Rapidly progressive glomerulonephritis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Accociate editor-in-Chief: Nazia Fuad, M.D

Overview

Rapidly progressive glomerulonephritis as obvious from its name is a syndrome that rapidly progresses to acute renal failure so early diagnosis by renal biopsy and serology is very important. The treatment should be initiated as soon as possible to minimize the irreversible renal injury. treatment include supportive treatment and specific treatment. supportive treatment is to treat the infection if there is one, correct the volume status with dislysis if required and smoking cessation . Specific therapy focuses on induction and maintenance of remission . Emperic therapy should be started immediatly if the disease is very severe or if renal biopsy result is delayed. After the diagnosis is established, specific therapy can be started according to subtype of the disease.

Medical therapy

Medical therapy focuses to induce and then maintain the remission.

Pharmacologic Therapy

Induction of remission

Two pharmacologic agents that are used for induction of remission in patients with rapidly progressive glomerulonephritis are;

• Corticosteroids(high dose)
• Cyclophosphamide

1. Methylprednisone

• Intravenous (IV) 7 mg/kg/d at a maximum dose of 1 g for

2. Prednisone

• 1 mg/kg/d ,PO at a maximum dose of 80 mg for 3 weeks

• 2 mg/kg/d at a maximum dose of 120 mg for 3 months.

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

Immunosuppressive Therapy

Cyclophosphamide

• Addition of cyclophosphamide is necessary to prevent relapse
• relapse is commonly seen in patients getting glucocorticoids alone

• Can be given intravenously or orally

• 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

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.