eMedicine Specialties > Nephrology > Glomerular Diseases
Glomerulonephritis, Rapidly Progressive: Treatment & Medication
Updated: Sep 4, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Therapy for ANCA-associated disease consists of a combination of corticosteroids and cyclophosphamide. Treatment with steroids alone results in a 3-fold increase in the risk of relapse compared to combination therapy. The only predictor of renal survival is the serum creatinine value at the time of diagnosis. Therefore, a high index of suspicion is imperative to establish the diagnosis quickly and to institute treatment as soon as possible. Renal failure requiring dialysis is not a contraindication to treatment. Many patients can be removed from dialysis for an extended period (18 mo to 2 y).
- The regimen used by the Glomerular Disease Collaborative Network at the University of North Carolina at Chapel Hill3,4 is as follows:
- Administer methylprednisolone at 7 mg/kg/d intravenously (not to exceed 1 g) for 3 days, followed by oral prednisone at 1 mg/kg/d (not to exceed 80 mg) for 3 weeks, and then oral prednisone at 2 mg/kg every other day (not to exceed 120 mg) for 3 months. This dose is decreased by 25% every 4 weeks until the patient stops taking prednisone.
- Administer cyclophosphamide either intravenously or orally. Intravenous therapy is initially administered at a dose of 0.5 g/m2, and the oral dose is 2 mg/kg. Both are adjusted according to a 2-week leukocyte nadir count (goal 3000-4000/µL). The maximum intravenous dose is 1 g/m2. Oral and intravenous cyclophosphamide appears to be equally efficacious. However, this remains an area of controversy, particularly in the case of Wegener granulomatosis, for which some advocate oral therapy. The advantage to using the intravenous preparation is that the risk of cumulative toxicity is lower because a lower total dose is used.
- Another protocol, which has been used widely and with success in Europe, is the substitution of azathioprine for cyclophosphamide after a 3-month induction period. Azathioprine is administered at 2 mg/kg orally in a single daily dose. This is continued for 6-12 months.
- Methotrexate has been substituted for cyclophosphamide in the initial treatment of Wegener granulomatosis for mild disease and has been used for treatment after initial induction therapy with cyclophosphamide in more severe disease.5
- Plasmapheresis may be a beneficial addition to therapy for patients who present with severe renal failure (serum creatinine >6 mg/dL) or those who progress despite treatment.
- Other medications have been used in an attempt to attain a remission, such as intravenous immunoglobulin, antithymocyte antibody, and humanized monoclonal antibody to CD4 and CD25. None of these therapies has been well studied. They appear in the literature as case reports.
Consultations
Nephrology consultation should be obtained as early as possible in suspected cases of rapidly progressive glomerulonephritis.
Medication
The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.
Antineoplastic agents
Has potent immunosuppressive properties.
Cyclophosphamide (Cytoxan)
Chemically related to nitrogen mustards. Transformed primarily in the liver to active alkylating metabolites. The mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. PO and IV administration appear to be equally efficacious, although controversy exists.
Adult
0.5 g/m2 IV; not to exceed 1 g/m2; alternatively, 2 mg/kg PO
Adjust both according to a 2-wk leukocyte nadir count (goal 3000-4000/µL)
Pediatric
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function; preexisting malignancy
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Risks are greater with PO route because larger total dose is administered; regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; increased risk of neoplasia, in particular transitional cell carcinoma of the bladder; also associated with lymphoma, sterility, and amenorrhea, which usually resolves after cessation of therapy
Corticosteroids
Used for immunosuppressive and anti-inflammatory effects.
Methylprednisolone (Solu-Medrol)
Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability. After 3 d, switch to PO prednisone.
Adult
7 mg/kg IV qd for 3 d; not to exceed 1 g/d
Pediatric
Not established
Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking concurrently with diuretics
Documented hypersensitivity; viral, fungal, or tubercular skin infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use
Prednisone (Deltasone, Sterapred, Orasone)
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Adult
1 mg/kg PO qd for 3 wk (not to exceed 80 mg/d), followed by 2 mg/kg PO qod for 3 mo (not to exceed 120 mg/d), and then decrease dose by 25% q4wk until patient stops taking prednisone
Pediatric
Not established
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Immunosuppressant agents
May be an effective substitution for cyclophosphamide.
Azathioprine (Imuran)
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Protocol widely and successfully used in Europe is substitution of azathioprine for cyclophosphamide after 3-mo induction period.
Adult
2 mg/kg PO qd for 6-12 mo; this follows a 3-mo induction period with cyclophosphamide
Pediatric
Not established
Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Documented hypersensitivity; low levels of serum thiopurine methyl transferase
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check thiopurine methyl transferase level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated
More on Glomerulonephritis, Rapidly Progressive |
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| Differential Diagnoses & Workup: Glomerulonephritis, Rapidly Progressive |
 Treatment & Medication: Glomerulonephritis, Rapidly Progressive |
| Follow-up: Glomerulonephritis, Rapidly Progressive |
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References
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Hall JB, Wadham BM, Wood CJ, et al. Vasculitis and glomerulonephritis: a subgroup with an antineutrophil cytoplasmic antibody. Aust N Z J Med. Jun 1984;14(3):277-8. [Medline].
Falk RJ, Hogan S, Carey TS, et al. Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network. Ann Intern Med. Nov 1 1990;113(9):656-63. [Medline].
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Hogan SL, Nachman PH, Wilkman AS, et al. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. Jan 1996;7(1):23-32. [Medline].
Hotta O, Ishida A, Kimura T, et al. Improvements in treatment strategies for patients with antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis. Ther Apher Dial. Oct 2006;10(5):390-5. [Medline].
Jayne DR, Gaskin G, Pusey CD, et al. ANCA and predicting relapse in systemic vasculitis. QJM. Feb 1995;88(2):127-33. [Medline].
[Best Evidence] Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. Jul 2007;18(7):2180-8. [Medline].
Jennette JC. Renal involvement in systemic vasculilits. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Hepinstall's Pathology of the Kidney. 5th ed. Philadelphia: Lippincott-Raven; 1998:1059-94.
Pusey CD, Rees AJ, Evans DJ, et al. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int. Oct 1991;40(4):757-63. [Medline].
Savige J, Davies D, Falk RJ, et al. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int. Mar 2000;57(3):846-62. [Medline].
Stilmant MM, Bolton WK, Sturgill BC, et al. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. Feb 1979;15(2):184-95. [Medline].
Further Reading
Keywords
rapidly progressive glomerulonephritis, RPGN, kidney disease, renal disease, kidney disorder, renal disorder, Wegener granulomatosis, WG, Wegener's granulomatosis, Churg-Strauss disease, CS, Churg-Strauss syndrome, CSS, CSD, microscopic polyangiitis, MPA, circulating antineutrophil cytoplasmic antibody associated glomerulonephritis, ANCA disease, ANCA-associated disease, ANCA glomerulonephritis, ANCA-associated vasculitis, fibrinoid necrosis, extensive crescent formation, pauci-immune disease, pauci immune disease, renal-limited necrotizing crescentic glomerulonephritis, NCGN, systemic lupus erythematosus, SLE, inflammatory bowel disease, IBD, sclerosing cholangitis, autoimmune hepatitis, rheumatoid arthritis, RA, Felty syndrome, Felty's syndrome, ANCA-associated vasculitides
