Cyclosporine A (CsA) had a major impact in the field of renal transplantation by increasing 1-year graft survival. However, long-term graft survival has not improved over the last two decades, probably as a result of immunological and nonimmunological factors causing additional renal insults. These factors include CsA therapy itself, which is known to induce a chronic form of nephropathy in nonrenal transplant recipients (1). CsA nephropathy may also occur in the transplanted kidney, but is often difficult to recognize because of coexisting renal injuries due to glomerular hyperfiltration and chronic rejection.
Over the last few years, new nonnephrotoxic immunosuppressive agents have become available. These include the drug mycophenolate-mofetil (MMF), an inhibitor of T and B lymphocyte proliferation that was used initially in combination with CsA and steroids. In early studies, MMF was shown to be effective in decreasing the incidence and the number of acute rejection episodes, and in treating acute refractory rejection (2). Since then, studies have been published documenting different modalities of MMF utilization. These include the use of MMF with prednisone (Pred) and low-dose CsA, MMF with CsA or, in rare cases, MMF with Pred. There also exists a number of studies (see Ref. 3 by way of illustration) in which renal transplant patients were treated from the outset with MMF, Pred, and monoclonal antibodies, but with no CsA.
In our study, we report our experience with 17 adult renal recipients whose immunosuppressive therapy was changed from a CsA-Pred regimen to a MMF-Pred regimen because of CsA nephrotoxicity. The patient demographics are summarized in Table 1. All underwent renal biopsy for the investigation of renal graft function deterioration (16 patients) or isolated proteinuria (1 patient). The patients experiencing progressive allograft dysfunction had a rise in mean serum creatinine from 127 μmol±31 (lowest value posttransplant) to 178 μmol±43 at the time of the CsA substitution by MMF. The patient with stable renal function had 24 hr proteinuria ranging 0.3 to 1.9 g during the 7 months preceding the change in immunosuppressive therapy. In all kidney transplant recipients, the biopsies revealed lesions suggestive of CsA nephrotoxicity (4), including focal interstitial fibrosis, tubular atrophy, and hyaline arteriolosclerosis. Transplant glomerulopathy was found in 2/17 kidneys and diabetic glomerulosclerosis in 2/17. None of the biopsies revealed signs of acute rejection.
All patients received a first cadaver kidney transplant between 1988 and 1996. The initial immunosuppressive regimen was CsA and Pred in all recipients, with no induction therapy. Sixteen patients also received diltiazem initially. In four patients, CsA was replaced by azathioprine (AZA) because of CsA nephrotoxicity—during the following 3 months, however, AZA intolerance necessitated reverting to the initial immunosuppressive regimen. Fifty-seven months posttransplant (range 12–109), therapy was changed from CsA-Pred to MMF-Pred in all recipients. At the time of conversion, the mean dosage of CsA was 3.2 mg/kg/day (range 2.1–5.2), and the mean plasma CsA level was 195 ng/liter (range 147–244). In 16 patients, MMF was started at 2 g/day, and in 1 patient, at 1 g/day. CsA was completely tapered over a mean period of 6 weeks (range 3–10). Pred was maintained at the same dosage throughout (mean 0.21 mg/kg; range 0.15–0.31). In the ±3 months of the CsA substitution by MMF, no specific recommendations concerning lifestyle or diet were made to the patients.
Clinicobiological parameters were monitored in all patients before and after substitution of CsA by MMF. Data are expressed as mean±SD (or range) or as total number of events. Student’s two-tail t tests (for continuous variables) or Fisher’s exact two-tailed tests (for categorical variables) were used to analyze differences between groups. The null hypothesis was rejected when a P < 0.05 was obtained. The statistical significance of changes in serum creatinine over time was determined using piecewise multiple regression analysis (5).
The results for renal function tests are summarized in Table 2. The serum creatinine levels decreased 26±17% 3 months after replacing CsA with MMF, and remained stable 20±8 months postsubstitution (range 16–32 months). None of the subjects had an increase in 24 hr proteinuria. By piecewise regression analysis (Fig. 1), the changes in creatinine values as function of time indicated significant slope inflexions at therapy substitution and at three months postsubstitution. The data demonstrate, thus, that creatinine decreases significantly after replacement of CsA by MMF, and that the improvement in renal function is maximal within 3 months of the change in therapy.
Blood pressure and serum lipid levels are also summarized in Table 2. Both the systolic and the diastolic blood pressure decreased significantly by 8 mmHg 6 months after the change in therapy (P <0.001), and were still significantly lower at the last visit. The number of antihypertensive drugs administered per patient was 2.10 before the conversion to MMF and 2.01 after the conversion (P =0.12). Serum cholesterol and triglycerides also decreased significantly (P <0.0001 and 0.05, respectively), although the number of prescribed lipid-lowering agents was comparable before and after the change in immunosuppressive therapy, i.e., 10/17 patients in both groups.
In this study, we have observed a rapid and sustained amelioration of allograft function after withdrawal of CsA and substitution with MMF. Because nonimmunosuppressive drugs were not modified substantially before and after the therapy replacement, the improvement in renal function is most likely related to the change in the immunosuppressive regimen. Under such circumstances, was the decrease in creatinine levels the result of CsA withdrawal or was it due to MMF therapy? The brisk decrease in serum creatinine in all patients during and subsequent to cessation of CsA suggests that adverse hemodynamic factors may have contributed to poor graft function before the conversion to MMF-Pred. It is also documented that CsA-related histological lesions occasionally regress after withdrawal of the immunosuppressant (6). This may have been the case in the subjects described here, although control biopsies were not obtained to quantify renal lesions posttherapy substitution. A recent study in which no benefit was reported from replacing AZA-CsA-Pred by MMF-CsA-Pred (7) further supports the possibility that improved graft function in our patients was associated with CsA withdrawal and not with MMF addition.
CsA nephrotoxicity in renal transplantation has been treated by reducing the doses of CsA or by replacing CsA by AZA. An important issue in such situation, and in this study, is the risk of subjecting recipients to inadequate immunosuppression. For example, there have been reports of increased incidence of delayed renal allograft rejection after lowering or discontinuing CsA (8), and of increased long-term renal graft survival correlating with higher CsA levels during chronic maintenance therapy (9). In our study, most patients did not undergo a postconversion allograft renal biopsy. Hence, it is not possible to exclude subclinical acute rejection in some of the recipients. It is still noteworthy, however, that CsA was completely tapered in all 17 patients after transplantation, and that no episodes of acute allograft rejection were observed clinically. Furthermore, renal function as well as 24-hr proteinuria improved initially, and were stable thereafter over the entire observation period. Thus, our data are not consistent with an increased risk of delayed acute rejections after CsA discontinuation. In addition, the therapy modification that we used did not require adjustments in steroid dosage.
Our results are in agreement with Ducloux’s earlier report (10) in which an improvement in renal function was observed after replacing CsA by MMF in six patients with suspected CsA nephropathy. In addition, our study includes a larger number of patients with a more extended follow-up. In another report, Weir et al. (11) observed stabilization of graft function after substituting a CsA-AZA-Pred regimen by a CsA-MMF-Pred regimen with lower doses of CsA. In the latter report, however, it is unclear whether stabilization of renal function was caused by CsA reduction or by addition of MMF because allograft nephropathy was present in the subjects’ biopsies.
In this report, we have also shown that conversion from a CsA-Pred regimen to a MMF-Pred regimen was beneficial in alleviating hypertension and hyperlipidemia, which are common complications of CsA therapy after renal transplantation. Both conditions are major risk factors for cardiovascular morbidity, and may contribute to progressive renal dysfunction in the transplant recipient.
In conclusion, we have reviewed the outcome of renal transplantation in 17 patients with biopsy-documented CsA nephropathy who were treated by changing CsA-Pred to MMF-Pred. This change of therapeutic approach resulted in sustained improvement of renal allograft function over a 17-month period, in the absence of acute rejection. This strategy also resulted in a better control of blood pressure and serum lipids. These data support the utility of a MMF-Pred regimen as an alternative immunosuppressive regimen for patients presenting CsA side effects. The results reported here warrant further evaluation of the approach with larger controlled clinical studies.
1. Bennet WM. Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int 1996; 50: 1089.
2. Hauser IA, Sterzel RB. Mycophenolate mofetil: therapeutic applications in kidney transplantation and immune-mediated renal disease. Curr Opin Nephrol Hypertens 1999; 8 (1): 1.
3. Vincenti F, Grinyó J, Ramos E, et al. Can antibody prophylaxis allow sparing of other immunosuppressives? Transplant Proc 1999; 31 (1–2): 1246.
4. Mihatsch MJ, Thiel G, Ryffel B. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988; 3: 759.
5. Nakamura T. BMDP program for piecewise linear regression. Comput Methods Programs Biomed 1986; 23 (1): 53.
6. Morozumi K, Thiel G, Albert FW, et al. Studies on morphological outcome of cyclosporine-associated arteriolopathy after discontinuation of cyclosporine in renal allografts. Clin Nephrol 1992; 38 (1): 1.
7. Glicklich D, Gupta B, Schurter-Frey G, et al. Chronic renal allograft rejection. Transplantation 1998; 66: 398.
8. Kasiske BL, Heim-Duthoy K, Ma JZ. Elective cyclosporine withdrawal after renal transplantation. A meta-analysis. JAMA 1993; 269: 395.
9. Almond PS, Matas A, Gillingham KF, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993; 55: 752.
10. Ducloux D, Fournier V, Bresson-Vautrin C. Mycophenolate mofetil in renal transplant recipients with cyclosporine-associated nephrotoxicity. Transplantation 1998; 65: 1504.
11. Weir MR. A novel approach to the treatment of chronic allograft nephropathy. Transplantation 1997; 64: 1706.