Pulmonary–Renal Syndromes

General Principles

Several distinct clinical entities make up the pulmonary–renal syndromes where there is vasculitic involvement of the alveolar and glomerular capillaries. Typically, this results in rapidly progressive renal failure often with concurrent pulmonary involvement in the form of alveolar hemorrhage. A nephritic picture predominates, with dysmorphic RBCs and RBC casts in the urine. Arthralgias, abdominal pain, and fever may represent other systemic manifestations.

Diagnosis

  • In anti-GBM antibody disease, circulating antibody to the α-3 chain of type IV collagen is deposited in the basement membrane of alveoli and glomeruli, resulting in linear staining on immunofluorescence. Goodpasture syndrome includes pulmonary involvement and can present with life-threatening alveolar hemorrhage. The presence of anti-GBM antibody in the serum supports the diagnosis, and 10%–30% of patients will have a positive ANCA serology as well.
  • In granulomatosis with polyangiitis (GPA; formerly known as Wegener granulomatosis), vasculitic lesions involve the small vessels of the kidneys and may also involve the lungs, skin, and gastrointestinal tract. As in anti-GBM antibody disease, pulmonary hemorrhage may be life threatening. Biopsy findings include a small-vessel vasculitis with noncaseating granuloma formation in the kidneys, lungs, or sinuses.
    • GPA is part of a group of diseases known as ANCA-positive vasculitis, or pauci-
immune glomerulonephritis (referring to the absence of immunostaining deposits), which includes Churg–Strauss syndrome (asthma and eosinophilia) and microscopic polyangiitis.
    • In GPA, there is a positive cytoplasmic ANCA (c-ANCA) directed against serine proteinase-3, whereas in microscopic polyangiitis and Churg-Strauss syndrome, there is a positive perinuclear ANCA (p-ANCA) directed against myeloperoxidase.

Treatment

  • In anti-GBM antibody disease, the goal of therapy is to clear the pathogenic antibody while suppressing new production. Treatment is with daily total volume plasmapheresis for approximately 14 days in conjunction with cyclophosphamide 2 mg/kg/d and glucocorticoids (IV methylprednisolone 7–15 mg/kg/d for 3 days, followed by oral prednisone 1 mg/kg/d). Immunosuppression is tapered over 8 weeks. Serial measurement of the anti-GBM antibody level is useful to monitor therapy, with plasmapheresis and immunosuppression continuing until it is undetectable.
  • Poor response to therapy is predicted by the presence of oliguria, Cr >5.7 mg/dL, or dialysis dependence on presentation. Even if the likelihood of renal recovery is low, evidence of pulmonary involvement warrants aggressive therapy.
  • Treatment of ANCA-positive vasculitis is with combined prednisone 1 mg/kg/d (with taper) and cyclophosphamide (IV at 1 g/m monthly or orally at 2 mg/kg/d) for at least 3 months to induce remission. Therapy should then continue with oral steroids for 1 year to prevent relapse. Rituximab given IV as four weekly doses of 375 mg/m, in combination with steroids, has also been approved for treatment of GPA.1 Addition of plasmapheresis does not appear to improve outcomes compared to prednisone/cyclophosphamide or prednisone/rituximab therapy alone. Double-strength sulfamethoxazole–trimethoprim given twice daily has been shown to reduce extrarenal relapses and to prevent Pneumocystis (carinii) jirovecii infection in patients on high-dose immunosuppression.

References

  1. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221-232.  [PMID:20647199]

Outline


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