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Original Articles: Clinical Transplantation

Three-Year Observational Follow-up of a Multicenter, Randomized Trial on Tacrolimus-Based Therapy with Withdrawal of Steroids or Mycophenolate Mofetil after Renal Transplant

Pascual, Julio1,7; van Hooff, Johannes P.2; Salmela, Kaija3; Lang, Philippe4; Rigotti, Paolo5; Budde, Klemens6 on behalf of all participating investigators

Author Information
doi: 10.1097/01.tp.0000225806.80890.5e
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Abstract

The effective prevention of early posttransplant acute rejection is a critical success factor in improving long-term patient and graft survival (1, 2). Clinical research in renal transplantation has focused on investigating immunosuppressive regimens that are able to reduce early acute rejection without causing undue toxicity. There is now focus on investigating whether it is possible to withdrawal one or more agents to reduce complications of immunosuppression (3–6) without compromising long-term patient and graft survival. While tacrolimus use is associated with more favorable lipid parameters and less hypertension (7–9), ciclosporin, sirolimus and especially steroids are known to exacerbate cardiovascular risk factors (10–12). Early cessation of steroids and steroid-free regimens are interventions to be considered to reduce cardiovascular risk providing that steroid withdrawal or omission does not adversely affect either the incidence of early acute rejection or long-term graft function.

The THOMAS study demonstrated that steroids or mycophenolate mofetil (MMF) could be safely withdrawn from a tacrolimus-based regimen with a minimal increase in the risk of acute rejection (3). In that study, steroid withdrawal resulted in significant reductions in total and LDL cholesterol and MMF discontinuation was associated with significant reductions in the incidence of leucopenia and serious cytomegalovirus (CMV) infection (3). Any long-term benefits of minimized immunosuppression, especially the safety of steroid withdrawal, can, however, only be extrapolated from data obtained in the early phases posttransplantation.

In light of a Canadian study on steroid withdrawal which demonstrated poorer long-term outcome following steroid withdrawal in ciclosporine-treated patients (13), the longer-term assessment of these parameters in conjunction with steroid withdrawal in a tacrolimus-based regimen warranted investigation. The original study investigated the withdrawal of steroids or MMF after three months from a tacrolimus-based triple regimen (Tac/MMF/steroids) in kidney transplant patients. We now report on the 3-year observational data on that study population.

PATIENTS AND METHODS

This was an open-label, prospective, parallel group, randomized clinical trial conducted in 47 transplant centers in Europe that compared triple therapy with tacrolimus, steroids, and MMF with withdrawal of either steroids or MMF at 3 months post renal transplantation. Full details of the original study design and 6-month results have been previously published (3). The study participants were adult patients who were recipients of a primary or a secondary renal transplant from a deceased, living-related or living-unrelated donor. Demographic and baseline characteristics were well-balanced among the three treatment groups; approximately 98% of the patients in each group were white. The entire population was immunologic lower risk (3). Immunosuppression consisted of tacrolimus 0.2 mg/kg/day given in two divided doses. Target whole blood trough levels were 10–20 ng/ml between days 0 and 14, and 5–15 ng/ml thereafter. Steroids (methylprednisolone or equivalent) were administered as an intravenous bolus of 500 mg or less on day 0 and 125 mg on day 1, followed by oral prednisone 20 mg/day on days 2–14, 15 mg/day on days 15–28, and 10 mg/day from day 29 onwards. MMF was given at 1 g/day beginning within 72 hours of reperfusion. MMF was discontinued completely on day 92 in the MMF stop group. In the steroid stop group, steroid dosage was tapered from 10–0 mg/day over a period of 14 days (days 92–105). All patients continued to receive tacrolimus at a dosage providing trough levels of 5–15 ng/ml. After the 6-month study period, changes in the immunosuppressive regimens were left to the investigators' discretion.

Follow-up Study Design

An investigator-initiated, observational, follow-up study of 3 years duration was started at completion of the original study. In accordance with the definition of observational studies, follow-up data collection did not include any specific requirements in terms of treatment, dosing and route of drug administration, diagnostic examinations, or criteria for discontinuation of medication.

Data from routine follow-up examinations were collected at 1, 2, and 3 years posttransplant under the supervision of a regional coordinator (J.P., J.vH., K.S., P.L., P.R., and K.B.). No additional assessment measurements, other than those routinely performed at the transplant center, were requested. The data were entered via internet into an electronic case record form (eCRF), or completed manually, then entered into an electronic database. The following parameters were solicited in the eCRF: patient and graft survival, vital signs, routine laboratory, rejection episodes, immunosuppressive medication (doses and trough levels), concomitant medication requirements, and adverse events. The quality control of data was supervised by a clinical research organization.

The objectives of this observational study were to assess long-term renal function under tacrolimus-based immunosuppressive therapy, provide information whether steroid withdrawal represents an important step towards reducing the risk of cardiovascular disease by improving lipid profiles in renal transplant patients, and to evaluate long-term patient and graft survival in adult kidney transplant recipients after discontinuation of steroids or MMF from a tacrolimus-based triple drug regimen.

For purposes of the follow-up study, data was collected on all patients included in the intent-to-treat (ITT) population of the original study defined as all enrolled patients who were transplanted and received at least one dose of the study medication. Data were also collected on patients who were prematurely withdrawn from the 6-month study but still available for follow-up data collection. Patients were attributed to the treatment group to which they had been randomized irrespective of the immunosuppressive treatment they were receiving at the time of follow-up visits.

Ethic committees and regulatory authorities were notified as applicable. Patients provided written informed consent in accordance with local policies on patient privacy protection. The study was conducted in accordance with the Declaration of Helsinki.

Statistical Analysis

The planned sample size of 540 (180 patients per treatment group) in the original study provided at least 80% power to reject the null hypothesis of equality of treatment groups in the absolute change in serum cholesterol between months 3 and 6 on a 5% significance level (analysis of variance) if in two of the three treatment groups this change differed by at least 20 mg/dL (0.52 mmol/L). No further power calculation for the follow-up study was performed: sample size was determined by the availability of patients for follow-up at the participating treatment center.

Percentages were calculated on the basis of patients with data available for a given parameter. Since complete data sets for all parameters on all patients were not provided, the denominators for the calculations may vary. For purposes of this study, the following analysis sets were defined: The ITT follow-up population (ITT-FU) defined as patients providing any data during the 3-year follow-up; the ITT 3-year population (ITT 3-yr) defined as patients providing data at the 3-year follow-up assessment; the efficacy population (EFF) defined as patients whose treatment at the end of the original 6-month study was the same as the randomized treatment irrespective of subsequent therapy changes during the 3-year follow-up; and, the efficacy-completers population (EFF-C) population defined as patients whose treatment at the end of the 6-month study was the same as the randomized treatment and who continued on randomized treatment throughout the entire 3-year follow-up period. Consistent documentation of the randomized treatment must have been provided throughout the follow-up period to be included in the EFF-C analysis set.

Renal function was analyzed by serum creatinine and estimated creatinine clearance [Cockroft-Gault formula (14)]. The rate of change in renal function was assessed by linear regression of the reciprocal creatinine concentration on time (slope analysis).

Statistical tests on differences between treatment groups were carried out as prespecified: acute rejections, use of concomitant medication, and adverse events were compared between groups by Fisher's exact test or Pearson chi-square test, as appropriate; blood lipids and blood pressure values were tested by one-way analysis of variance or Kruskal-Wallis test, as appropriate; patient and graft survival estimates were analyzed by Kaplan-Meier methods and compared between groups by Wilcoxon-Gehan test. A P value of < 0.05 was considered to be statistically significant. All statistical testing was exploratory only.

RESULTS

The intent to treat (ITT) population in the original study totaled 833 patients (Table 1). Of these, 751 patients provided follow-up data (ITT-FU set). Of the ITT-FU set, 718 patients (86.2% of the original ITT cohort) provided data at a three-year follow-up examination. Unless otherwise specified, results are presented for the ITT 3-yr set. The efficacy population (EFF) (n=627) and the efficacy completer population (EFF-C) (n=302) were used in the calculations of supporting analysis.

TABLE 1
TABLE 1:
Populations for follow-up analysis

Data was collected between December 2000 and June 2003. Demographic and baseline characteristics of patients as well as donor characteristics were comparable among treatment groups.

Immunosuppressive Therapy

The mean tacrolimus daily dose at Year 3 was 0.065 mg/kg in the triple-therapy group and 0.071 mg/kg in both the steroid stop and the MMF stop groups. Mean tacrolimus trough levels were similar in all groups at Year 3: triple, 8.4 ng/ml; steroid stop, 8.6 ng/ml; MMF stop, 8.8 ng/ml). Mean total daily MMF dose was 0.99 g in the triple therapy group, 0.96 g in the steroid stop group, and 1.1 g in those patients in the MMF stop group who had resumed MMF therapy at Year 3. Median steroid dose was 5 mg/day in all groups.

At Year 3, 45.6% of patients in the triple group, 62.6% of patients in the steroid stop group, and 53.9% of patients in the MMF stop group were taking the regimen to which they had been randomized. Further, 23.3% of patients in the steroid stop group had resumed taking steroids in combination with any other immunosuppressant(s) and 25.4% of patients in the MMF stop group had resumed taking MMF in combination with any other immunosuppressant(s). In case of a change in regimen during the course of the follow-up period, the most frequent first switch in patients in the triple therapy group was a switch to a dual tacrolimus + MMF (29.4%) or alternatively a switch to tacrolimus + steroids (11.8%) regimen. In comparison, fewer patients were switched back to a triple regimen as a first switch (12.8%, steroid stop group; 16.8%, MMF stop group). The main reason given by investigators for changing an immunosuppressive regimen was to comply with center practice, the second reason was a switch because of adverse events. Rejection was seldom the reason reported for a switch in regimen.

Patient and Graft Survival

Estimated Kaplan-Meier 3-year patient survival rates were similar in all groups (Table 2). In total, 17 deaths occurred during the 3-year follow-up period; the most common cause of death was a cardiovascular event (five patients). Four patients, in total, died because of a malignancy (solid tumor and lymphoma).

TABLE 2
TABLE 2:
Kaplan-Meier estimated rate of patient/graft survival and incidence of rejection at year 3 (percentage of patients)

Similarly, graft survival rates at Year 3 were comparable among treatment groups (Table 2). The most commonly reported causes of graft loss between Month 7 and Year 3 were 11 losses from infection (mainly BK virus or CMV), 10 from refractory acute rejection (biopsy- and nonbiopsy-proven), and nine from chronic allograft nephropathy (CAN). More than one cause of graft loss was reported in most cases.

Graft Rejection

Incidences of biopsy-proven acute rejection (BPAR) occurring between Month 7 and Year 3 were low and comparable among treatment groups in the ITT-FU set: triple, 3/245 (1.2%); steroid stop, 5/252 (2.0%); MMF stop, 5/254 (2.0%). During the same period, the incidences of biopsy-proven steroid-resistant acute rejection were: triple, 2/240 (0.8%); steroid stop, 3/252 (1.2%); MMF stop, 1/254 (0.4%). The cumulative incidences of graft rejection for all analysis sets are presented in Table 2. The more the analysis sets are restricted, the lower the rejection rates (applicable to all three treatment groups). This tendency is most prominent in the MMF stop group where rates of BPAR were more than doubled in the ITT-FU set compared with the EFF-C set and in the steroid stop group where rates of BPAR in the ITT-FU set were the double of those in the EFF-C set. Incidence rates in the triple group showed only minor differences between the ITT-FU set and the EFF-C set.

A first acute rejection episode was reported in 1/245 patient in the triple group at Year 1, in 1/245 triple, 3/252 steroid stop, and 1/254 MMF stop patients at Year 2 and in 1/254 patient in the MMF stop group at Year 3 (based on ITT-FU set).

Renal Function

Median serum creatinine remained constant at 1-, 2-, and 3-year follow-up and was similar in all groups at Year 3 (Table 3). For purposes of analysis, creatinine values were classified into three categories: ≤100 μmol/L, >100 to ≤150 μmol/L, and >150 μmol/L. Creatinine values were >150 μmol/L in approximately 26% of patients in both the triple and steroid stop groups compared with 32% of patients in the MMF stop group. Estimated median creatinine clearance (Cockroft-Gault formula) was 61.9 ml/min in the triple-therapy group, 63.0 ml/min in the steroid stop group, and 63.3 ml/min in the MMF stop group at Year 3. Slope analysis of reciprocal serum creatinine versus time showed that after resumption of renal function posttransplantation, renal function remained stable in all groups throughout the follow-up period. No statistically significant differences were found in any comparisons of creatinine values.

TABLE 3
TABLE 3:
Serum creatinine values: intent-to-treat 3-year set

Cardiovascular Risk Factors

Using a classification system (≤5, >5 to ≤6, >6 mmol/L), total serum cholesterol values fell within the lower ranges for the majority of patients (Fig. 1). Mean total cholesterol, LDL, HDL and triglyceride values were lower in the steroid stop group compared with the other two treatment groups at Year 3 (Table 4). By Year 3, the patients in the steroid stop group had significant lower total mean cholesterol (P=0.015) and mean HDL-cholesterol (P=0.016) compared with the other two treatment groups. In comparison, the mean change in HDL and calculated LDL values remained relatively unchanged in both the triple and MMF stop groups during this time period. The mean total cholesterol/HDL ratio was 4.4 (SD±2.64) in the steroid stop group compared with 3.91 (±1.35) in the triple and 3.8 (±1.32) in the MMF stop groups (p=NS). The mean LDL/HDL ratio was comparable among groups: triple 2.3 (SD±1.14), steroid stop 2.63 (±2.21), and MMF stop 2.21 (±1.1) (P=NS).

FIGURE 1.
FIGURE 1.:
Total cholesterol levels in the majority of patients in all three treatment groups fell within acceptable ranges at 3 years.
TABLE 4
TABLE 4:
Lipid profile values at year 3 compared with month 3: intent-to-treat 3-year set (mmol/L)

Mean systolic blood pressure was lower in the steroid stop group than in the other groups (triple therapy, 136.2 mmHg; steroid stop, 133.6 mmHg; MMF stop, 139.8 mmHg; P=0.002), whereas mean diastolic blood pressure at Year 3 was similar in all groups (triple therapy 79.2 mmHg, steroid stop 80.3 mmHg, MMF stop 81.3 mmHg; P=0.191).

Significantly fewer patients in the steroid stop group as compared with the two other groups required antihypertensive medication (triple therapy, 66.2%; steroid stop, 61.3%; MMF stop, 74.4%; P=0.008) at Year 3. The mean number of different antihypertensive medications administered to a single patient was 1.8 in the triple therapy group, 1.8 in the steroid stop group and 2.0 in the MMF stop group. Significantly fewer patients in the steroid stop group (16.6%) compared with the triple (26.3%) and the MMF stop (28.1%) groups received antihyperlipidemic concomitant medication at the Year 3 follow-up assessment (P<0.05).

Insulin was required by 13.9% of patients in the triple therapy group, 9.8% in the steroid stop group, and 12.6% in the MMF stop group. The incidence of new-onset diabetes mellitus, defined as insulin use in patients who were not diabetics when they entered the original study, was 5.5% in the triple, 2.9% in the steroid stop, and 6.1% in the MMF stop treatment group at the Year 3 follow-up. There were no significant differences among groups.

The incidence of new-onset insulin treatment remained constant in all treatment groups: insulin use was transient in a proportion of patients and this proportion remained constant during the follow-up period. The cumulative incidences of new-onset diabetes mellitus during the 3-year follow-up period, considering patients with at least one report of insulin administration at any time, were 6.7%: triple, 8.0%; steroid stop, 4.5%; MMF stop, 7.6% (P=NS).

Adverse Events

The cumulative incidence and type of adverse events occurring during the 3-year follow-up period were similar in all treatment groups. The overall incidence of infection, the most frequently reported adverse event, was comparable in all groups (32.2%, triple; 32.5%, steroid stop; 32.6%, MMF stop). A CMV infection was reported in a total of 22 (3.2%) patients and a BK infection in a total of nine (1.3%) patients during the three-year follow-up. Fractures and bone and joint disease accounted for approximately 15% of adverse events in each group. The cumulative incidence of malignancies was approximately 4% and comparable between groups. There were no significant differences in comparisons among groups.

DISCUSSION

The THOMAS study was the first large, randomized controlled trial to investigate the withdrawal of steroids or MMF after 3 months from a tacrolimus-based triple regimen. In this observational, 3-year follow-up of that study, we found no disadvantages in efficacy or safety associated with the discontinuation of either steroids or MMF. The present findings of low incidences of late acute rejection and long-term stable graft function coincide with the 2-year follow-up results of another large European study which compared standard tacrolimus and ciclosporin regimens (15). We analyzed the main efficacy and safety parameters (patient and graft survival, allograft rejection) by comparing the ITT-FU, EFF, and EFF-C sets. The EFF and EFF-C sets were chosen to confirm the robustness of the ITT and ITT-FU results against randomized treatment scheme deviations. Evaluation of efficacy and safety parameters in the ITT, ITT-FU, EFF, and EFF-C sets revealed similar results.

There was a greater tendency to switch patients from a triple to a dual regimen during the follow-up period then to change the components of the dual maintenance regimen. Advantages to minimization of immunosuppression include decreasing susceptibility to and risk of infection, malignancy, cardiovascular risk, and hematological disorders (16). A steroid-free dual regimen was maintained by the largest percentage of patients although a substantial percentage was maintained on a tacrolimus + steroid regimen (MMF stop group). Standards of practice, costs of medications, complexities of monitoring, and convenience may have all influenced decisions to maintain this regimen.

The type of treatment regimen had no apparent effect on patient and graft survival as these rates were comparable between groups at Year 3. The Canadian study indicated poorer graft survival after steroid withdrawal with a single-drug (ciclosporin) immunosuppression regimen (13) whereas a recent comparison of seven-year outcomes in renal transplant recipients who mainly received ciclosporin-based immunosuppression with steroid discontinuation at six-months showed a significantly better graft and patient survival compared with retrospectively matched controls (4). No late (5 year) deterioration in graft function or survival was found in patients on a prednisone-free, dual drug maintenance regimen (5). It is intended to continue this observational study to assess graft and patient survival at 5 years.

In our study, median serum creatinine values were comparable in all three treatment groups showing no late deleterious effect on renal function following steroid withdrawal as similarly reported in an early steroid withdrawal trial (17). Stable renal function over time may translate into prolongation of graft half-life as indicated from registry data (18).

An objective of this study was to provide information on whether steroid withdrawal represents an important step towards reducing the risk of cardiovascular disease by improving lipid profiles in renal transplant patients. Total cholesterol and calculated LDL levels were decreased in parallel in the steroid stop group and changes in these values at Year 3 compared with Month 3 were greater in comparison to changes which occurred in the other two treatment groups. These results differ from those of another European study (6) which showed a time-limited improvement in serum lipids with very early steroid withdraw. In terms of other risk factors for cardiovascular disease, although mean systolic blood pressure measurements were lower in the steroid stop group, these results should be interpreted with the knowledge that blood pressure was measured on one occasion each year and may not, therefore, represent an accurate clinical picture. The use of antihypertensive treatment was, however, significantly lower in the steroid stop group. Although not statistically significant, reported cases of new-onset diabetes mellitus and the use of insulin were both numerically lower in the steroid stop group throughout the 3-year follow-up compared with the other two treatment groups. These improvements in factors contributing to cardiovascular risk were reported in the original 6-month study and after 3 years the difference in comparison with the other two treatment groups was sustained.

A meta analysis of immunosuppression withdrawal trials using ciclosporin as mainstay immunosuppressant reported increased relative risk of acute rejection and graft failure after steroid withdrawal (19). The results we observed with a tacrolimus-based regimen, low incidences of acute rejection and graft failure following steroid withdrawal, are more in line with the findings of a more recent meta analysis (20) which analyzed steroid withdrawal in patients on calcineurin inhibitors plus MMF therapy and found no increases in short-term graft loss.

Neither long-term patient and graft survival or renal function was adversely affected by MMF withdrawal at Month 3. Given the fact that MMF withdrawal was safe and did not lead to under-immunosuppression, there may be an economical advantage to MMF discontinuation although this study was not designed to specifically examine this aspect.

In conclusion, this observational analysis demonstrated that patient and graft survival at three years were not compromised by withdrawal of concomitant immunosuppression at three months from a tacrolimus-based regimen. Renal function was maintained in all groups and the incidence of late acute rejection was low. Early steroid withdrawal was advantageous in terms of improving lipid profiles and therefore cardiovascular risk factors. Continued follow-up data collection is required to assess if minimized maintenance immunosuppression actually translates into improved long-term patient and graft survival beyond 3 years.

ACKNOWLEDGMENTS

The following investigators participated in follow-up data collection: Y Vanrenterghem, Leuven; J Squifflet, Brussels; E Ancona, Padova; S Rodger, Glasgow; H Ekberg, Malmö; R Marcen, Madrid; C Jimenez, Madrid; S Gil-Vernet, Barcelona; JN Boletis, Athens; JC Ruiz, Santander; M Castagneto, Roma; L Baeckman, Goeteborg; J M Morales, Madrid; M A Gentil, Sevilla; R Lauzurica, Badalona; D Del Castillo, Cordoba; M G Molina, Malaga; J Garcia, Valencia; D Durand, Toulouse; S Stefoni, Bologna; G Rizzo, Pisa; H Seiter, Rostock; PJ Cosmes, Salamanca; A Palmer, London; M Meurisse, Liege; F Anaya, Madrid; M Rengel, Madrid; B Ringe, Göttingen; D Cantarovich, Nantes; G Rifle, Dijon; P Vialtel, Grenoble; F Mignon, Paris; M Kessler, Vandoeuvre les Nancy; Nonnast-Daniel, Erlangen; M Rivero, Cadiz; B Charpentier, Le Kremlin Bicêtre; Y Lebranchu, Tours; K Claesson, Uppsala; G Kirste, Freiburg; P Deteix, Clermont-Ferrand; F Mühlbacher, Vienna; C Legendre, Paris

We thank C. Krcmar for preparation of the manuscript, J. Dunkel for statistical support, and S. Schleibner for expert medical advice. The original study and data collection for the follow-up study were supported by Astellas Pharma, Munich, Germany.

REFERENCES

1. Baboolal K, Jones GA, Janezic A, et al. Molecular and structural consequences of early renal allograft injury. Kidney Int 2002; 61(2): 686.
2. Jindal RM, Hariharan S. Chronic rejection in kidney transplants. An in-depth review. Nephron 1999; 83: 13.
3. Vanrenterghem Y, van Hooff JP, Squifflet JP, et al. Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant 2005; 5(1): 87.
4. Opelz G, Dohler B, Laux G. Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 2005; 5(4): 720.
5. Matas AJ, Kandaswamy R, Gillingham KJ, et al. Prednisone-free maintenance immunosuppression - A 5-year experience. Am J Transplant 2005; 5(10): 2473.
6. ter Meulen CG, van Riemsdijk I, Hene RJ, et al. Steroid-withdrawal at 3 Days after renal transplantation with anti-IL-2 receptor therapy: A prospective, randomized, multicenter study. Am J Transplant 2004; 4(5): 803.
7. Artz MA, Boots JMM, Ligtenberg G, et al. Conversion from cyclosporine to tacrolimus improves quality-of-life indices, renal graft function and cardiovascular risk profile. Am J Transplant 2004; 4(6): 937.
8. Penson MG, Winter WE, Fricker FJ, et al. Tacrolimus-based triple-drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients. J Heart Lung Transplant 1999; 18(7): 707.
9. Kohnle M, Zimmermann U, Lutkes P, et al. Conversion from cyclosporine A to tacrolimus after kidney transplantation due to hyperlipidemia. Transpl Int 2000; Suppl 1: S345.
10. Fellström B. Risk factors for and management of post-transplantation cardiovascular disease. Bio Drugs 2001; 15(4): 261.
11. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67(7): 1036.
12. Kew CE, Curtis JJ. Cardiovascular disease in kidney transplant patients. Curr Opin Organ Transplant 1998; 3: 183.
13. Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts: The Canadian Multicentre Transplant Study Group. CMAJ 1992; 147(5): 645.
14. Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31.
15. Kraemer BK, Montagnino G, del Castillo D, et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant 2005; 20(5): 968.
16. Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002; 346(8): 580.
17. Ratcliffe PJ, Dudley CRK, Higgins RM, et al. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Lancet 1996; 348: 643.
18. Hariharan S, McBride MA, Cherikh WS, et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002; 62(1): 311.
19. Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11(10): 1910.
20. Pascual J, Quereda C, Zamora J, Hernández D. Spanish Group for Evidence Based Medicine in Renal Transplantation. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 2004; 78(10): 1548.
Keywords:

Tacrolimus; Immunosuppression minimization; 3-year follow-up

© 2006 Lippincott Williams & Wilkins, Inc.