New Cross Hospital, Wolverhampton, 1 Department of Nephrology, Queen Elizabeth Hospital, Birmingham and 2 Department of Pathology, University of Birmingham, Birmingham, UK
Abstract
Background. A small proportion of patients with initially steroid-sensitive nephrotic syndrome relapse frequently, despite treatment with cyclophosphamide and/or cyclosporin. We investigated the efficacy of mycophenolate mofetil (MMF) in this group.
Methods. Seven patients with nephrotic syndrome due to minimal change nephropathy (MCN) or classical focal segmental glomerulosclerosis (FSGS) who had suffered multiple relapses over many years despite treatment with several different agents were commenced on MMF 1 g twice daily, together with a reducing dose of corticosteroids.
Results. Six patients went into complete remission and the seventh into partial remission. At 1 year, five remained in complete remission. The median (range) serum albumin concentration rose from 19 g/l (1642 g/l) pre-MMF to 42 g/l (2545 g/l) after 12 months (P=0.023), and the median (range) dose of prednisolone fell from 40 mg/day (3060 mg/day) to 7.5 mg/day (040 mg/day) at 12 months (P=0.0008).
Conclusion. MMF appears to be of benefit in the treatment of multiply relapsing nephrotic syndrome caused by MCN or FSGS. Controlled trials are required to establish the role of MMF in these disorders.
Keywords: focal segmental glomerulosclerosis; minimal change nephropathy; mycophenolate mofetil; nephrotic syndrome
Introduction
A small proportion of patients with initially steroid-responsive nephrotic syndrome due to minimal change nephropathy (MCN) or classical focal segmental glomerulosclerosis (FSGS) run a multiply relapsing course, despite treatment with cyclophosphamide. Some go into remission with cyclosporin but are dependent on this drug, which with prolonged usage can lead to nephrotoxicity [1]. Mycophenolate mofetil (MMF) is an immunosuppressant drug that inhibits inosine monophosphate dehydrogenase and thus de novo purine synthesis [2]. We investigated whether MMF, which has an established role in solid organ transplantation [3], was of benefit in the treatment of patients with intractable nephrotic syndrome who had become dependent on prednisolone or cyclosporin.
Subjects and methods
We report data on all the patients with MCN and FSGS who were treated with MMF. The clinical details of these patients are summarized in Table 1. All the patients were initially steroid responsive. This includes the two patients with FSGS. However, only one of the patients with FSGS was diagnosed on the initial renal biopsy; the other (case 1) was initially disgnosed as having MCN on several renal biopsies over 13 years before a renal biopsy diagnosed FSGS. By this time he was not steroid responsive. Six patients were steroid dependent at the time MMF was started. Five patients were being treated with cyclosporin immediately before MMF was initiated, but this was ineffective, and in two a repeat renal biopsy showed evidence of cyclosporin toxicity. A further patient was taking azathioprine but this too was ineffective. All except one had had relapsing nephrotic syndrome for >10 years, with significant treatment-related toxicity. MMF was given to all patients in an oral dose of 1 g twice daily, together with prednisolone.
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Results
Two patients had a renal biopsy in the 6 months prior to commencing MMF, two in the preceding 2 years and two in the previous 4 years. The seventh patient had a renal biopsy 9 years prior to commencing therapy with MMF. Six patients went into complete remission (urine albumin 0 g/24 h) and the seventh into partial remission (urine albumin <2 g/24 h). Five patients (cases 2, 3 and 57) remained in complete remission at the last follow-up. Two of these relapsed through initial non-compliance but returned to complete remission on resumption of MMF. Two patients (cases 1 and 4) relapsed on reduction of their steroid dose, but case 1 was in complete remission at the last follow-up after a transient increase in steroid dose. This patient had not previously achieved prolonged remission despite multiple drugs for many years. The median (range) serum albumin concentration rose from 19 g/l (1642 g/l) pre-MMF to 42 g/l (2545 g/l) after 12 months (P=0.023) (Figure 1A). The median (range) dose of prednisolone was 40 mg/day (3060 mg/day) at the start of therapy with MMF, and fell to 7.5 mg/day (040 mg/day) at 12 months (P=0.0008) (Figure 1B
). There were no episodes of leucopenia or prolonged gastrointestinal side-effects requiring dose reduction.
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Discussion
In this group of patients with treatment-resistant, frequently relapsing nephrotic syndrome due to MCN and FSGS, MMF appeared to be of benefit. These patients had relapsed despite prior treatment with second line agents and required high doses of steroid treatment at the time MMF was started. All seven patients showed a response to MMF and this allowed a reduction in the dose of prednisolone.
MMF is a potent immunosuppressant with an established role in renal transplantation [3]. MMF inhibits inosine monophosphate (IMP) dehydrogenase, which catalyses the conversion of IMP to xanthine monophosphate, a precursor of guanine nucleotides. This leads to inhibition of lymphocyte proliferation as lymphocytes rely predominantly on this pathway of purine synthesis and are not able to utilize purine salvage pathways, which are present in most other cells [2,4,5].
Studies showing that MMF may have efficacy in the treatment of experimental and human glomerulonephritis have been reviewed elsewhere [6,7]. Briggs et al. reported on the use of MMF in eight patients with glomerulonephritis [8]. Six patients had nephrotic syndrome (due to membranous nephropathy in three, MCN in two and FSGS in one), but in none was it adequately controlled by methylprednisolone and cyclosporin. Two patients with MCN went into remission with MMF. One with FSGS also achieved a prolonged remission, but discontinued MMF after 21 months due to gastrointestinal side effects. In this patient there was an initial slight decline in renal function and increase in proteinuria, but this subsequently remained stable off treatment. Follow-up data of this group showed that one patient with membranous nephropathy and one with MCN relapsed within 1 month after cessation of a 6-month course of MMF [9]. Recommencing the drug produced a complete remission in the former patient but only a partial remission in the patient with MCN. The patient with FSGS experienced a further decline in renal function in the 6 months after MMF was stopped.
Our findings suggest that MMF may be a useful drug in patients with MCN and FSGS who continue to relapse despite prior treatment with prednisolone, cyclophosphamide and cyclosporin. Our experience is that MMF behaves like prednisolone or cyclosporin in that it maintains remission but it is unclear whether it also reduces the likelihood of relapse once the drug is discontinued. Randomized, controlled studies are needed to establish the role of MMF in this group of patients.
Notes
Correspondence and offprint requests to: Dr D. Adu, Department of Nephrology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. Email: dwoms{at}aol.com
References