To incorporate the effects of patients who discontinued treatment, two additional analyses were performed; a modified last observation carried-forward analysis and a comparison of the slope of the inverse serum creatinine between treatment groups using a t test. For the modified last observation carried-forward analysis, the last available serum creatinine value was used for patients without a value at 60 months. For patients with a graft loss, a value of 8.0 mg/dL was assigned, and serum creatinine values for all patients were capped at 8.0 mg/dL. Using the modified last observation carried-forward analysis, the median serum creatinine levels through 60 months (tacrolimus=3.3 mg/dL; cyclosporine=3.5 mg/dL; P=0.42) were lower with tacrolimus treatment and not statistically significant. A comparison of the slope of inverse serum creatinine revealed that fewer patients in the tacrolimus group (19%) than in the cyclosporine group (32%, P=0.63 for slope at 60 months) experienced a decrease from baseline in inverse serum creatinine of more than 40% at any time over follow-up.
The median estimated creatinine clearance was higher in the tacrolimus group than in the cyclosporine group throughout the 60-month follow-up period (Fig. 2B). At 60 months, the median estimated creatinine clearance was 37.15 mg/mL in the tacrolimus group and 32.10 mg/mL in the cyclosporine group (P=0.048). The change from baseline in the median estimated creatinine clearance was 1.2 in the tacrolimus group and −4.1 in the cyclosporine group (P=0.019). Significantly fewer patients in the tacrolimus group (73%) than in the cyclosporine group (89%, P=0.026) had an estimated creatinine clearance level lower than 35 mL/min at any time over follow-up. However, no similar statistical difference was observed between groups in the proportion of patients with estimated creatinine clearance values lower than 45 mL/min at any time over the 60 months (92% vs. 93%, P=1.0).
No significant differences were observed between the two treatment groups in the incidence of acute or chronic rejection through 60 months. At least one acute rejection episode was confirmed by biopsy in 11 (9%) patients in the tacrolimus group and 5 (8%) patients in the cyclosporine group (P=0.93). Thirty-three (26%) patients in the tacrolimus group and 15 (25%) patients in the cyclosporine group had chronic rejection confirmed by biopsy (P=0.86). Among patients who had a biopsy at 60 months, the severity of biopsy-confirmed chronic rejection had increased compared with baseline (including patients with no chronic rejection at baseline) in 9 of 25 (36%) patients in the tacrolimus group and 7 of 11 (64%) patients in the cyclosporine group (P=0.16).
Patient and Graft Survival
At month 60, kidney graft loss (including patients who died with a functioning graft) was similar between treatment groups and had occurred in 69 (55%) patients in the tacrolimus group and 34 (57%) patients in the cyclosporine group (P=0.897, log-rank test; Fig. 3). The most common reason for kidney graft loss was rejection. In the tacrolimus group, there was no significant difference in graft survival at 60 months between patients with mild chronic rejection at baseline and those with moderate/severe chronic rejection at baseline (42% vs. 27%; P=0.362), whereas, among patients in the cyclosporine group, the probability of graft survival was significantly higher for patients with mild chronic rejection than for those with moderate/severe chronic rejection at baseline (58% vs. 15%; P=0.001). Twenty-three (18%) patients in the tacrolimus group and 13 (22%) patients in the cyclosporine group died during the study (P=0.60), of whom 11 and 5 patients, respectively, had experienced graft loss before death. Death with a functioning graft was considered a graft loss.
Through 60 months of follow-up, no significant differences were observed between patients in the tacrolimus and cyclosporine groups in the proportion of patients with glucose more than 126 mg/dL (46.2% for tacrolimus and 44.6% for cyclosporine treatment), hemoglobin A1C more than 6.0%, total cholesterol more than 200 mg/dL, high-density lipoprotein less than 40 mg/dL, or triglycerides more than 200 mg/dL (Table 4). However, significantly fewer patients in the tacrolimus group than in the cyclosporine group had values of blood urea nitrogen more than 50 mg/dL (47% vs. 64%, P=0.036) or LDL cholesterol more than 130 mg/dL (29% vs. 57%, P=0.002) at any time over the 60-month follow-up period. The incidence of diabetes, hyperglycemia, hypertension, lymphoma, or malignancies among patients who did not have these conditions at baseline was generally low and comparable between groups. Among patients who had follow-up data available pertaining to cardiac conditions, significantly fewer patients in the tacrolimus group (13 of 123, 10.6%) developed new cardiac conditions than in the cyclosporine group (16 of 58, 27.6%; P=0.004). Conditions from most common to least common included coronary artery disease, myocardial infarction, congestive heart failure, angina, atrial fibrillation, tachycardia, angioplasty, atrial flutter, endocarditis, pericarditis, left ventricular hypertrophy, valvular disease, murmur, pacemaker inserted, and cerebrovascular accident. Additionally, a lower proportion of patients in the tacrolimus group (4 of 17, 24%) than in the cyclosporine group (six of nine, 67%; P=0.046) developed hyperlipidemia during the follow-up period. New opportunistic infections (lack of cytomegalovirus infection at baseline; 110 tacrolimus- and 50 cyclosporine-treated patients) were reported during the 60 month follow-up period by 24 (22%) patients in the tacrolimus group and 13 (26%) patients in the cyclosporine group (P=0.56).
Twenty-six of 126 (21%) patients in the tacrolimus group and 14 of 60 (23%) patients in the cyclosporine group discontinued their randomized treatment for reasons other than graft loss or death. In each group, adverse events (not including refractory rejection) led to treatment discontinuation in approximately 8% of these patients.
The incidence of serious adverse events was similar for both treatment groups. Thirty-four (27%) patients in the tacrolimus group and 19 (32%) patients in the cyclosporine group experienced serious adverse events, of whom 12 (10%) and 8 (13%) patients, respectively, experienced serious adverse events that were considered possibly or probably related to use of the study drug.
Patients with functional grafts after 2 and 5 years of follow-up experienced significant improvements in renal function with tacrolimus treatment compared with patients who remained on cyclosporine. Among this cohort, the median serum creatinine level was lower, and estimated creatinine clearance was higher in the tacrolimus group than in the cyclosporine group throughout the 60-month follow-up period. Notably, compared with results of the 2-year analysis (23), further reductions in median serum creatinine were observed with conversion to tacrolimus at 5 years (2.3 vs. 2.0 mg/dL, respectively). In contrast, the median serum creatinine level had increased at 5 years with ongoing cyclosporine use compared with results at 2 years (2.7 mg/dL vs. 2.6 mg/dL, respectively).
Our findings substantiate results of other studies comparing the long-term effects of tacrolimus and cyclosporine on renal function. In a 2-year study of 223 allograft recipients, renal function estimated by serum creatinine levels was significantly better (P=0.04) in patients treated with tacrolimus and MMF or tacrolimus and azathioprine than in patients treated with cyclosporine and MMF at 24 months (26). Similarly, results of a long-term study of 412 renal transplant recipients showed a significantly lower median serum creatinine level at 5 years among patients in the tacrolimus group (1.4 mg/dL) compared with those in the cyclosporine group (1.7 mg/dL, P=0.0014) (20). A European trial of 451 renal transplant patients reported lower serum creatinine levels at 5 years in patients treated with tacrolimus (1.70 mg/dL) compared with patients treated with cyclosporine (1.74 mg/dL); a significantly lower incidence of chronic rejection was observed in these tacrolimus-treated patients (27). Thus, compared with cyclosporine-based immunosuppression therapy, tacrolimus-based regimens are consistently associated with improved renal function.
It has been established that episodes of acute rejection, particularly late rejection episodes, increase the risk of CRAF (8, 9). In this study, switching from a cyclosporine-based to a tacrolimus-based immunosuppression regimen was not associated with an increase in the frequency of episodes of late-onset acute or chronic rejection. Overall, patients in both groups experienced similar rates of acute rejection (approximately 8% in each group, P=0.93) and chronic rejection (approximately 25% in each group, P=0.86).
Conservation of creatinine levels and favorable changes occurring in these levels within the first year after transplant correlate best with long-term graft survival (21). Despite improvements in renal function with tacrolimus treatment after 5 years, no differences in patient and graft survival were observed between treatment groups. However, at the time of enrollment, an average time period of 5.3 years for cyclosporine-treated patients and 4.7 years for tacrolimus-treated patients had elapsed from transplant to enrollment. Mean serum creatinine was 2.5 mg/dL for both treatment groups at baseline and approximately 90% of patients had already experienced CAN. Consequently, kidneys from both patient cohorts were compromised, and most patients were not optimal candidates for continued long-term graft survival. Improved renal function occurred probably after irreversible damage to the kidneys had been sustained; too late for any measurable change in patient or graft survival.
There were limitations to this study. Patients were recruited into this study strictly on the basis of serum creatinine concentration. Moreover, even though the protocol stated that a biopsy would be performed after 60 months, the procedure was not completed for many patients. Of the patients who completed the study with a functioning graft, 10 of 21 (47.6%) patients treated with cyclosporine and 21 of 45 (46.7%) patients treated with tacrolimus did not have biopsies. Furthermore, the study was not powered to detect subpopulations of tacrolimus-treated patients that may have shown better graft stability.
Our findings also demonstrated that switching from cyclosporine to tacrolimus was not associated with an increase in the incidence of coexisting conditions or other risk factors for CRAF. The proportion of patients who developed diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was similar for both groups. Results of a previous comparative study of tacrolimus and cyclosporine demonstrated an increased risk of posttransplant diabetes of approximately 15% with use of tacrolimus compared with use of cyclosporine (28). More recent studies have disputed these findings, and have demonstrated that use of tacrolimus is not associated with a significant increased risk of new-onset diabetes or hyperglycemia (26, 29), possibly because of better patient management and new adjunctive therapies. Our findings concur. Additionally, no significant difference in the occurrence of infections was observed between groups.
As the study progressed, differences in new cardiac conditions and in metabolic profile favoring tacrolimus treatment became apparent. Significantly fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%; P=0.004) or had LDL cholesterol values more than 130 mg/dL over follow-up. Additionally, fewer patients in the tacrolimus group than in the cyclosporine group developed hyperlipidemia (24% vs. 67%, P=0.046) over follow-up. There was a small number of patients without hyperlipidemia at baseline n=17 in the tacrolimus group and n=9 in the cyclosporine group. Although current definitions for diabetes mellitus, hyperglycemia, hypertension, and hyperlipidemia have become more stringent since this study was initiated, these collected data are still relevant and are indicative of a worsening health status. These observations are also important to patient health because cardiovascular disease (hyperlipidemia is a risk factor) is a significant cause of death in renal transplant patients (22, 30).
Both the tacrolimus and cyclosporine treatments were well tolerated. The proportion of patients who discontinued their randomized treatment because of adverse events and who experienced serious adverse events considered possibly or probably related to use of the study drug was similar for both treatment groups.
This study demonstrates the efficacy and safety of switching from cyclosporine-based to tacrolimus-based immunosuppression in patients at risk for CRAF, and corroborates findings from the 2-year report (23). Two and 5 years after switching treatment regimens, tacrolimus resulted in improved renal function in patients with functioning grafts and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, without a subsequent increase in the incidence of new-onset diabetes, new-onset hyperglycemia, infections, or other significant conditions. Acute and chronic rejection rates were comparable between treatment groups. Despite improvements in renal function and overall health status observed with tacrolimus, treatment did not correlate with improved patient and graft survivals.
The manuscript was drafted by the medical writing department of Astellas Pharma US, Inc. (Yolanda Cartwright, PhD, and Sharon Rogers, PhD), which also provided editorial assistance to the authors. The authors made a substantial contribution to the study’s conception and design, acquisition of data, and analysis and interpretation of data; participated in the drafting and review of the manuscript; and approved the final version.
Members of the CRAF Study Group
Members of the CRAF Study Group include: Thomas Waid, MD (University of Texas Medical Center, Lexington, KY); Edward Alfrey, MD (MS Hershey Medical Center, Hershey, PA); Laura C. Mulloy, DO (Medical College of Georgia, Augusta, GA); Fuad S. Shihab, MD (University of Utah, Salt Lake City, UT); David Conti, MD (Albany Medical College, Albany, NY); Richard Freeman, MD (New England Medical Center, Boston, MA); Angelo M. deMattos, MD (Oregon Health and Science University, Portland, OR); Stephen C. Jensik, MD, PhD (Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL); Stanley Jordan, MD (Cedars Sinai Medical Center, Los Angeles, CA); George C. Francos, MD (Thomas Jefferson University Hospital, Philadelphia, PA); David Van Buren, MD (Vanderbilt University, Nashville, TN); Larry Chan, MD (University of Colorado, Denver, CO); Robert W. Steiner, MD (University of California San Diego Medical Center, San Diego, CA); Giacomo Basadonna, MD (Yale University School of Medicine, New Haven, CT); Karl Brinker, MDCM, FRCP (Dallas Transplant Institute, Dallas, TX); Steven Steinberg, MD (Sharp Memorial Hospital, San Diego, CA); Arthur J. Matas, MD (University of Minnesota, Minneapolis, MN); Anne L. King, MD (Medical College of Virginia, Richmond, VA); Bertram L. Kasiske, MD (Hennepin County Medical Center, Minneapolis, MN); David J. Cohen, MD (New York Presbyterian Hospital-Columbia, New York, NY); David Surer, MD (New York Presbyterian Hospital Rogosin Institute, New York, NY); Sharon Inokuchi, MD, PharmD (California Pacific Medical Center, San Francisco, CA); John D. Pirsch, MD (University of Wisconsin, Madison, WI); Jonathan S. Bromberg, MD, PhD (Mount Sinai Medical Center, New York, NY); Matthew R. Weir, MD (University of Maryland, Baltimore, MD); Stuart M. Greenstein, MD (Montefiore Medical Center, Bronx, NY); Stephen J. Tomlanovich, MD (UCSF Medical Center, San Francisco, CA); Robert Mendez, MD (St. Vincent/NIT, Los Angeles, CA); Lawrence Kahana, MD (Tampa General Hospital, Tampa, FL); Alice K. Henning, MS (The EMMES Corporation, Rockville, MD); M. Roy First, MD, William E. Fitzsimmons, PharmD, Kim Salm, RN, Diane Tolzman, RN (Astellas Pharma US, Deerfield, IL).
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
Cyclosporine; Graft rejection; Renal transplantation; Tacrolimus