metastatic lung cancer (n=1), necrotizing fasciitis (n=1), and cerebrovascular accident (n=1) in group II. Although not statistically different, it should be noted that 3 of 4 deaths due to infection occurred in group II.
Percentages and types of infections during the study were equivalent in the two groups (Table 6). In total, 27% (54 of 200) developed an infection (29 in group I; 25 in group II, P=0.52); 43 of 54 patients had infections during the first year posttransplant (22 in group I; 21 in group II, N.S.). Only four patients developed cytomegalovirus (CMV) infection (CMV syndrome for one case in group I; CMV syndrome for two cases and CMV hepatitis for one case in group II). Three patients developed polyoma viral infection (one in group I; two in group II). No patients developed posttransplant lymphoproliferative disorder (PTLD).
Among patients having no pretransplant history of diabetes, new onset diabetes mellitus after transplantation (NODAT) developed in 8 of 75 group I vs. 8 of 70 group II patients (P=0.88); 10 of 16 events (six in group I; four in group II) occurred during the first 12 months posttransplant (N.S.). NODAT patients requiring insulin:oral hypoglycemic agents were 6:2 vs. 7:1 in groups I and II, respectively; 2 of 16 were placed on maintenance steroids before the development of NODAT. Finally, there were no noteworthy differences in lipid profiles or in percentages of patients requiring antilipidmia therapy between groups (not shown).
In our two earliest trials using five doses of Dac combined with TAC/mycophenolate mofetil and corticosteroid maintenance (5, 6), the 1 year BPAR rates were 5.1% and 4.0% (excluding borderline cases), with 1 year mean TAC trough levels of 8.0 to 9.0 ng/mL. Our next trial (13) comparing single-agent induction with ATG versus alemtuzumab versus Dac (early CSWD in the alemtuzumab group only) yielded disappointing 1 year BPAR rates of 17% in each group, with rTd and 1 year mean TAC trough levels of 6.0 to 7.0 ng/mL. Based on these findings, we then embarked on the dual ATG/Dac induction strategy (using fewer doses of each agent than if used alone) along with rTd and planned early CSWD, achieving an overall 1 year BPAR rate of 6.0% (23), and thus providing rationale for this study.
In February 2006, we initiated a prospective, single-center, open-label randomized trial of 200 (mostly non-white) patients administering the dual-induction combinations of ATG/Dac (three doses of ATG, two doses of Dac) versus ATG/C1H (one dose each), along with (in both arms) rTd, EC-MPS, and early CSWD (7 days). To our knowledge, this is the first such randomized trial to compare two distinct dual-induction strategies, with both arms using fewer doses of ATG, Dac, and C1H than if used alone at our center. Given the known association of acute rejection with decreased long-term graft survival (33), the goal in using dual-induction therapy was to produce rapid and effective lymphocyte depletion, resulting in lower daily requirements of maintenance therapy while achieving favorable long-term graft and patient survival (4, 11–15, 26, 27, 30). With a median follow-up of 38 months posttransplant, there were no notable differences between the two study arms in BPAR rate, both during the first 12 months posttransplant and throughout the follow-up period. Overall BPAR incidence for both groups combined at 48 months posttransplant was 27 of 200 (actuarial estimate: 15%) including borderline and 19 of 200 (actuarial estimate: 11%) excluding borderline cases, demonstrating the long-term antirejection efficacy of both study arms.
In a recently published report by Ekberg et al. (2), among 401 (mostly white) patients who received five doses of Dac, rTd, mycophenolate mofetil, and corticosteroids, the rejection rate at 36 months was 14% (excluding borderline), being similar to our overall actuarial estimate of 11% at 48 months posttransplant. Renal function was also favorably high as in our study, demonstrating the effective use of rTd in combination with an IMPDH inhibitor (34, 35), known to have antiproliferative effects on vascular smooth muscle cells, perhaps decreasing arterial intimal thickening (36), angiogenesis, and other less well-defined causes of CAI, which contribute to long-term graft loss (37).
One half the standard daily EC-MPS dose was targeted in group II to avoid severe leukopenia as previously seen with C1H use at our center (13–15). Consequently, two interesting findings were observed. First, even with the planned lower dose of EC-MPS in group II, a moderately higher incidence of EC-MPS withholding due to leukopenia still occurred. Second, none of the patients in group II had EC-MPS withheld due to GI symptoms (suggesting that a threshold dose to cause this complication may exist) versus a 7% (7 of 100) incidence in group I (P=0.007). Because higher AR incidence (38–40) and greater graft loss rates (40, 41) have been reported after the development of GI symptoms and subsequent IMPDH inhibitor dose reduction/withholding, planned use of dual-induction therapy combined with lower (than standard) target dosing of EC-MPS may provide a solution for overcoming this problem.
Long-term corticosteroid therapy is still considered by many to be part of standard maintenance immunosuppression, but multiple side effects including increases in known cardiovascular risk factors (high triglycerides, NODAT requiring insulin, and weight gain) are known. Recently, Woodle et al. (18) reported similar 5-year renal allograft survival and function in a prospective, multicenter randomized trial between early (7 days) CSWD (n=191) versus low-dose corticosteroid therapy (n=195), with CSWD also providing improvements in cardiovascular risks factors. In terms of BPAR, however, CSWD was associated with a significantly higher BPAR (17.8%) in comparison with low-dose corticosteroid therapy (10.8%) (P=0.04, log-rank test). Similar results were also reported in a recent meta-analysis (42).
Promisingly, 76.5% (153 of 200) of our study patients have been withdrawn from corticosteroids, with no apparent increase in the AR rate, and actuarial graft and death-censored graft survival for the whole cohort at 48 months were 87% and 94%, respectively. In addition, the incidence rates of infectious diseases and NODAT were acceptably low in both study arms. In fact, the rates of viral infections were low, with only four CMV and three polyoma viral infections (and no PTLDs) being observed overall (BK viral titers were not monitored routinely).
Limitations in drawing conclusions from any single-center study do exist. First, as this was a randomized trial of 200 patients, limitations of statistical power with respect to comparing patient and graft survival (and the incidence of adverse events such as PTLD/malignancy) clearly occurred at earlier periods of follow-up. Second, any potential generalization of our study results to other patient populations would require independent validation, particularly as the majority of our patients were non-white (although no differential effects of treatment arm by race/ethnicity were observed). Although bioavailability of TAC is known to be markedly lower among African Americans (i.e., a higher TAC dose is required to achieve a specified 12-hour trough level) (43, 44), the observed trend for lower bioavailability of TAC in the ATG/C1H arm will require further observation, as factors such as race/ethnicity, use of alemtuzumab, or a lower EC-MPS dose in the ATG/C1H arm may have contributed to this surprising finding, although it may have occurred by chance alone. Furthermore, although Dac is no longer available, successful combination of ATG/basiliximab as dual induction in kidney transplantation has been reported (21, 22) along with equivalency in clinical outcomes using basiliximab versus Dac (10). Finally, although determination of a best single-agent induction strategy in renal transplantation is still of great interest as demonstrated by two recent randomized trials comparing ATG and basiliximab versus alemtuzumab (45, 46), the focus of the current study was to compare two distinct dual-induction strategies using less aggressive dosing for each agent than if used alone at our center.
In conclusion, our attempt to improve long-term patient and graft survival by using innovative immunosuppression strategies designed to reduce the BPAR rate without increasing the rates of other adverse events seems promising. Although this protocol will require longer term follow-up (currently planned) to demonstrate its ultimate relationship with patient and graft survival (in particular, to determine whether there will be any long-term graft survival inferiority in group II, given that its actuarial estimate at 48 months was 83% vs. 91% in group I), the randomized trial component of this protocol (with median follow-up of 38 months) yielded no notable differences in major clinical outcomes between study arms.
MATERIALS AND METHODS
Between February 2006 and April 2009, 200 adult recipients (age, 18–71 years) of deceased donor or non-human leukocyte antigen identical living donor first kidney transplants were randomized in this open-label study immediately before transplantation. In the ATG/Dac arm (group I) (n=100), ATG (1 mg/kg) (Thymoglobulin) was given intraoperatively, with equivalent additional doses given on days 2 and 3 posttransplant. The first dose of Dac (1 mg/kg) (Zenapax) was also given intraoperatively, with one additional dose given 14 days later (23, 24). In the ATG/C1H arm (group II) (n=100), ATG (1 mg/kg) was given intraoperatively, and C1H (0.3 mg/kg) was given within 24 hr posttransplant. The center institutional review board approved the protocol, and all patients gave written informed consent before enrollment. In both groups, tacrolimus was initiated at 0.1 mg/kg twice daily after renal function had improved (serum Cr concentration <4 mg/dL absent dialysis), with a target (12 hr) trough level of 4 to 8 ng/mL. Target EC-MPS dosing was 720 mg vs. 360 mg twice daily for groups I and II, respectively. One half of the standard daily EC-MPS dose was targeted in group II to avoid severe leukopenia previously seen with C1H (12–14). Any withholding of EC-MPS for a minimum period of 1 month was documented along with reasons for withholding. Methylprednisolone was given intravenously at 500 mg/day for 3 days postoperatively followed up by daily oral methylprednisolone or IV Solumedrol at 0.5 to 1 mg/kg/day during the first week primarily to avoid hypersensitivity reactions to the induction antibodies. No further corticosteroid use was planned after the first postoperative week. All patients were documented as intent-to-treat.
The schedule of nonimmunosuppressive adjunctive therapy was the same as in our previous protocols (5–8, 13–15, 23, 24). For CMV prophylaxis, all patients were treated immediately posttransplant with intravenous ganciclovir (Roche Laboratories, Palo Alto, CA) for 3 days, followed up by daily valganciclovir orally for 3 months with doses based on renal function. In donor CMV Ig+/recipient CMV Ig− combinations, treatment was given for 6 months postoperatively. In patients developing rejection that required steroids or antilymphocyte therapy, intravenous ganciclovir or valganciclovir was reinstituted. Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole was also given (5–8, 13–15, 23, 24).
Histocompatibility typing of human leukocyte antigen-A, -B, and -DR loci, donor-specific crossmatching, panel-reactive antibodies, and donor-specific antibody monitoring (at baseline and any time of suspected acute rejection) were determined serologically by the University of Miami Histocompatibility Testing Laboratory. All deceased donor organs were cryopreserved using Water's RM3 Renal Preservation Machine with Belzer-MPS Machine Perfusion Solution (Trans-Med Corp., Elk River, MN) (47).
Tacrolimus trough levels were routinely compiled for each patient, performed by whole blood immunoassay, with blood samples taken 3/wk, 2/wk, and 1/wk during the first 3 months, respectively, monthly for the next 9 months, and then once every 2 months thereafter. Dosing of all maintenance drugs at those times were recorded. DGF was defined as the requirement for dialysis during the first week posttransplant; SGF as serum Cr decreasing less than 0.5 mg/dL during the first 24 hr posttransplant. All patients were followed for the incidence of BPAR, graft loss, death, CAI, renal function (serum Cr and eGFR) (48), NODAT, and infections.
BPAR was defined as a rise of 0.3 mg/dL or greater from the nadir Cr, accompanied by a confirmatory kidney transplant biopsy within 24 hr of initiation of antirejection therapy; Banff criteria were used to determine biopsy rejection severity and CAI (interstitial fibrosis/tubular atrophy) (49). Graft loss was determined as the time of reestablishment of long-term dialysis or death. NODAT was defined as the use of insulin or oral antihyperglycemic agents for more than or equal to 30 days in patients without a preoperative history of diabetes mellitus. Peripheral blood myeloid and lymphoid cell counts, dyslipidemias, and statin therapy were also compiled.
Primary endpoint was the incidence of first BPAR (including treated borderline cases) at 12 months posttransplant. Our previously reported trial using dual ATG/Dac induction in all 150 patients achieved an overall 12-month BPAR rate of 6% (9 of 150) (22, 23). Thus, this study was designed with 100 patients per treatment arm to ensure that good statistical power (≥0.80) existed (using a two-sided test with 0.05 type I error) for detecting a 14% to 15% difference: 6% vs. 20%, 8% vs. 23%, or 10% vs. 25%. Detection of secondary outcomes such as patient and graft survival with good statistical power would clearly require long-term follow-up.
Statistical analysis was performed using an intent-to-treat approach. Standard t tests were used to compare mean values between treatment arms; percentages were compared using the Pearson (uncorrected) chi square test. Arithmetic means±SEs were calculated except for variables that were skewed toward larger values, in which case geometric means and corresponding SEs were reported, with comparisons based on log-transformed values (50). Incidences of first BPAR, NODAT, graft failure (death-censored graft loss), graft loss, and death were compared by the log-rank test, with time-to-failure curves generated using the Kaplan-Meier method. P values less than or equal to 0.05 were considered to be statistically significant. With the exception of patient survival, all clinical outcomes were censored (patients not followed) beyond the date of graft failure. Thus, analyses of renal function (serum Cr and eGFR) at various times posttransplant were based on comparing patients who were still alive with functioning grafts at those times. Although imputation of an arbitrarily chosen low value for eGFR (say, 10 mL/min) was considered for patients who previously experienced graft failure (1, 2), the results were quite similar to those found without using imputation and will therefore not be shown.
A randomized block scheme using Proc Plan in SAS (Statistical Analysis Systems) was implemented to perform the randomization of patients into the study. Specifically, patients were randomly assigned to the two treatment arms in blocks of 4 and 6 patients (block sizes were also randomly selected), ensuring a balance of patients after each block of patients was randomized.
As of the last follow-up date, May 1, 2010, median follow-up among 170 ongoing survivors with a functioning graft was 38 months (range, 13–50 months), with 21 patients experiencing graft loss, and 10 patients being lost-to-follow-up (range, 3–40 months, all but one with a functioning graft) (5 in group I, 5 in group II). For each clinical outcome, actuarial percentages of failure at 48 months posttransplant were calculated. For each time-to-event outcome, patients who were lost to follow-up were censored at their lost-to-follow-up times. With the exception of tabulating infections (last value carried forward approach), all other measurements (drug dose, drug trough level, serum Cr, etc.) performed at various times beyond the dates of patients being lost-to-follow-up were assumed to be missing (i.e., no imputation). A flow diagram for the study is presented in Figure 2.
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