Department of Pathophysiology, Medical School, University of Athens, 1Department of Nephrology, Laikon General Hospital and 2Euroclinic of Athens, Athens, Greece.
Correspondence to: H. M. Moutsopoulos, Department of Pathophysiology, School of Medicine, National University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece. E-mail: hmoutsop{at}med.uoa.gr
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Abstract |
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Methods. Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy) were included. With five exceptions, all patients had been treated previously with cyclophosphamide and were selected because of either toxicity or inadequate clinical response to treatment. MMF was given at 2 g daily in combination with steroids for up to 31months (mean 15.3 months). The side-effects of MMF were recorded and efficacy was assessed as the renal function profile.
Results. Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Two patients developed gastrointestinal complaints and infectious meningitis occurred in one patient.
Conclusion. MMF appears to be an efficacious and safe treatment in patients with proliferative forms of lupus nephritis who do not respond to or cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous nephropathy remains unclear.
KEY WORDS: Mycophenolate mofetil, Lupus nephritis, Proliferative nephritis, Lupus membranous nephropathy, Immunosuppression.
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Introduction |
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Mycophenolate mofetil (MMF) is widely used in solid organ transplantation and it reduces the rate of acute rejection following renal transplantation [6]. It has also been used to treat patients with other immune-mediated disorders such as immunoglobulin A nephropathy, small-vessel vasculitides and psoriasis.
MMF has been demonstrated to be effective in mouse models of lupus nephritis [7, 8]. There is limited clinical experience of the use of MMF in patients with lupus nephritis [912]. In a recent randomized controlled trial in patients with DPGN, MMF has been shown to be as effective as CYC [12]. However, at the longer follow-up, patients treated with MMF developed a significantly higher incidence of relapse compared with patients who received CYC, even though renal function remained similar in the two groups [13]. Furthermore, the role of MMF in lupus membranous nephropathy is unclear because of the lack of prospective data. We describe our experience of the use of MMF in 20 patients with lupus nephritis, six of whom had lupus membranous nephropathy.
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Patients and methods |
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The medical records of the patients were reviewed and their clinical course and laboratory profile, which included routine blood and urine biochemical tests, were assessed during the follow-up. Creatinine clearance was calculated using the CockroftGault formula. Observation onset was defined as the time that MMF was introduced for each patient. Follow-up was censored on 31 November 2001.
Renal biopsy files were also reviewed and histopathological changes had been classified according to the WHO classification of 1982. In addition, the activity index and chronicity index, where applicable, were recorded. For patients with two or more renal biopsies (eight patients), the most recent one was considered.
Complete remission was defined as proteinuria less than 0.5 g/24 h, with normal urinary sediment and normal values for both serum creatinine and creatinine clearance. Partial remission was defined as either a reduction of more than 30% in proteinuria or proteinuria less than 2 g/24 h in a previously nephrotic patient with normal urinary sediment and stable renal function. Treatment failure was defined as no remission at the end of follow-up.
Comparison of laboratory characteristics was performed using the Wilcoxon signed rank test. McNemar's test was used for comparisons of dichotomous variables before and after treatment (P < 0.05 was considered significant).
The patients written consent to participation in the study was obtained according to the Declaration of Helsinki, and the design of the study conformed to standards currently applied in Greece.
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Results |
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Two patients developed gastrointestinal intolerance which necessitated a reduction of the MMF dose to 1.5 g/day in one patient and transient discontinuation in the other. Pneumococcal meningitis occurred in one patient, who died from respiratory failure due to diaphragm myositis 1 yr later, while in partial remission.
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Discussion |
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Mycophenolate acid, the active metabolite of MMF, is a more specific immunosuppressive than CYC. The preferential antiproliferative effects of MMF on lymphocytes and kidney mesangial cells, combined with its inhibitory action on cell adhesion molecules and the migration of inflammatory cells, may provide an additional clinical benefit in the treatment of lupus nephritis [15]
A number of uncontrolled studies have been conducted to assess the efficacy and toxicity of MMF in the treatment of lupus nephritis, and the evidence to date was recently reviewed by Mok et al. [15]. These authors highlighted the methodological limitations of these studies, which are shared to some extent by the present study. A heterogeneous group of patients was included; data on renal histological characteristics and damage after MMF treatment were not available; both steroid and MMF were administered (and in the absence of a control population steroid might also have contributed in part to the improvement in renal parameters); and the contribution of previous immunosuppression cannot be excluded. Controlled trials of MMF in lupus nephritis are few, and some are now in progress. In a recent randomized controlled study, the combination of MMF and prednisolone was demonstrated to be as effective as a regimen of CYC and prednisolone followed by azathioprine and prednisolone [12]. Nevertheless, this study involved only a small cohort of patients and the follow-up was too short to address the efficacy of MMF in the long-term preservation of renal function compared with the established therapeutic treatments. On the other hand, the therapeutic role of MMF in lupus membranous nephropathy remains unclear, as there are only 13 cases reported in the literature so far, of whom six are children.
Because experience with the use of MMF in lupus nephritis is still preliminary, we add our observations on 18 patients with lupus nephritis treated with MMF. Complete or partial remission was observed in 14 patients. In terms of renal histology, while all patients with proliferative forms of lupus nephritis had either complete or partial remission, four out of six patients with membranous glomerulonephritis failed to respond. Given the relatively short follow-up (mean 15.3 months) and the small numbers treated, our observations regarding this relatively uncommon form of lupus nephritis need cautious interpretation. The coexistence of proliferative changes in three of the four non-responders may partially explain this finding. Pasquali et al. [16] have shown that among patients with lupus membranous nephropathy, those with more proliferative change on renal biopsy, were more likely to have persistent non-nephrotic proteinuria, and were less likely to have complete resolution of proteinuria. Furthermore, the frequently reported transformation of diffuse proliferative glomerulonephritis by treatment into the membranous form may represent the residuum that aggressive therapy is unable to reverse [17]. In a recently published report, Najafi et al. [18] have highlighted the relatively malignant nature of complex membranous forms of lupus glomerulonephritis. On the other hand, two out of three patients with pure membranous nephropathy had complete remission, whereas the remaining patient failed to respond after having been treated for 9 months. Thus, in our study population patients with pure membranous nephropathy tended to have a better response to MMF treatment compared with patients with complex membranous nephropathy.
There was a statistically significant improvement in mean creatinine clearance and proteinuria for patients with proliferative nephritis during treatment with MMF. Proteinuria also decreased in patients with membranous nephritis, although the decrease was not statistically significant. Drugs like ACE inhibitors and statins also affect proteinuria but none of these medications was introduced in any patient during the study period. Interestingly, MMF has been shown to reduce proteinuria without changing serum creatinine in patients with idiopathic membranous nephropathy [19, 20]. Given the lack of formal studies of MMF in lupus membranous glomerulonephritis, this observation is noteworthy because one might look to idiopathic membranous glomerulonephritis as a model for the former one (lupus membranous nephropathy). The steroid dose could be reduced in 14 of the 18 patients administered steroid at the time of introduction of MMF.
With regard to side-effects, gastrointestinal intolerance developed in two of our patients and resolved on dose reduction and transient discontinuation of MMF. Pneumococcal meningitis occurred in one patient during lupus flare. Treatment with MMF was withdrawn and reintroduced after patient recovery. Gastrointestinal complaints such as diarrhoea, vomiting and nausea appear to be the most frequently reported side-effects in published retrospective studies [10, 11]. In the controlled study by Chan et al. [12], infection was the most common adverse event, but it was mild and insignificant in all cases. Thus, adverse events associated with the use of MMF in lupus nephritis are infrequent and relatively mild compared with those reported in transplant recipients. This is possibly due to a lower intensity of immunosuppression.
The present report is not intended to definitively address the many critical issues of the role of MMF in the treatment of lupus nephritis. However, our study does indicate that MMF is a safe and probably efficacious treatment in patients with proliferative forms of lupus nephritis who do not respond or cannot tolerate conventional treatment. We suggest that further prospective controlled trials are warranted to compare the long-term efficacy and safety of MMF with those of established treatments. Inclusion of patients with lupus membranous nephropathy and accurate histopathological stratification of renal biopsies would be helpful in order to clarify the role of MMF in this infrequent type of lupus nephritis [18].
The authors have declared no conflicts of interest.
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References |
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