Definitions for the levels of evidence (I–IV) can be found at the end of the "Major Recommendations" field.
Guidelines
No recommendations possible based on Level I or II evidence
Suggestions for Clinical Care
(Suggestions are based on Level III and IV evidence)
- While there have been mixed reports of success with a number of agents, further evidence is required before they can be recommended as second line therapy in membranous glomerulonephritis (MGN).
Azathioprine
Studies in the treatment of idiopathic MGN have found mixed benefits from using azathioprine combined with corticosteroids over steroid alone.
- One study demonstrated that the addition of oral azathioprine to a regimen of intravenous pulse methylprednisolone and oral prednisone could reverse or stabilize progressive kidney failure in patients with membranous nephropathy.
Most series have not shown any benefit.
- In a small controlled trial, five patients with the nephrotic syndrome due to idiopathic MGN received azathioprine, 2.5 mg/kg/d, while four others received placebo. After 1 year of treatment there was no significant difference in creatinine clearance or 24-hour excretion of protein between the two groups.
- The Sheffield Kidney Institute reviewed 58 patients with idiopathic MGN and nephrotic-range proteinuria. Thirty-eight patients were treated with prednisolone (1 mg/kg/d) and azathioprine (2 mg/kg/d) for a median period of 26 months. Twenty patients received no specific treatment for MGN and served as a control group. Neither the level of proteinuria, the rate of renal decline nor the proportion of patients with deteriorating renal function differed significantly between the groups. In addition, adverse effects of immunosuppressive treatment were observed in 9 patients.
Immunoglobulin
Pooled intravenous immunoglobulin (IgG) in a few small series has been shown to reduce proteinuria and stabilize renal function in patients with resistant nephrotic syndrome [Level III evidence, single study, additional selected case series].
- One study followed 9 patients with idiopathic MGN following treatment with pulse doses of IgG (0.4 g/kg body weight) for 3 consecutive days, repeated 3 times at 21-day intervals for 10 months. In 5 patients, a complete remission of proteinuria (daily proteinuria less than 0.2 g) was observed, and 3 patients showed partial remission (proteinuria 2 g/day). In responder patients, clinical and biological findings of the nephrotic syndrome disappeared and a statistically significant increase of creatinine clearance was observed.
- Another study reviewed 86 patients with primary MGN for at least 5 years. They treated 30 of these patients with 1–3 short-term courses of low-dose intravenous immune globulin (5–10 g/day) [100–150 mg/kg/day] for 6 consecutive days. There was no difference in the long-term outcome in patients treated with intravenous immunoglobulin therapy compared with patients not receiving therapy with immunoglobulin. A subgroup of patients with 'homogenous type MGN with electron microscopy findings of synchronous electron-dense deposits' had earlier induction of remission.
Fludarabine
Fludarabine has been reported to lead to remission in some patients with MGN (Level IV evidence, anecdotal reports).
- Treatment of refractory chronic lymphocytic leukaemia (CLL) with fludarabine, a purine nucleoside analogue, has been associated with remission of malignancy-associated MGN.
- In one study, the investigators treated 7 patients with refractory idiopathic membranous nephropathy with 6-monthly cycles of fludarabine. Although all patients developed significant lymphopenia, proteinuria decreased by > 50% in 5 of 7 patients (P = 0.11) and glomerular filtration rate (GFR) improved in all those with renal failure at baseline.
Mycophenolate mofetil
Mycophenolate appears to reduce proteinuria in some patients with resistant MGN (Level IV evidence, small case series, variable results).
- One study treated 18 patients with refractory MGN, 13 of whom achieved remission on 1.0–2.0 g/d for 3–6 months.
- One study treated 16 nephrotic patients with MGN with mycophenolate mofetil. Fifteen patients had steroid-resistant disease; cytotoxic agents had failed in 6 patients and cyclosporin therapy had failed in 5 patients. Six patients experienced a halving of proteinuria, which occurred after a mean duration of 6 months of therapy. Partial remissions occurred in 2 patients. There were no significant changes in mean values for serum creatinine during the study.
- One study also described reductions in proteinuria and stabilising of creatinine in 3 patients with MGN.
- One group of investigators studied 17 patients with MGN including 15 with nephrotic range proteinuria and 6 with renal insufficiency. Indications for mycophenolate mofetil treatment were steroid- (11/17), cyclosporine- (4/17) or cytotoxic (1/17) dependency. After 5-12 months of follow-up, there was a 61.1% reduction in protein excretion. Two patients (13.3%), both of whom were nephrotic, achieved a complete remission; 8 patients (60%), all of whom were nephrotic, achieved a partial remission; and 2 patients (13.3%), including 1 nephrotic, had increased proteinuria. Eight of the 15 (53.3%) nephrotic patients improved to sub-nephrotic proteinuria with treatment. Two patients relapsed after mycophenolate mofetil was stopped, and they both responded to re-treatment. Three of 6 patients with renal insufficiency experienced substantial improvement in excretory renal function.
- One study gave mycophenolate mofetil 2 g/day for 9 months to 8 patients with stage III–IV idiopathic membranous nephropathy. Previous treatment had failed in 5 of 8 patients (three patients had received cyclosporin and steroids, one cyclosporin, steroids and cyclophosphamide and one an alternative use of steroids and chlorambucil). Proteinuria decreased significantly during the treatment (P < 0.05), from 4.4 g/d at the start, to 2.0 g/day after 3 months, and 1.9 g/day after 6 months and 9 months. Renal function improved slightly, but not significantly (P > 0.05).
Monoclonal antibodies
Monoclonal antibodies against the cell surface antigen CD20 of B cells may reduce proteinuria in some patients with idiopathic MGN.
- One study followed 8 patients with idiopathic MGN and long-lasting persistent proteinuria, following an intravenous infusion of the anti-CD20 monoclonal antibody, rituximab. After 20 weeks of treatment, there was a 60% reduction in urinary proteinuria. At 12 months, proteinuria decreased to < 0.5 g/24 h or < 3.5 g/24 h in two and three patients, respectively. There was no significant loss of renal function in any patient.
- Eculizumab, a humanized monoclonal antibody that prevents the cleavage of human complement component C5 into its proinflammatory elements, did not appear to have any significant effect on proteinuria or renal function in patients with membranous nephropathy, although this Phase II study was not designed to test this outcome and the dose required for efficacy testing may not have been achieved.
Definitions:
Levels of Evidence
Level I: Evidence obtained from a systematic review of all relevant randomized controlled trials (RCTs)
Level II: Evidence obtained from at least one properly designed RCT
Level III: Evidence obtained from well-designed pseudo-randomized controlled trials (alternate allocation or some other method); comparative studies with concurrent controls and allocation not randomized, cohort studies, case-control studies, interrupted time series with a control group; comparative studies with historical control, two or more single arm studies, interrupted time series without a parallel control group
Level IV: Evidence obtained from case series, either post-test or pretest/post-test
