Crescentic Glomerulonephritis Medication
- Author: Malvinder S Parmar, MB, MS; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Principles of therapy include supportive and specific therapies. Supportive therapy involves control of infection (especially Pneumocystis jiroveci (PCP) infection with trimethoprim-sulfamethoxazole or Atovaquone), control of volume status (providing dialysis if required), and smoking cessation.
Goals of specific therapy
Induction of remission
The initial therapy is to induce remission and typically consists of glucocorticoids and cyclophosphamide, and this induces remission in 85-90% of patients in 2-6 months, with about 75% achieving complete remission. Recently, rituximab in RAVE[4, 5] and RITUXIVAS trials was shown to be not inferior to cyclophosphamide and may be used in patients who cannot take or refuse to take cyclophosphamide. Methotrexate is an option in patients with mild disease, but the relapse rate was significantly higher with methotrexate compared with cyclophosphamide (70% vs 47%, respectively). Etanercept in the WGET (Wegener's Granulomatosis Etanercept Trial) achieved remission in just over 90% of patients but had about a 50% relapse rate at 27 months.
At present, the mainstay of therapy remains cyclophosphamide and steroids for induction of remission, with an option to consider rituximab in select patients.
Plasma exchange, although still controversial in patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal limited necrotizing glomerulonephritis, is useful in patients with advanced renal failure (serum creatinine >500 µmol/L or requiring dialysis), in patients with severe pulmonary hemorrhage, and when associated with antiglomerular basement membrane antibody disease. Although short-term results with plasma exchange are encouraging, the long-term benefits remain unclear, and the PEXIVAS (Plasma Exchange in VASculitis) trial is currently ongoing to better define the role of plasma exchange.
Maintenance of remission to prevent relapse
As relapses are common, especially in granulomatosis with polyangiitis and microscopic polyangiitis, it is important to continue with immunosuppressive therapy, using less toxic agents, to maintain remission and prevent relapse. Most often, either azathioprine or methotrexate is used for maintenance therapy to reduce risk of relapse. Other agents that have been used for maintenance therapy include etanercept in WGET and mycophenolate.
In a recent pilot study, rituximab maintenance therapy was well tolerated but did not completely prevent relapses and persistent "grumbling" disease ; however, in the interim analysis of an ongoing trial, rituximab at 500 mg every 6-months by the French Vasculitis Study Group in the MAINRISTAN trial show a remarkable reduction in relapse rate with rituximab versus azathioprine, at 28 months (5% vs 25%) .
Pulses of intravenous methylprednisolone (5-20 mg/kg) followed by high-dose oral prednisone (2 mg/kg) daily or on alternate days for 2-3 months have shown improved 1-year renal survival rates of 40-70%.
Potent anti-inflammatory steroid with greater anti-inflammatory potency and fewer tendencies to induce retention of salt and water than prednisolone.
Decreases inflammation through multiple mechanisms. Reduced to its pharmacologically active form prednisolone. When used on a long-term basis, alternate-day therapy may elicit fewer adverse effects than daily therapy.
Immunosuppressive agents (cytotoxics)
Addition of cytotoxic agents to corticosteroids has yielded varying success in treating patients with crescentic glomerulonephritis. Although pulse cyclophosphamide is often preferred in lupus nephritis, oral cyclophosphamide appears to have an advantage in Wegener granulomatosis.
Oral versus intravenous: Recently completed, prospectively randomized Cyclophosphamide daily oral versus PulSed (CYCLOPS) trial has shown very little difference in time to remission and time to relapse between daily oral or intermittent intravenous cyclophosphamide for induction therapy.
Cyclophosphamide 3 mg/kg/d for 12 weeks is a common recommendation, but the duration of therapy may be longer (4-6 mo) in patients with pauci-immune glomerulonephritis. This therapy should be followed by the administration of azathioprine (1.5-2 mg/kg/d) or methotrexate (5-20 mg qwk as a single dose) until the patient is in remission for at least 6-12 months. The duration of azathioprine therapy to prevent further relapses is unknown, but it should be at least for 2 years.
Continuing cyclophosphamide for longer than 6 months is not necessary, as recently shown by Cyclophosphamide versus Azathioprine during Remission (CYCAZAREM) trial, where the time to relapse was identical whether the patient was given cyclophosphamide for less than 6 months or more than 6 months.
Mycophenolate mofetil at 0.75-1 g twice daily versus azathioprine was compared for maintenance of remission in an open-label, randomized, controlled trial. Both agents were withdrawn after 42 months and at a median follow-up of 39 months, but relapses were significantly higher in mycophenolate-treated group than in the azathioprine group (55% vs 38%).
Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none–type reaction.
Mechanism by which azathioprine affects autoimmune diseases is unknown. Slow acting, and its effects may persist after discontinuation.
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy- chain variable region sequences and human constant region sequences.
Therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.
Long-term treatment with TMP (160 mg) and SMX (800 mg) bid has been reported in a prospective, controlled, double-blind trial to sustain remission of Wegener granulomatosis. The mechanism of this effect is not clear. Eradication of Staphylococcus aureus in the anterior nares of patients with Wegener granulomatosis has recently been reported to sustain remission of Wegener granulomatosis. TMP-SMX is also helpful as Pneumocystis carinii pneumonia (PCP) prophylaxis in patients who are on corticosteroids and other immunosuppressive agents.
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