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J Am Soc Nephrol 12:1750-1757, 2001
© 2001 American Society of Nephrology

A Controlled Trial Comparing Two Doses of Cyclosporine in Conjunction with Mycophenolate Mofetil and Corticosteroids

RUUD G. L. DE SÉVAUX*, PETER J. H. SMAK GREGOOR{dagger}, RONALD J. HENÉ{ddagger}, ANDRIES J. HOITSMA*, PIETER VOS{ddagger}, WILLEM WEIMAR{dagger}, TEUN VAN GELDER{dagger} and LUKAS B. HILBRANDS*

* Department of Nephrology, University Hospital of Nijmegen, The Netherlands.
{dagger} Department of Nephrology, University Hospital of Rotterdam, The Netherlands.
{ddagger} Department of Nephrology, University Hospital of Utrecht, The Netherlands.

Correspondence to Dr. Ruud de Sévaux, Department of Nephrology, University Hospital Nijmegen, P.O. Box 9101; 6500 HB Nijmegen, The Netherlands. Phone: +31-24-3614761; Fax: +31-24-3540022; E-mail: R.deSevaux{at}nefro.azn.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Abstract. It is unknown whether the addition of mycophenolate mofetil (MMF) to cyclosporine (CsA) and prednisone after renal transplantation (RTx) allows for a reduced dose of CsA, to minimize the incidence of CsA-related side effects and to reduce costs. Therefore, 313 renal allograft recipients were randomized for treatment with MMF (1000 mg twice a day), prednisone, and either conventional- or low-dose CsA during the first 3 mo after RTx. The target trough levels were 300 and 150 ng/ml, respectively, during the first 3 mo and 150 ng/ml in both groups thereafter. A total of 313 patients were included: 161 patients received a conventional dose and 152 received a low dose of CsA. During the first 6 mo after RTx, graft failure or patient death occurred in 19 of 161 patients (12%) in the conventional-dose group and in 11 of 152 patients (7%) in the low-dose group (not significant). Biopsy-proven acute rejection occurred in 36 of 161 patients (22%) in the conventional-dose group and in 29 of 152 patients (19%) in the low-dose group (not significant). The incidence of delayed graft function was similar in both groups (31 of 161 [19%] versus 28 of 152 [18%]; not significant). Serum creatinine did not differ between the conventional- and the low-dose groups: 151 ± 56 µmol/L versus 142 ± 49 µmol/L at 3 mo and 141 ± 60 µmol/L versus 136 ± 49 µmol/L at 6 mo. There were no differences between the groups regarding BP, lipid metabolism, and infectious complications. In the low-dose group, an estimated $500 per patient was saved on the costs of CsA. In conclusion, the addition of MMF to CsA and prednisone after RTx allows the use of a lower-than-conventional dose of CsA, without increasing the risk of rejection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
The addition of mycophenolate mofetil (MMF) to a standard immunosuppressive regimen consisting of cyclosporine (CsA) and prednisone has led to a major reduction in the rejection rate during the first 6 mo after renal transplantation (RTx) (1,2,3,4). In the three so-called "pivotal" trials, designed to investigate the efficacy of MMF when added to standard therapy, patients were treated with a full dose of CsA. Although there was no clear increase in the incidence of side effects related to overimmunosuppression, the results gave rise to concerns regarding the long-term safety of this triple-drug regimen (1,2). One possible way to reduce the risk of overimmunosuppression is to lower the standard dose of CsA. If this would not hamper the efficacy of the triple-drug regimen, then it might have the additional benefit of a reduction in CsA-related side effects, such as nephrotoxicity, hypertension, and delayed graft function, which frequently complicate the course after RTx. With a reduced CsA dose, the differentiation between rejection and CsA nephrotoxicity also might be easier. Finally, a reduction of the CsA dose might compensate partly for the increase in costs of medication, caused by the addition of MMF. In this multicenter, open-label trial, recipients of a renal allograft were randomized to treatment with a conventional dose or with a low dose of CsA, in combination with MMF and prednisone.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Patients
Adult recipients of a first or second RTx from a living related or cadaveric donor were eligible for this study. Excluded were recipients of a graft from an HLA-identical living related donor or a non—heart-beating donor; patients who had liver function disturbances, peptic ulcer, diarrhea, leukocytopenia, or thrombocytopenia; patients who had a hemolytic uremic syndrome as original renal disease; women who were not using adequate contraception, and patients who were taking immunosuppressive medication other than corticosteroids at the time of RTx.

The study design was approved by the institutional review boards of the three participating hospitals, and written informed consent was obtained from all participants before RTx.

Immunosuppression
During the first two postoperative days, CsA was given intravenously in a dose of 3 mg/kg per d in the conventional-dose group and 2 mg/kg per d in the low-dose group. From the third postoperative day, CsA was given orally (starting dose, 10 and 6 mg/kg per d, respectively) and was dosed to reach a target trough level during the first 3 mo of 300 ng/ml (250 to 350) in the conventional-dose group and of 150 ng/ml (125 to 175) in the low-dose group. From 3 to 6 mo after RTx, the target trough level was 150 ng/ml in both groups. Interruption of CsA treatment was allowed for a maximum of 28 d. The microemulsion formulation of CsA (Neoral; Novartis, Arnhem, The Netherlands) was used in all patients. CsA whole blood levels were measured with a monoclonal antibody against the CsA parent molecule, using the fluorescence-polarization immunoassay on an Abbott TDx analyzer (Abbott Laboratories, North Chicago, IL) or an enzyme-multiplied immunoassay technique on a COBAS-MIRA analyzer (Dade-Behring, San Jose, CA).

MMF was administered in a fixed dose of 1000 mg twice a day. Dose reduction or interruption of MMF treatment was allowed in cases of leukocytopenia, primary cytomegalovirus (CMV) infection, or severe gastrointestinal side effects. A reduction in the dose of MMF to <1000 mg/d during more than 14 d was considered a violation of the treatment protocol.

Prednisone was given 100 mg intravenously during the first 3 d, followed by an oral dose of 0.4 mg/kg per d from days 4 to 14 and then tapering gradually to 0.1 mg/kg per d at 3 mo; this last dose was continued thereafter. Induction therapy with anti—T-cell preparations was not used.

Rejections were treated primarily with methylprednisolone 1000 mg intravenously for three consecutive days. In cases of steroid-resistant rejection, anti—T-cell therapy was given (either rabbit polyclonal antithymocyte globulin or the mouse anti-CD3 monoclonal antibody WT32 (5)). When patients in the low-dose group needed anti—T-cell treatment during the first 3 mo after RTx, they were treated subsequently with the conventional dose of CsA.

Additional Medication
All patients received prophylaxis for peptic ulcers (famotidine 20 mg or ranitidine 150 mg once daily) and Pneumocystis carinii pneumonia (cotrimoxazole 480 mg once daily). CMV prophylaxis with ganciclovir or CMV hyperimmune globulin was prescribed during anti—T-cell therapy in patients who were 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. Every month, vital signs, body weight, and the results of routine laboratory measurements were recorded. Data on rejection episodes, CsA nephrotoxicity and dialysis requirements, concomitant medication, adverse events, and infections were recorded throughout the entire study period. A biopsy was performed in cases of deteriorating graft function without an obvious pre- or postrenal cause. No protocol biopsies were performed.

Biopsies were examined by the local nephropathologist and were classified according to the Banff 1993 biopsy scoring system (borderline, grade 1 (mild), grade 2 (moderate), and grade 3 (severe) rejection) (6). Delayed graft function was defined as the need for one or more dialysis sessions more than 24 h after RTx. For calculation of the creatinine clearance, the 24-h urinary creatinine excretion and serum creatinine were measured. Infections were classified using the Centers for Disease Control and Prevention's definitions for nosocomial infections (7). CMV disease was defined as mild in cases of fever for more than 3 d with leuko- or thrombocytopenia or liver function disturbances; in cases of proven organ localization, CMV disease was defined as severe.

A questionnaire that assessed the severity of known side effects of immunosuppressive drugs on a semiquantitative scale was completed by the patient at 1, 3, and 6 mo (see Appendix).

Randomization Procedure
Shortly before RTx, patients were assigned randomly to one of the treatment groups in a 1:1 ratio, with stratification for cadaveric/living related RTx and for center. Randomization was carried out by opening a sealed envelope with the lowest available study number.

End Points
The primary end points were the incidence of biopsy-proven acute rejection (Banff grade 1 or higher) and of CsA nephrotoxicity during the first 3 mo after RTx. CsA nephrotoxicity was defined as an otherwise unexplained rise in serum creatinine of more than 15% above the previous level, which was reversible after lowering of the CsA dose. Secondary end points included time to first acute rejection, number of acute rejections within the first 3 mo, number of biopsies, incidence and duration of delayed graft function, and graft function at 1 and 3 mo. All end points also were assessed at 6 mo after RTx.

Statistical Analyses
Results are given as mean ± SD unless stated otherwise. The statistical analyses were performed on an intention-to-treat basis.

Comparison of continuous variables between the groups was performed using the Wilcoxon rank sum test. Categorical variables were analyzed with the {chi}2 test. Comparison of time to first rejection was performed using the Kaplan-Meier procedure with Log Rank testing. P < 0.05 was considered significant. Calculations were performed using the SAS system, version 6.12 (SAS Institute, Cary, NC) and Graphpad Instat, version 3.00 for Windows (Graphpad Software Inc., San Diego, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Between January 1, 1997, and December 31, 1998, 313 patients were enrolled. The demographic data of these patients are summarized in Table 1; no significant differences existed between the groups.


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  		Table 1. Patient and donor characteristicsa
 

CsA Levels
During the first 3 mo, mean CsA levels exceeded the target levels in both groups, despite frequent dose reductions (Table 2). Nevertheless, in accordance with the design of the study, CsA levels were significantly different between both groups during the first 3 mo after RTx. However, some overlap in CsA levels between the groups existed; approximately 25% of levels in the conventional-dose group fell below the 75th percentile of the low-dose group during the first 3 mo. Despite a similar CsA dose in both groups from 3 mo after RTx, CsA levels remained slightly higher in the conventional-dose group. At 6 mo after RTx, both CsA dose and CsA level were not significantly different between groups (Table 2).


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  		Table 2. CsA level and dose during the first 6 mo after transplantation (median and 25th to 75th percentile)
 

Rejections and Biopsies
The incidence of biopsy-proven rejection within the first 6 mo was 36 of 161 (22%) in the conventional-dose group and 29 of 152 (19%) in the low-dose group (not significant). The histologic severity of these biopsy-proven rejections was not different between the groups (Table 3). Moreover, the median time to the first acute rejection episode was similar in both groups: 15 and 9 d, respectively (not significant; Figure 1).


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  		Table 3. Rejection episodes during the first 6 mo after transplantation
 


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  		Figure 1. Rejection-free survival in the conventional dose (-) and the low-dose (- - -) groups (Kaplan-Meier curves).

 

The incidence of presumed rejections was similar in both groups (conventional dose, 15 of 161 [9%]; low dose 10 of 152 [7%]), as was the incidence of borderline biopsies (7 of 161 [4%] and 8 of 152 [5%], respectively) (Table 3).

Treatment for a biopsy-proven or a presumed rejection was given in 58 of 161 patients (36%) in the conventional-dose group and in 45 of 152 patients (30%) in the low-dose group (not significant; Table 3). In all but four cases, first-line anti-rejection treatment consisted of a course of methylprednisolone. Treatment with one course of methylprednisolone was sufficient in 38 of 58 patients (66%) in the conventional-dose group and 30 of 45 patients (67%) in the low-dose group. In 4 patients in the conventional-dose group and 1 patient in the low-dose group, additional corticosteroids were administered. In 14 of 58 patients (24%) in the conventional-dose group and 12 of 45 patients (27%) in the low-dose group, methylprednisolone treatment was followed by anti—T-cell therapy because of steroid-resistant rejection. Two patients in each group were treated primarily with anti—T-cell therapy.

In 11 patients in the conventional-dose group and in 12 patients in the low-dose group, one or more subsequent rejection episodes occurred; in 8 and 9 patients, respectively, these second rejections were biopsy proven. Anti—T-cell treatment for a recurrent rejection episode was needed in 5 patients in each group.

Graft Failure, Patient Death, and Protocol Failure
Within 6 mo after RTx, graft failure occurred in 14 of 161 patients (9%) in the conventional-dose group and in 8 of 152 patients (5%) in the low-dose group (not significant). The reasons for graft loss were not different between groups and included ongoing rejection (four in conventional-dose group, two in low-dose group), vascular thrombosis (five in conventional-dose group, two in low-dose group), primary nonfunction (two in conventional-dose group, four in low-dose group), and other causes (three in conventional-dose group, zero in low-dose group).

Patient death with functioning graft occurred in 5 of 161 (3%) patients in the conventional-dose group and in 3 of 152 (2%) patients in the low-dose group (not significant). Causes of patient death were not different between groups and included cardiovascular events (two versus one), infections (one versus zero), and other reasons (two versus two).

In 27 of 161 patients (17%) in the conventional-dose group and in 20 of 152 patients (13%) in the low-dose group, cessation or interruption of one or more of the immunosuppressive drugs was judged necessary for clinical reasons. CsA was discontinued in 15 and 11 patients, MMF in 6 and 8 patients, CsA + MMF in 4 and 1 patients, and prednisone in 2 and 0 patients, respectively. In 6 of 27 and 3 of 20 patients with treatment failure, graft failure or death with functioning graft occurred subsequently (not significant).

Altogether, treatment with the combination of CsA, MMF, and prednisone was continued during the 6-mo study period in 121 of 161 patients (75%) in the conventional-dose group and in 124 of 152 patients (82%) in the low-dose group (not significant).

Graft Function and BP
The incidence of delayed graft function was equal in the conventional- and the low-dose groups: 31 of 161 (19%) versus 28 of 152 (18%) patients (not significant). The median duration of dialysis treatment in these patients also was similar in both groups: median, 7 d (ranges, 1 to 35 and 1 to 55 d, respectively; not significant). At all time points during follow-up, serum creatinine and calculated creatinine clearances and proteinuria were comparable in both groups (Table 4).


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  		Table 4. Graft function and BP at 3 and 6 mo after transplantation
 

According to the criteria given in the Materials and Methods section, episodes of CsA nephrotoxicity occurred in 13 of 161 patients (8%) in the conventional-dose group and in 4 of 152 patients (3%) in the low-dose group (P = 0.06).

Episodes of graft dysfunction that resulted in performing a biopsy tended to occur more frequently in the conventional-dose group (number of biopsies per patient, 0.65 versus 0.49; P = 0.09). To examine whether episodes of CsA-induced graft dysfunction might have contributed to this finding, we compared the biopsy results between both groups. The number of biopsies that showed no histologic abnormalities, which is compatible with the presence of the acute, reversible form of CsA-induced renal dysfunction, was higher in the conventional-dose group (13 versus 1% of all biopsies; P = 0.02).

Throughout the study period, there were no differences between the groups regarding BP or the number of antihypertensive drugs (Table 4).

Safety and Costs
Within the first 6 mo after RTx, there were no cases of post-RTx lymphoproliferative disease or other malignancies.

The number of infections per patient was equal in both groups (1.7 ± 0.7 per patient). The most frequent infections were urinary tract infections (34 and 38 episodes), oral candidiasis (14 and 12 episodes), and CMV infection. The overall incidence of CMV disease was 31 of 161 patients (19%) in the conventional-dose group and 35 of 152 patients (23%) in the low-dose group (not significant). When analyzed per serologic donor—recipient combination, there also were no differences between the two groups in the incidence or the severity of CMV disease.

During the first 6 mo after RTx, there were no significant differences between the conventional- and the low-dose groups in total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol and lipoprotein(a).

The number of patients who experienced at least one recorded adverse event was similar in both groups: 74 and 78%, respectively (not significant). Diabetes mellitus developed in six patients in both groups. Liver function disturbances were rare, occurring in fewer than 2% in both groups.

The questionnaire revealed no significant differences in the incidence or in the severity of drug-related side effects (Table 5)


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  		Table 5. Questionnaire: percentage of patients who noticed a specific side effect at a certain time point (most frequent side effects only, i.e., >50% of patients reporting the side effect)
 

An estimation of the savings on the costs of CsA, based on an actual price of $4/100 mg CsA, revealed that cost savings in the low-dose group amounted to approximately $500 during the first 6 mo after RTx, which means a reduction by 20%.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
The results of this prospective trial indicate that in RTx patients who are treated with the combination of CsA, MMF, and prednisone, prescribing a lower-than-usual dose of CsA does not increase the incidence or the severity of acute rejections. Previous studies demonstrated that in the setting of double therapy with steroids or triple therapy with azathioprine and steroids, lower CsA levels are associated with an increased risk of acute rejection (8,9). Our findings suggest that the more recently introduced immunosuppressive drug MMF can exert a so-called "CsA-sparing" effect. Recently, a similar CsA-sparing effect was observed when rapamycin was added to the combination of CsA and steroids (10).

Although CsA levels were measured frequently and doses were adjusted repeatedly to reach the desired range, mean CsA trough levels in both groups somewhat exceeded the target, especially during the first 3 mo. Apparently, to reach trough levels of CsA of 300 and 150 ng/ml, respectively, the starting dose of CsA should be lower than was prescribed in our protocol (10 and 6 mg/kg per d). Nevertheless, in agreement with the aim of the study protocol, there was a significant and potentially meaningful difference in CsA levels and doses between the two groups during the first 3 mo. Furthermore, nearly 80% of all included and analyzed patients were treated according to the study protocol during the full 6 mo. Taken together, it seems unlikely that insufficient adherence to the study design obscured a conceivable detrimental effect of a lower target CsA level on the rejection incidence.

The incidence of biopsy-proven acute rejection in our study population (22 and 19%, respectively) seems to be slightly higher than in the three so-called "pivotal" clinical trials with MMF, in which an incidence of acute rejection of 17 to 20% was found (1,2,3). Several factors might be responsible for this difference: the use of induction therapy (1), a considerably higher corticosteroid dose (1,3), a much higher CsA dose, or a combination of these factors (1,2) in these three studies. However, a concise comparison with regard to these factors cannot be made, as the exact dosing schedules of prednisone and CsA were not described in two of these three studies. Nevertheless, despite this slightly higher rejection incidence in our study, patient and graft survivals in our study were comparable to the survival data in the three "pivotal" studies.

When designing the study protocol, we expected to find a difference in the incidence of CsA-related side effects between the treatment groups.

Several studies indicate that the avoidance of CsA during the first days after RTx, by treating the patients with induction therapy with antilymphocyte antibodies, results in an earlier recovery of delayed graft function and an overall better graft function (11). The same could be true for the use of a low dose of CsA early after RTx (12). In this study, however, we did not find a difference in the incidence or duration of delayed graft function or in the duration of dialysis between the groups. Nevertheless, some findings indicated a beneficial effect of a lower CsA dose on graft function. First, according to predefined criteria, there were fewer episodes of CsA nephrotoxicity. Second, the number of biopsies was lower in the low-dose group, and this could be attributed largely to a reduction in the number of biopsies that showed no abnormalities. As the finding of a histologically normal transplant biopsy in the setting of a rise in creatinine is highly suggestive of acute CsA-induced renal dysfunction, it seems that the use of a low dose of CsA can help to avoid this latter condition.

The use of CsA is frequently accompanied by side effects such as hypertension, hyperlipidemia, neurologic symptoms, and hirsutism, requiring additional therapy in the majority of RTx patients (13). The incidence of these side effects possibly could be lowered by reducing the dose of CsA. However, in our study, BP, the number of antihypertensive drugs, cholesterol levels, the incidence of adverse events, and the severity of side effects as reported in the patient questionnaire did not differ between groups.

A possible explanation for the lack of differences in rejection incidence and side effects is that although the CsA trough levels for the two groups were different, the area under the curve (AUC) of CsA may have been highly variable for individual patients. It is now widely known that trough levels and AUC are only weakly correlated, even for the microemulsion preparation (14), and that the total exposure to CsA, represented by the AUC of CsA, has a better correlation with the acute rejection incidence and early graft survival than trough levels of CsA (8,14). However, repeated measurement of AUC is very laborious. A promising approach is the monitoring of CsA dose on the basis of mini-AUC or 2-h postdose levels (15). This possibly would have given us a better separation between the two groups and a better chance of finding differences in rejection incidence or CsA-related side effects.

From the start of this study, standard treatment of RTx patients in the participating centers was changed from CsA+prednisone to triple therapy with CsA, prednisone, and MMF. It was our impression that this switch to triple therapy significantly increased CMV-related morbidity, with gastrointestinal localizations being the most prominent finding. In a subsequent retrospective analysis of patients who were at risk for a primary CMV infection, it was found that the addition of MMF did not affect the incidence of CMV infection but did increase the risk of developing CMV disease (16). Like many other centers, we now routinely use ganciclovir prophylaxis in CMV-seronegative patients who receive a graft from a CMV-seropositive donor.

By lowering the CsA dose, a significant reduction of $500 per patient in the costs of CsA could be obtained. However, the overall effect of the introduction of MMF on the costs of RTx remains uncertain, because the addition of MMF leads to a major increase in the costs of immunosuppressive maintenance therapy. Conversely, by lowering the rejection rate, substantial savings in the costs of hospitalization and anti—T-cell therapy can be achieved. A formal pharmacoeconomic analysis is required to evaluate the cost-benefit balance of the use of MMF more thoroughly (17).

The results obtained in this study could be flattered by the use of a selected study population. However, the three participating centers together perform approximately half of all RTx in The Netherlands, and in each of the centers more than 90% of all eligible patients agreed to participate in the study. Furthermore, several patient categories known to have a higher risk for acute rejection (e.g., second RTx or the presence of preformed HLA antibodies) were included in the study. Because of the composition of our general population, however, the number of black patients, known to have a higher risk for acute rejection, too (18), was small (<5%). Taken together, we think that our study group is representative of all of our RTx patients and that the risk of bias by using a selected population is very low.

In summary, we demonstrated that the addition of MMF to a standard immunosuppressive regimen consisting of CsA and prednisone allows the use of a lower-than-usual dose of CsA during the first 3 mo after RTx without increasing the risk of acute rejection. Besides some evidence for a decline in the incidence of CsA nephrotoxicity, the reduction in the CsA dose was not accompanied by an obvious decrease in CsA-related side effects. However, savings on drug expenditure would be a major benefit of widespread use of a lower CsA dose.


   Appendix
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Questions regarding side effects, caused by the use of CsA, MMF, and prednisone. The severity of side effects was scored by the patients on a semiquantitative scale: 0, absent; 1, slight; 2, mild; 3, severe.

  1. Fatigue
  2. Feeling weak
  3. Feeling ill
  4. Sleep disturbance
  5. Increased appetite
  6. Feeling obese
  7. Increased hair growth
  8. Swollen face
  9. Acne
  10. Dry or itchy skin
  11. Headache
  12. Dizziness
  13. Trembling of the hands
  14. Paresthesias of the hands
  15. Painful or stiff muscles
  16. Dyspnea
  17. Edema of the ankles
  18. Hematomas
  19. Gingival hypertrophy
  20. Gingival bleeding
  21. Nausea or vomiting
  22. Decreased appetite
  23. Pyrosis
  24. Upper abdominal pain
  25. Diarrhea
  26. Bone pain
  27. Fractures


   Acknowledgments
 
The results of this study were presented in part in part at the 17th annual meeting of the ASTP, may 1998, Chicago, IL, and the 31st annual meeting of the ASN, November 1998, Philadelphia, PA.

The authors thank M. van Helden for her expert assistance in collecting the data and Roche Pharmaceuticals, Mijdrecht, The Netherlands, for financial support.

This study was designed by L. Hilbrands and T. van Gelder. R. de Sévaux, P. Smak Gregoor, P. Vos, and R. Hené collected the data. Data analysis was performed by R. de Sévaux and L. Hilbrands. The first draft of the article was written by R. de Sévaux, L. Hilbrands, and P. Smak Gregoor. All authors contributed to the writing of the final manuscript.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

  1. Sollinger HW: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 60:225 -232, 1995[Medline]
  2. European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 345:1321 -1325, 1995[Medline]
  3. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 61:1029 -1037, 1996[Medline]
  4. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C: Mycophenolate mofetil in renal allograft recipients: A pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 63:39 -47, 1997[Medline]
  5. Tax WJ, van de Heijden HM, Willems HW, Hoitsma AJ, Berden JH, Capel PJ, Koene RA: Immunosuppression with monoclonal anti-T3 antibody (WT32) in renal transplantation. Transplant Proc19 : 1905-1907,1987[Medline]
  6. Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, Croker BP, Droz D, Dunnill MS, Halloran PF: International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney Int 44: 411-422,1993[Medline]
  7. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM: CDC definitions for nosocomial infections. Am J Infect Control 16:128 -140, 1988[Medline]
  8. Senel MF, Van Buren CT, Welsh M, Kahan BD: Impact of early cyclosporin average blood concentration on early kidney transplant failure. Transpl Int 11:46 -52, 1998[Medline]
  9. Lindholm A, Ohlman S, Albrechtsen D, Tufveson G, Persson H, Persson NH: The impact of acute rejection episodes on long-term graft function and outcome in 1347 primary renal transplants treated by 3 cyclosporine regimens. Transplantation 56:307 -315, 1993[Medline]
  10. Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J: Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: A phase II trial. Rapamune Study Group. Transplantation 68:1526 -1532, 1999[Medline]
  11. Canafax DM, Torres A, Fryd DS, Heil JE, Strand MH, Ascher NL, Payne WD, Sutherland DE, Simmons RL, Najarian JS: The effects of delayed function on recipients of cadaver renal allografts. A study of 158 patients randomized to cyclosporine or ALG-azathioprine. Transplantation41 : 177-181,1986[Medline]
  12. Barry JM, Shively N, Hubert B, Hefty T, Norman DJ, Bennett WM: Significance of delayed graft function in cyclosporine-treated recipients of cadaver kidney transplants. Transplantation45 : 346-348,1988[Medline]
  13. Kahan BD, Flechner SM, Lorber MI, Jensen C, Golden D, Van Buren CT: Complications of cyclosporin therapy. World J Surg10 : 348-360,1986[Medline]
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  15. Mahalati K, Belitsky P, Sketris I, West K, Panek R: Neoral monitoring by simplified sparse sampling area under the concentration-time curve: Its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation68 : 55-62,1999[Medline]
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Received for publication October 26, 2000. Accepted for publication December 6, 2000.




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