The long-term effect of switching from cyclosporin A to mycophenolate mofetil in chronic renal graft dysfunction compared with conventional management

Hélène François1, Antoine Dürrbach1,3, Mounia Amor1, Rachid Djeffal1, Fayçal Kriaa1, Valérie Paradis2, Pierre Bedossa2 and Bernard Charpentier1,3

1 Nephrology Unit and 2 Anatomopathology Unit, 94270 Le Kremlin-Bicêtre and 3 INSERM U542, 94800 Villejuif, France

Correspondence and offprint requests to: Antoine Dürrbach, Nephrology Unit, University Hospital of Bicêtre, 78 rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France. Email: antoine.durrbach{at}bct.ap-hop-paris.fr



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. To overcome toxicity of calcineurin inhibitors, recent trials have proposed substituting cyclosporin (CysA) with mycophenolate mofetil (MMF). No data concerning the long-term side effects and long-term renal outcome of this strategy have been published.

Methods. We retrospectively compared 39 renal transplant patients with chronic graft dysfunction who were subjected to CysA to MMF substitution (group 1) with 39 matched renal transplant patients who were continued on conventional management (group 2). The mean serum creatinine and the slope of deterioration of renal function before the date of the therapeutic intervention (T0) were similar in both groups. Follow-up in both groups was 76 ± 42 months before T0 and 44 ± 11 months after T0.

Results. In group 1, conversion was associated with a decrease of mean serum creatinine concentrations from 192 to 172 µmol/l at 1 year (P = 0.004) and 159 µmol/l at 3 years (P < 0.003) after T0, whereas it remained unchanged in group 2. The systolic blood pressure decreased in group 1 from 155 mmHg before T0 to 145 mmHg at 1 year (P < 0.01) and 133 mmHg at 3 years (P < 0.001) without any increase of the antihypertensive drug, whereas it did not change in group 2. Lipid profile tended to improve in group 1 after T0 and was unchanged in group 2. None of the patients in group 1 developed acute rejection after T0, whereas two acute rejections occurred in group 2. Graft survival, however, was similar in both groups. In group 1, several side effects occurred related to MMF treatment, and led to its discontinuation in two cases and the reduction of its dose for 18 patients (64%).

Conclusion. CysA/MMF substitution improves renal function and blood pressure in chronic allograft dysfunction when compared with conventional management. However, CysA/MMF substitution is associated with a high rate of MMF-related side effects, requiring modulation of its dose.

Keywords: cyclosporin A; graft dysfunction; mycophenolate mofetil; substitution



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The use of cyclosporin A (CysA), a calcineurin inhibitor, has significantly decreased the rate and the severity of early acute rejections in renal transplant recipients. Consequently, the 1-year survival rate of kidney grafts has improved since its introduction in 1982 [1,2]; however, contrary to expectations, graft half-life has not improved concomitantly. Chronic graft dysfunction related to chronic rejection or calcineurin inhibitor nephrotoxicity, or both, explains why the long-term survival rate of transplanted kidneys did not improve as much as expected. Newly developed immunosuppressive drugs, some of which have less pronounced nephrotoxicity, may reduce chronic dysfunction. When used in association with CysA and steroids, mycophenolate mofetil (MMF), an inosine monophosphate dehydrogenase inhibitor, efficiently prevents acute rejection [35]. In addition, in vitro studies and animal models of chronic allograft vasculopathy have shown that MMF inhibits the proliferation of vascular smooth muscle cells [6]. Such proliferations have been observed in the small arteries of the kidney during chronic renal dysfunction. Thus, MMF may be an interesting drug for treating and preventing chronic allograft nephropathy and for reducing calcineurin inhibitor nephrotoxicity. Preliminary reports have demonstrated that switching from CysA to MMF (CysA/MMF conversion) is associated with improved renal function, blood pressure control and lipid profiles in patients with chronic renal dysfunction [711]. However, the long-term benefits and side effects of CysA/MMF conversion have yet to be widely studied, particularly in patients with impaired renal graft function and in late substitutions. Side effects such as diarrhoea and bone marrow suppression could limit the use of MMF by decreasing treatment compliance and efficacy. Moreover, CysA/MMF conversion after transplantations could lead to over-immunosuppression, especially when treatment overlap is prolonged, and may facilitate the development of infections and malignancies—although this problem has not been reported in published short-term trials. On the other hand, the rapid withdrawal of CysA may be associated with an insufficient immunosuppression leading to acute graft rejection. In addition, previous studies included no control groups, making it impossible to compare the natural histories of the two types of management. The aim of this study was to determine whether or not CysA/MMF conversion is safe and improves renal function, cardiovascular risk factors (blood pressure, lipid profile) and long-term renal outcome in renal transplant recipients with chronic graft dysfunction.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
MMF group (group 1)
We retrospectively studied two groups of patients who were selected from our database and matched for age, transplantation date, renal function and renal function deterioration slope. Between December 1996 and July 2000, 39 patients who had received a first renal transplant in the Nephrology Unit of Le Kremlin-Bicêtre Hospital were subjected to CysA/MMF conversion because of gout or the chronic dysfunction of their grafts (suspected when serum creatinine concentration increased by 20% above the baseline value without any other explanation). Graft biopsies were performed in 28 patients suspected of graft dysfunction. They revealed chronic allograft nephropathy according to the Banff 97 criteria, with lesions compatible with CysA nephrotoxicity in 25 patients (hyaline deposits in afferent arterioles associated with interstitial fibrosis and tubular atrophy) or chronic rejection lesions, or both, in eight patients. No evidence of acute rejection was found. After introducing MMF (2 g/day) (T0), CysA was decreased progressively (by 25 mg per month). Azathioprine (Aza) was discontinued, but corticosteroid treatment was not modified. Mycophenolic acid (MPA) concentration was not determined.

Control group (group 2)
To analyse the long-term benefits and risks of CysA/MMF conversion, patients from group 1 were compared with matched patients with chronic graft dysfunction who were continued on conventional management (hypertension and dyslipidaemia treatment, CysA dose modulation). Patients were matched for age (±5 years), mean follow-up before intervention time (T0) (±2 years), mean serum creatinine concentration at T0 and slope of renal function deterioration (Table 1). From group 2, 16 patients underwent renal biopsies (T0). No evidence of acute rejection was observed, but chronic allograft nephropathy was present in seven patients, according to the Banff 97 criteria, with lesions compatible with CysA nephrotoxicity, and chronic rejection lesions alone in nine patients. Lesions compatible with CysA nephrotoxicity tended to be more frequent in the conversion group than in the control group.


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Table 1. Renal function before T0

 
Both groups were treated with CysA, steroids and in some cases with Aza before T0 (Table 2). After matching, patients in both groups were comparable for gender, age, number of acute rejection episodes, and initial and T0 CysA dosage (Table 2). In all patients, renal dysfunction was treated with conventional therapy including strict control of hypertension and dyslipidaemia, and the introduction of angiotensin-converting enzyme (ACE) inhibitors when possible for a better control of hypertension.


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Table 2. Patient characteristics

 
Follow-up
Renal function (mean serum creatinine concentration, creatinine clearance calculated with the Cockcroft formula), proteinuria, acute rejection episodes, blood pressure and lipid profiles were determined in both groups at 1, 2 and 3 years after T0.

Information concerning infections, side effects related to immunosuppressive treatment (including MMF- and CysA-related side effects) and cardiovascular events were also noted.

Statistical analysis
Data are presented as mean ± SD. Data were compared using Yate’s corrected {chi}2 test (non-parametric variables), paired and unpaired Student's t-tests (parametric variables). A P-value <0.05 was considered to be statistically significant.



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Renal function
The conversion process in group 1 was implemented late after transplantation. The mean time between transplantation and T0 (date at which CysA/MMF conversion was started) was 76.7 ± 40.5 months in group 1, and the mean length of follow-up after T0 was 44 ± 11.3 months (Table 2). The mean time between transplantation and T0 for matched patients (group 2) was comparable (75.85 ± 41.81 months), as was the mean length of follow-up (43.6 ± 11.3 months).

The number of episodes of acute rejection before T0 was similar in both groups (Table 2). Both groups of patients had chronic renal dysfunction. Their serum creatinine concentrations, creatinine clearances and the slopes of renal function deterioration between transplantation and T0 (Table 1) were comparable. CysA/MMF conversion was associated with a significant decrease in the mean serum creatinine concentration, from 192 ± 50 µmol/l at T0 to 172 ± 57 µmol/l at T0 + 1 year, 155 ± 36 µmol/l at T0 + 2 years and 159 ± 47 at T0 + 3 years (P < 0.003, Table 3). In contrast, the mean serum creatinine value remained unchanged in group 2 (187 ± 50 µmol/l at T0, 188 ± 60 µmol/l at T0 + 1 year, 187 ± 70 µmol/l at T0 + 2 years and 172 ± 48 µmol/l at T0 + 3 years; NS). In group 1, creatinine clearance increased from 41.7 ± 14.1 ml/min at T0 to 46.8 ± 16.3 ml/min at T0 + 1 year, 48.6 ± 16.3 at T0 + 2 years and 47 ± 14.2 ml/min at T0 + 3 years (P < 0.001). In contrast, the creatinine clearance did not vary significantly with time in the control group.


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Table 3. Renal function

 
Proteinuria did not vary significantly during follow-up after T0 in either group.

Patient and graft survival
For group 1, six graft losses occurred (three deaths with functioning grafts, three chronic rejections) between T0 and the end of follow-up (44 ± 11.3 months). During the corresponding period, nine graft losses occurred in group 2 (three deaths with functioning grafts, five chronic rejections, one acute rejection); the difference was not significant (NS) (Figure 1).



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Fig. 1. Patient and graft survival.

 
Of the three deaths in the conversion group, two were attributed to severe infection and one was due to post-transplant lymphoma. The death of one patient in group 2 was the result of severe infection, and two died of malignancies.

Graft survival rates, the number of patients requiring dialysis and the delays between transplantation and dialysis were similar in both groups. Since immunosuppressor modification may destabilize graft acceptance, we also determined the occurrence of acute graft rejection after conversion. No acute rejection occurred in group 1 during follow-up, whereas two acute rejection episodes occurred in group 2 due to poor compliance with immunosuppressive treatment.

Cardiovascular risk factors
Blood pressure. Following CysA/MMF conversion, systolic blood pressure decreased significantly in group 1. Its mean value was 155 ± 21 mmHg at T0, 146 ± 18 at T0 + 1 year, 137 ± 16 at T0 + 2 years and 133 ± 17 at T0 + 3 years (P < 0.01, P < 0.001 and P < 0.001, respectively). Diastolic blood pressure also decreased significantly, from 87 ± 9 mmHg at T0 to 83 ± 11 mmHg at T0 + 1 year and 75 ± 10 mmHg at T0 + 3 years (P < 0.05 and P < 0.001, respectively). Systolic and diastolic blood pressures remained unchanged in group 2. Moreover, the mean number of antihypertensive drugs used by group 2 increased from 1.79 ± 0.99 at T0 to 2.27 ± 1.24 at T0 + 3 years (P < 0.01), whereas it remained unchanged in group 1 (Table 4). This indicated that CysA/MMF conversion was associated with a decreased incidence of hypertension, one of the main cardiovascular risk factors.


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Table 4. Blood pressure

 
Lipid profile. In group 1, there was a non-significant decrease in serum cholesterol concentration after CysA/MMF conversion (6.34 ± 1.21 mmol/l at T0, 6.14 ± 1.44 mmol/l at T0 ± 1 year, 5.85 ± 1.44 mmol/l at T0 + 2 years, 5.72 ± 1.55 at T0 + 3 years, NS). Cholesterol concentrations remained stable in group 2, 6.45 ± 1.42 mmol/l at T0 and 6.7 ± 1.25 mmol/l at 2 years (also NS). In both groups, there was a non-significant decrease in triglyceride concentrations (Table 5). The number of patients treated with lipid-lowering agents was similar in both groups and remained unchanged with time in group 1, whereas it increased slightly in group 2.


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Table 5. Lipid profile

 
Side effects related to immunosuppressive treatment
During follow-up after T0, numerous side effects occurred. Side effects were more common in group 1 (n = 48 vs n = 27 in group 2) (Table 6). Severe side effects—including life-threatening infections, malignant tumours or severe skin rash—were more frequent in group 1 (n = 20) than in group 2 (n = 10; P < 0.05). Moderate side effects also occurred significantly more often in group 1 (group 1 n = 28, group 2 n = 17; P < 0.05). Most of these events consisted of bone marrow toxicity or digestive disturbances. For example, four of the patients in group 1 had anaemia, which required blood transfusions or treatment with recombinant erythropoietin (bleeding and other causes of anaemia were excluded). In the conversion group, three patients had leucothrombopenia and 11 had digestive problems related to MMF (mostly diarrhoea). Bone marrow and gastrointestinal side effects generally occurred within 6 months after the switch, whereas tumours and infections generally occurred at least 12 months after T0 (Table 7).


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Table 6. Treatment side effects after T0

 

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Table 7. Time between T0 and the appearance of the side effects (months/range)

 
Side effects related to immunosuppression led to definitive MMF withdrawal in two group 1 patients and decreased doses in 18. At the end of follow-up, the mean MMF dose was 1.19 ± 0.69 g per day compared with 2 g per day at T0, and only 19 patients (67%) had achieved complete CysA withdrawal. For the nine patients remaining at the end of follow-up, a complete withdrawal of CysA was not possible because of the need for a decreased MMF dosage in order to minimize the risk of acute rejection. However, seven of these patients had a decrease of >50% of their initial (T0) CysA dose, and the mean CysA trough level in group 1 was 20 ± 35 ng/ml at the end of follow-up. In comparison, there were minimal changes in CysA doses in group 2 during follow-up (Table 8). In the control group, immunosuppressive treatment was reduced in eight patients (P = 0.0304) and three had their immunosuppressive therapy withdrawn because of malignancies.


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Table 8. Immunosuppressive regimen T0 + 3 years

 
For the subgroup of patients from group 1 who had complete CsA withdrawal (n = 19), the overall results are similar to those of the control subgroup matched to it. Total CsA withdrawal is associated with improved renal function and reduced systolic and diastolic blood pressure, but no significant improvement in cholesterol and triglyceride levels.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Understanding the pathophysiology and management of chronic graft dysfunction, which is responsible for graft loss, is a major issue in renal transplantation. Several factors, acting alone or in concert, are responsible for renal dysfunction. They include: chronic rejection, dyslipidaemia, hypertension, reduced glomerular filtration rate and drug nephrotoxicity. Although calcineurin inhibitors improve the early outcomes of transplants, they are responsible for chronic renal vascular lesions, ultimately leading to the loss of renal function. Therefore, alternative therapeutic strategies have been proposed to reduce the adverse effects of those inhibitors. Among these strategies is switching from CysA to MMF several months after transplantation. Several studies have already examined the short-term benefits of this substitution in chronic rejection [7], CysA nephropathy [9,10] and stable renal transplant recipients [11,12], but no studies have reported on its long-term benefits or side effects. In this study, we determined the long-term benefits of this substitution on renal function, hypertension and lipid profile.

To be able to evaluate the effect of CysA/MMF conversion, two cohorts of matched patients were selected. All of them had chronic graft dysfunction, and renal biopsies were done on several patients in both groups, finding, however, that arteriolar lesions compatible with CysA nephrotoxicity were more common in the conversion group of patients.

Efficacy of CysA/MMF conversion
Renal function. We showed that CysA/MMF conversion induces a sustained decrease in the serum creatinine concentration at 1, 2 and 3 years. The benefit of CysA withdrawal on renal graft function became rapidly obvious within the first year following the switch. However, the mean serum creatinine concentration did not change in the matched controls, this being due to a better management of cardiovascular risk factors, in particular hypertension, in the control group and the more frequent dependence in recent years on ACE inhibitors. Indeed, it is noteworthy that the therapeutic index increased in the control group when compared with the substitution group. In most of the control patients, the new drug added was an ACE inhibitor. Although as previously described, a significant improvement occurred, we did not observe any differences in graft or patient survival between the two groups during 44 months of follow-up. This may be due to the slow regression rate of renal function in both groups or to the fact that the substitution was made when the renal function was too severely affected. In fact, all of the patients who experienced graft loss appeared to have had poor renal function before the substitution (268 ± 33 µmol/l in group 1, 256 ± 52µmol/l in group 2). This is in keeping with the the severity of the lesions of chronic allograft nephropathy observed on biopsy. This suggests that immunosuppressive substitution cannot prevent graft loss when renal lesions are serious. Therefore, substitution probably should be carried out before the development of severe lesions.

The early improvement of graft function is probably due to haemodynamic changes in the kidneys induced by the withdrawal of CysA [13]. As reported by Schrama et al. [11], in stable renal transplant recipients, CysA withdrawal decreases renal vascular resistance and increases renal plasma flow and glomerular filtration rate. The persistent improvement of renal graft function 2 years after the switch may also result from the interruption of the extracellular matrix deposition observed in arterioles and in the interstitium, as reducing the dose of CysA leads to a decrease in transforming growth factor-ß (TGF-ß) production [14]. The beneficial effects could also be related to the introduction of MMF, as recent studies have shown that MMF can attenuate the fibrosis induced by nephron reduction in rats [1517] and can inhibit vascular smooth muscle cell proliferation both in vitro and in vivo [6].

Cardiovascular risk factors. To determine whether CysA modified cardiovascular risk factors such as dyslipidaemia or hypertension, we evaluated the effect of the CysA/MMF conversion on the progression of these risk factors. Systolic and diastolic blood pressures decreased significantly in group 1 without an increase in the mean treatment index. In group 2, diastolic blood pressure remained stable; however, systolic blood pressure decreased slightly. This is associated with a marked increase of the mean treatment index during the follow-up, as reported by others [911]. The lipid profile, which is one non-immunological factor involved in chronic rejection [18], and an important cardiovascular risk factor, was not significantly modified. We observed a slight decrease in cholesterol levels in group 1 and in serum triglyceride levels in both groups. It is noteworthy that these beneficial effects were observed although the MMF dose was reduced in some cases because of MMF-related side effects, and even though CysA was not completely withdrawn in 32% of patients. Therefore, intermediate strategies using lower MMF doses or partial reduction of the dose of CysA, or both, may be envisaged, since MMF favours an improvement of cardiovascular risk factors such as blood pressure and total cholesterol concentration.

Acute rejection. The introduction of CysA in immunosuppressive regimens has led to a major reduction in the number of severe acute rejections. CysA/MMF conversion might increase the occurrence of episodes of acute rejection, as recently reported, from 10 [610] to 20% [12] of cases. This complication could be deleterious in the long term, as it may increase the occurrence of chronic graft rejection and in some cases it may convert chronic nephrotoxicity to chronic rejection. Two factors seem to be related to the occurrence of acute rejection following CysA/MMF conversion: (i) rapid withdrawal of CysA (in <6 weeks); and (ii) early conversion (within 6–9 months after the transplantation) [12]. For these reasons, we decided to decrease the amount of CysA slowly and only after the sixth month post-transplantation. In most cases, the substitution was implemented at least 1 year after transplantation. We did not observe any cases of acute rejection following full conversion.

Patients’ tolerance of the CysA/MMF substitution
CysA/MMF substitution was also associated with numerous side effects. Unlike previous studies that examined the tolerance for CysA/MMF conversion, we report a high frequency of side effects—severe (malignancies, life-threatening infections, toxidermia) and moderate (bone marrow toxicity and gastrointestinal problems)—in the converted group. Our observations possibly were a result of the long follow-up, as most of them occurred later than 12 months after the switch, and therefore were not reported in previous reports based on shorter follow-ups. The rates of malignancies and life-threatening infections were comparable in both groups, suggesting that they were not related to the substitution alone. The high number of carcinomas in both groups might be powered by the important immunosuppression administered to both groups. In contrast, numerous moderate side effects that can be attributed to MMF treatment were observed in group 1, mostly mild bone marrow toxicity (anaemia and leucothrombopenia) and gastrointestinal disturbances. The frequency of anaemia was 20.5%, which is considerably higher than that reported in the ‘European Mycophenolate Mofetil Cooperative Study’ [4] (4.2% for 2 g/day MMF and 6.8% for 3 g/day MMF) and the ‘Tricontinental Mycophenolate Mofetil Study’ [3] (9% for 2 g/day MMF and 15% for 3 g/day MMF). However, anaemia associated with MMF treatment has been reported in cases of impaired renal function [7,8] or is correlated with the concentration of MPA, the active metabolite of MMF [19]. Moreover, MPA and glucuro-conjugated MPA accumulate during chronic renal failure, which suggests the need to monitor MPA and its free fraction in these patients. Indeed, because the bulk of MPA is linked to proteins, and because only the free fraction of MPA is active, recent data suggest that the free MPA concentration is a better indicator of side effects and drug efficacy than the total MPA concentration. Like haematological disorders, gastrointestinal disturbances, mostly diarrhoea, were observed frequently in our patients (20.5%), as in large randomized controlled trials [35]. In most of the patients, the gastrointestinal disorders disappeared when the dose of MMF was reduced. This is in accordance with results from Van Gelder et al., who reported that the withdrawal, necessitated by adverse events, of patients from a prospective trial was correlated with the daily dose of MMF but not with the MPA concentration or AUC based on the measurements of the total MPA [20]. It is noteworthy that almost 50% of patients from group 1 had either to stop taking MMF or to decrease the dose of MMF during follow-up because of those specific side effects.

In conclusion, this stepwise CysA/MMF substitution strategy (to 2 g of MMF per day) is effective in preventing acute graft rejection, improving renal graft function and decreasing cardiovascular risks in patients with allograft dysfunction when compared with conventional management. However, it is associated with a high rate of MMF-related side effects. A lower dose of MMF will probably give similar or even better results with fewer adverse side effects. Given the maintenance doses of MMF taken by patients (1.19 ± 0.69 g) at the end of the follow-up period, we suggest that 1.5 g or even 1 g per day would be sufficient. These doses must be evaluated in prospective randomized studies of the prevention of acute and chronic rejection.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 16. 8.02
Accepted in revised form: 12. 2.03





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