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*Department of Internal Medicine, University Hospital Rotterdam, Rotterdam, the Netherlands; Department of Nephrology, University Medical Centre St. Radboud, Nijmegen, the Netherlands; and Department of Nephrology, University Medical Centre Utrecht, Utrecht, the Netherlands.
Correspondence to: Dr. Peter Smak Gregoor, Department of Internal Medicine, Room D-412, University Hospital Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Phone: 31-10-4639222; Fax: 31-10-4366372; E-mail: smakgregoor{at}inw1.azr.nl
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Introduction |
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Materials and Methods |
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During the first 6 mo after transplantation, 22 patients had lost their graft and 8 patients died with a functioning graft. Excluded from randomization were patients with two or more acute rejections during the first 6 mo after transplantation (n = 15), patients with biopsy-proven chronic vascular rejection (n = 3), patients with proteinuria of more than 3 g/d (n = 2), patients with an unstable graft function (n = 9), and patients not treated with triple drug therapy (MMF, CsA, Pred) at the time of randomization (n = 29). At the time of randomization, seven patients refused to participate in the study. In five cases, the treating physician decided not to ask the patient for participation because of multiple HLA-mismatches, previous severe acute rejection, or liver function disturbances. One patient was lost to follow-up before randomization. The study design was approved by the institutional review boards of the three participating hospitals, and written informed consent was obtained from all participants.
Randomization Procedure
Patients were randomly assigned to one of the three treatment groups in a 1:1:1 ratio, with stratification for cadaveric/living related transplant, for center, and for the number of acute rejections during the first 6 mo after transplantation. Randomization was carried out by opening a sealed envelope with the lowest available study number.
Immunosuppression
Patients were treated with 1000 mg of MMF twice daily, 0.1 mg/kg Pred per day, and CsA targeted at trough levels between 125 and 175 ng/ml (from 3 mo after transplantation). The microemulsion formulation of CsA (Neoral; Novartis, East Hanover, NJ) was used in all patients. No induction antibody therapy was used. Dose reduction or interruption of MMF treatment was allowed in cases of leukocytopenia or anemia, primary cytomegalovirus (CMV) infection, or severe gastrointestinal side effects. In the patients randomized for discontinuation of CsA, the CsA dose was reduced by 50% for 2 wk before complete cessation while increasing the prednisone dose to 0.15 mg/kg per d and continuing 2 g of MMF daily. In nine patients, the CsA dose was reduced by 25% every 3 wk before complete discontinuation. The patients randomized for discontinuation of Pred were tapered off the Pred to 0 mg in 10 wk (according to protocol) while continuing CsA and MMF in unchanged dosages.
Acute rejections were treated primarily with 1000 mg of intravenous methylprednisolone during three consecutive days. Steroid-resistant rejections were treated with anti-T cell therapy, either rabbit polyclonal antithymocyte globulin (ATG) or a mouse anti-CD3 monoclonal antibody (WT32) (8). If patients in one of the withdrawal groups needed anti-T cell rejection treatment, therapy with CsA or Pred was reinstituted. CMV prophylaxis with ganciclovir or CMV hyperimmune globulin was prescribed during anti-T cell therapy in patients at risk for CMV disease (donor and/or recipient seropositive).
Assessments
At baseline, the medical history, physical examination, routine laboratory tests, lipid profile, and histocompatibility data were obtained. Vital signs, body weight, and the results of routine laboratory measurements were recorded every month. Data on rejection episodes, CsA nephrotoxicity, concomitant medication, adverse events, and infections were gathered throughout the entire study period. CsA whole blood levels were measured with a monoclonal antibody against the CsA parent molecule, using the fluorescence-polarization immunoassay on an Abbott TDx analyser (Abbott Laboratories, North Chicago, IL) or with an enzyme-multiplied immunoassay on a COBAS-MIRA analyser (Dade-Behring, San José, CA). A biopsy was performed in cases of deteriorating graft function without an obvious prerenal or postrenal cause, suspected CsA nephrotoxicity, or in cases of increasing proteinuria. No protocol biopsies were performed.
Biopsies were examined by the local pathologist and were classified according to the Banff 1993 biopsy scoring system (grade 1, mild rejection; grade 2, moderate rejection; grade 3, severe rejection) (9). Patients were presumed to have acute rejection if antirejection treatment without prior biopsy resulted in a decrease in serum creatinine without an obvious prerenal or postrenal cause. The creatinine clearance was estimated according to the Cockcroft and Gault method (10). Infections were classified by using the Centers for Disease Control definitions for nosocomial infections (11).
Statistical Analyses
Primary end points for analysis were first biopsy-proven acute or chronic rejection between 6 mo (i.e., time of randomization) and 24 mo after transplantation. Secondary end points were patient and graft survival, renal function at 1 and 2 yr after transplantation, the incidence of infections and malignancies, and changes in BP and lipid metabolism.
Data were analyzed on an intention-to-treat basis. For comparisons of numerical data within groups, a paired nonparametric test was performed (Wilcoxon signed rank test). When appropriate, a t test was performed. For comparisons of numerical data among different groups, a nonparametric ANOVA was performed (Kruskal-Wallis test). Comparison of time to first biopsy-proven acute rejection was performed using the Kaplan-Meier procedure with log rank testing. Multiple logistic regression analysis was performed to determine risk-factors associated with the occurrence of acute rejection after randomization. The following variables were entered: gender, age, panel reactive antibodies (PRA), number of transplantation, postmortal or living donor, number of HLA mismatches, serum creatinine at randomization, biopsy-proven rejection during the first 6 mo, and randomization group.
A second analysis, on treatment, was performed for renal function at 1 and 2 yr after transplantation and changes in lipid metabolism at 2 yr after transplantation. For renal function, patients with or without calcineurin inhibitors were compared; comparison among groups was performed with a Mann-Whitney test, and a repeated measurements analysis (general linear model) was performed to exclude a putative influence of a baseline difference between the two groups. Comparison of numerical data for changes in lipid metabolism was performed with nonparametric ANOVA (Kruskal-Wallis test).
Results are given as median with range or as mean with SD, unless stated otherwise. P < 0.05 was considered statistically significant; all tests were two-sided. Calculations were performed using the software programs, SPSS 8.0 for Windows (SPSS Inc., Chicago, IL) and Graphpad Instat, version 3.00 for Windows (Graphpad Software Inc., San Diego, CA).
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Results |
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Acute Rejections
In Table 2, all first biopsy-proven acute rejections after randomization are shown. The incidence of acute rejection was significantly higher after withdrawal of CsA than after withdrawal of steroids or during continuation of triple therapy. As depicted in Figure 1, most rejections occurred within 3 mo after conversion from triple to double therapy. The median time from randomization to first biopsy-proven acute rejection was 74 d (26 to 244 d) and 72 d (22 to 211 d) for the CsA and Pred withdrawal groups, respectively.
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In the CsA withdrawal group, there were two patients with a presumed acute rejection. No biopsy was performed in these two patients, but a course of methylprednisolone resulted in recovery of the serum creatinine to initial values. Of the nine patients who tapered their CsA dosage during a 9-wk period, only one patient developed a biopsy-proven acute rejection. However, this was not significantly different from the rejection incidence (13 of 54) in patients who discontinued CsA in 2 wk. A second biopsy-proven acute rejection occurred in five patients in the CsA withdrawal group; in three of five cases, this second acute rejection was steroid-resistant. One patient in the CsA withdrawal group was treated with methylprednisolone for a presumed second rejection (not biopsy-proven). In the Pred withdrawal group, one patient developed a second biopsy-proven acute rejection that responded to treatment with methylprednisolone. There were no presumed rejections in this group.
The only patient randomized for triple drug therapy who developed an acute rejection had stopped MMF 9 d earlier because of side effects.
Chronic Rejections and CsA Nephrotoxicity
In the CsA withdrawal group, nine patients had a biopsy showing histologic changes compatible with chronic rejection. In five of these patients, there were no concomitant signs of acute rejection. The incidence of biopsy-proven chronic rejection in the CsA withdrawal group (9 of 63) was significantly higher than in the control group (1 of 73; P = 0.006). Four patients in the Pred withdrawal group had histologic evidence of chronic rejection, and two of these patients had concomitant acute rejection. When comparing the incidence of chronic rejection in biopsies only, there was no statistically significant difference among all groups; 9 of 33 versus 4 of 19 versus 1 of 9 for the CsA and Pred withdrawal and control groups, respectively.
Histologic changes compatible with CsA nephrotoxicity were present in one patient in the CsA withdrawal group, in three patients in the Pred withdrawal group, and in four patients in the control group.
Graft Failure, Patient Death, and Treatment Failure
Graft failure without patient death occurred in 2 of 63 patients in the CsA withdrawal group. The cause of graft failure was chronic rejection in both patients. Graft failure, without patient death, occurred once in the Pred withdrawal group because of chronic rejection. In 2 patients in the control group, immunosuppressive medication was stopped completely, followed by graft failure. The reasons for cessation of immunosuppressive medication were severe myositis and posttransplant lymphoma (the latter patient died 2 mo later). Patient death with functioning graft only occurred in the groups continuing CsA (3 of 149). In one case, the cause of death was documented myocardial infarction; two patients were found dead at home, presumably as a result of fatal myocardial infarction (Table 3). Treatment failure, defined as changes in immunosuppressive therapy or reinstitution of the discontinued drug, resulted from various causes (Table 4). In the CsA withdrawal group, calcineurin inhibitors were mostly restarted after acute rejection episodes requiring anti-T cell therapy (protocol driven). Pred withdrawal was uneventful for almost all patients.
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At randomization, proteinuria (>0.5 g/d) was present in 18% of patients in the CsA withdrawal group, 16% in the Pred withdrawal group, and 15% in the control group. After 18 mo of follow-up, these percentages were 18% in the CsA withdrawal group compared with 20% in the Pred withdrawal group and 12% in the control group (no significant differences or changes).
In Table 6, the results regarding BP are shown. Only in the Pred withdrawal group was a statistically significant reduction in mean arterial pressure observed without a concomitant increase in the number of antihypertensive drugs.
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Lipid Metabolism
To appreciate the immediate as well as the chronic effects of withdrawal of CsA and Pred on lipid metabolism, values at the time of randomization are compared with those obtained at 3 mo and at 18 mo after randomization (Table 8). The withdrawal of either CsA or Pred was followed by a rapid fall in total cholesterol levels. However, discontinuation of Pred also resulted in a transient significant decrease in HDL-cholesterol. Consequently, there was an unbeneficial rise in the total/HDL cholesterol ratio in this group 3 mo after randomization. Among the three groups, there was an equally distributed percentage of patients treated with cholesterol-lowering drugs (mostly statins).
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Discussion |
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In our study, the patients discontinuing CsA had the highest incidence of acute rejection (22%), and these acute rejections were severe (
grade II) in 9 of 14 cases. Severe acute vascular rejections are known to have a poor prognosis for long-term graft survival (21). Our data are in variance with the results of a recent meta-analysis by Kasiske et al. (22), which reported a risk for acute rejection after CsA withdrawal of 11% without increased graft loss during long-term follow-up (>5 yr). A possible contributing factor to the increased incidence of biopsy-proven rejections in our study might be the rapid CsA withdrawal. Although no significant difference was observed in our study between patients with two different withdrawal-schedules, lower rejection rates have been described with a longer period of stepwise CsA withdrawal (18,23). Despite the higher incidence of acute rejections after discontinuation of CsA, no detrimental effect on creatinine clearance was noted. This might be caused by a simultaneously occurring disappearance of CsA-associated nephrotoxicity during the first 3 mo after withdrawing CsA. The on-treatment analysis of patients with or without calcineurin inhibitors confirmed the positive effect of CsA withdrawal on renal function.
Pred withdrawal did not increase the incidence of acute rejection episodes compared with the control group. Similar results were previously reported by Grinyó et al. (24), although the risk for acute rejection after Pred withdrawal was 14% in a meta-analysis (22). However, the continuation of CsA and MMF was not used as baseline immunosuppression after Pred withdrawal in most studies included in this meta-analysis.
Two multicenter trials of Pred withdrawal from 3 mo after kidney transplantation in patients maintained on CsA and MMF demonstrated an incidence of acute rejection at 1 yr after transplantation of 30.8% (US trial) and 25% (European trial), respectively (17,25). The US trial had the highest incidence of acute rejection in African Americans (39.6%) compared with 16% in non-African Americans (25). Possible explanations for the lower incidence of acute rejections between our study and the US and the European trials might be the time of Pred withdrawal after transplantation (6 mo versus 3 mo) and how rapidly Pred was withdrawn (10 wk versus 8 wk). No African Americans were present in our study. No induction therapy was given in our study, in contrast to 27% of patients in the US and in the European trial. However, no protective effect of induction therapy could be demonstrated in the US trial (underpowered test). The European trial demonstrated an incidence of biopsy-proven acute rejection of 16% compared with 27% in the withdrawal patients with or without induction therapy, respectively, a difference that was not statistically significant (17).
There appears to be an increased incidence of chronic rejection in the CsA withdrawal group compared with the other groups. It must be stressed however that there was a substantially higher number of biopsies performed in the CsA withdrawal group and the indication for the biopsies was the suspicion of an acute rather than a chronic rejection in most cases.
Although no significant differences exist in patient survival among groups, the causes of death were cardiovascular in patients continuing CsA. In the Pred withdrawal group, there was a significant decrease in mean arterial pressure without the need for more medication; patients continuing triple therapy required more antihypertensive medication to prevent a rise in mean arterial pressure. This positive effect of Pred withdrawal on BP has previously been reported for patients withdrawing prednisone at 3 mo or 1 yr after kidney transplantation (26,27). Long-term follow-up data (>5 yr) of patients withdrawing CsA from 3 mo after transplantation showed less cardiovascular deaths, less hypertension, and better renal function compared with patients continuing CsA (28). In our study, withdrawal of CsA was also followed by a decrease in mean arterial pressure, but this was achieved by an increase in antihypertensive medication. As a consequence of the intention-to-treat analysis, the effects of discontinuation of CsA are obscured by the proportion of patients in whom this drug was reintroduced (29%). In conversion studies with patients switching from CsA to azathioprine or MMF, beneficial effects on BP and lipid profile were also noted (18,26,29).
Three months after withdrawing either CsA or Pred, a substantial decrease in total cholesterol was observed. However, a more favorable cardiovascular risk-profile, reflected by a lower total/HDL cholesterol ratio, was only present in the CsA withdrawal group at 3-mo follow-up. There were no statistically significant differences in lipid parameters among the three groups at the end of follow-up. This may be due to the fact that >15% of the patients in all groups used cholesterol-lowering drugs. It should furthermore be noted that 77% of patients used calcineurin inhibitors at that time. On-treatment analysis of changes in the total cholesterol from randomization until the end of follow-up only demonstrated a beneficial effect for patients withdrawing Pred.
There was no evidence of over-immunosuppression or an increased cardiovascular risk in these patients, although the follow-up period of 18 mo does not allow firm conclusions regarding these issues.
Do the results of our study help decide which immunosuppressive regimen is preferred as maintenance therapy? The relatively short follow-up of 18 mo potentially underestimates the benefits of improving the cardiovascular risk-profile in the CsA and Pred withdrawal groups. Likewise, CsA-induced interstitial fibrosis with subsequent loss of renal function may only become apparent after prolonged use of this drug. Nevertheless, the increased number of acute rejections in the CsA withdrawal group could deter clinicians from following this strategy. There is a clear need for screening tests that identify those patients at increased risk for acute rejection after tapering of immunosuppressive medication. We recently showed that measurement of the frequency of precursor cytotoxic T lymphocytes in peripheral blood allows the identification of a subgroup of patients in whom tapering of immunosuppression was safe (30,31). In the future, such tests may aid physicians not only in the selection of patients in whom drug treatment can be tapered but also to know which degree the level of immunosuppression can be reduced in the individual patient.
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