Rapidly progressive glomerulonephritis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Medical therapy

Treatment of RPGN must be very aggressive due to its generally poor prognosis if left unmanaged. Hence, treatment must not await the results of the kidney biopsy; but must be initiated as soon as possible because fibrosis may start very early during the course of the disease. Presence of fibrosis marks irreversible damage.

In some studies, patients already on dialysis were also responsive to therapy and treatment should not be delayed for these patients either. Nonetheless, the true response among this specific sub-population and their associated risks and outcomes are poorly understood.

Pharmacologic Therapy

In 1990, the Glomerular Disease Collaborative Network published its findings after a 24-month follow-up of 70 patients with ANCA and pauci-immune necrotizing and crescentic glomerulonephritis. In the cohort trial, 14 patients were treated with corticosteroids, 30 patients received both corticosteroids and oral cyclophosphamide, 15 patients received both corticosteroids and intravenous cyclophosphamide, and 11 patients received no treatment. The authors concluded that oral corticosteroids with either oral or intravenous cyclophosphamide regimens are equally effective treatment options for patients with ANCA-associated glomerulonephritis for patients with renal-limited disease, glomerulonephritis, and alveolar hemorrhage.

In 1996, Nachman and colleagues outlined a protocol for therapeutic management of patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with ANCA. In the trial, 107 patients were enrolled. 25 patients received only corticosteroids, 72 received cyclophosphamide and corticosteroids, and 10 patients did not receive cyclophosphamide or corticosteroids. The authors concluded that 77.3% of those receiving therapy remitted, and 67% of those who were not in remission following the first regimen were in remission after a second course of the same regimen.

Glucocorticoids

Regimen

Follow step 1, then 2, then 3
1. Methylprednisone

• Route: Intravenous (IV)
• Dose: 7 mg/kg/d at a maximum dose of 1 g
• Duration: 3 days

2. Prednisone

• Route: Per Os (PO)
• First Dose: 1 mg/kg/d at a maximum dose of 80 mg for 3 weeks
• Second Dose: 2 mg/kg/d at a maximum dose of 120 mg for 3 months

3. Taper

• Taper patient off steroids by deceasing 25% of prednisone dose every 4 weeks until patient stops

Immunosuppressive Therapy

Cyclophosphamide

• Route: IV or PO
• Dose:
  • IV: 0.5 g/m2, at a maximum dose of 1g/m2. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL.
  • PO: 2 mg/kg. Dose adjusted to a 2-week leukocyte nadir count goal 3000-4000/uL

Addition of cyclophosphamides for patients with RPGN is necessary to prevent relapse, which is commonly seen in patients receiving glucocorticoids alone and leads to remission in more than 80% of the cases. The studies excluded patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis). In cases of granulomatosis with polyangiitis (formerly Wegener granulomatosis), oral therapy has been preferred by some experts. IV cyclophosphamide generally have less total dose and thus less toxicity than its oral counterpart.

Azathioprine
PO azathioprine (AZA) has been recommended by some experts to replace cyclophosphamide after an initial 3-month induction period of cyclophosphamide.

• Route: PO
• Dose: 2 mg/kg
• Duration: 6-12 months

Methotrexate
Methotrexate (MTX) has been used in mild forms of granulomatosis with polyangiitis (formerly Wegener granulomatosis) as a replacement for cyclophosphamide. In more severe forms, it has been used following short-term induction therapy with cyclophosphamide. Villa-Forte and colleagues enrolled 82 patients in 2007; 70% of those had severe disease on admission and required cyclophosphamide for remission induction. Severity was based on clinical and histopathological findings: pulmonary hemorrhage, neurological abnormalities, need for dialysis, serum creatinine > 2 mg/dL, and RPGN. 72% of patients were in remission after 1 year, and 91% reached remission at any duration. Relapse rates were as high as 66% within 2 years, most of which responded to reinitiation of therapy.

Induction of Remission for Severe Cases:

• Cyclophosphamide
  • Route: PO
  • Dose: 2 mg/kg adjusted for renal function and WBC count
• Prednisone
  • Route: PO
  • Dose: 1 mg/kg

Initial Treatment:

• Methotrexate (MTX)
  • Route: PO
  • Dose: 15 mg/wk increased over 4-8 weeks to 25 mg/wk if tolerated and if necessary
  • Duration: At least 2 years
• Prednisone
  • Route: PO
  • Dose: 1 mg/kg/d to gradually decrease as long as no documented disease recurrence

Rituximab
The RITUXVAS (Randomized trial of Rituximab vs. Cyclophosphamide in ANCA-Associated Vasculitis) and RAVE (Rituximab in ANCA-Associated Vasculitis Trial) trials showed in 2012 that anti-B therapy by rituximab, a chimeric anti-human CD20 monoclonal antibody, may improve renal survival in patients with vasculitis and positive ANCA and had renal impairment, including patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis). The findings were based on earlier reports of improved outcome using rituximab. Regimen: Rituximab:

• Route: IV
• Dose: 375 mg/m2
• Duration: Once weekly 4 consecutive weeks

Cyclophosphamide

• Route: IV
• Dose: 15 mg/kg
• Duration: Co-administed with 1st and 3rd rituximab doses

Methylprednisolone

• Route: IV and PO
• Dose: 1g IV then followed by daily low-dose oral corticosteroids for maintenance

Other
Some medications have never been studied. However, they have been shown to be effective based on findings in case reports. These medications include:

• IV immunoglobulins (Igs)
• Antithymocyte antibody
• Monoclonal antibodies to CD4
• Monoclonal antibodies to CD25

Plasma Exchange

Indications of plasma exchange:

• Removal of circulating auto-antibodies in patients with anti-GBM antibody disease

• Patients with high risk of renal failure

• Patients with serum creatinine > 2.3 mg/dL
• Patients who do not respond to pharmacologic therapy

• Patients diagnosed with pauci-immune crescenteric glomerulonephriits with ESRD and need dialysis

The true value of plasma exchange has been demonstrated by a few small trials in secondary analysis. The real indications and benefit to risk ratio of plasma exchange are yet to be elucidated.