Pulmonary-Renal Syndromes

GENERAL PRINCIPLES

Several distinct clinical entities make up the pulmonary-renal syndromes with vasculitic involvement of the alveolar and glomerular capillaries. Typically, this results in rapidly progressive renal failure with concurrent pulmonary involvement in the form of alveolar hemorrhage.

DIAGNOSIS

• In anti-GBM antibody disease, circulating antibody to the α-3 subunit of the noncollagenous (NCI) domain of type IV collagen is deposited in the basement membrane of glomeruli, resulting in linear staining on immunofluorescence. Goodpasture syndrome includes pulmonary involvement with damage to the alveolar basement membrane 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 also have a positive ANCA serology. This disease is more common in Caucasian patients, with peak age of 20-30 years and another peak at 60-70 years.

• In granulomatosis with polyangiitis (GPA), 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 small-vessel vasculitis with noncaseating granuloma formation in the kidneys, lungs, or sinuses.

î GPA is part of a group of diseases known as ANCA-associated vasculitis, or pauci-immune glomerulonephritis (referring to the absence of immunostaining deposits), which includes eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA).

î In GPA, there is a positive cytoplasmic ANCA (c-ANCA) directed against serine proteinase-3 (PR3) in 80%-90% of cases, whereas in MPA and EGPA, there is a positive perinuclear ANCA (p- ANCA) directed against myeloperoxidase (MPO) in 60% of cases.

TREATMENT

• In anti-GBM antibody disease, the goal of therapy is to clear and suppress production of the pathogenic antibodies. Treatment is with daily total volume (4 L) plasmapheresis for approximately 14 days PLUS oral cyclophosphamide 2 mg/kg/d for 3 months PLUS glucocorticoids (IV methylprednisolone 500 to 1000 mg/d IV for 3 days followed by oral prednisone, 1 mg/kg/d based on ideal body weight not exceeding a total of 80 mg/day with a slow taper off by 6 months). Serial measurement of the anti-GBM antibody level is useful to monitor therapy; the treatment goal is to achieve an undetectable level.

• 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.

• Management of ANCA-associated vasculitis includes corticosteroids (IV methylprednisolone 1 g/d for 3 days followed by prednisone 1 mg/kg/d not exceeding a total of 80 mg/d, tapered over 3-6 months), and either cyclophosphamide (15 mg/kg IV every 2 weeks for three doses then every 3 weeks for 3-6 months, or as 1.5-2 mg/kg/d PO for 3-6 months) or rituximab (either as 375 mg/m² weekly for 4 weeks, or as 1 g with two doses 14 days apart) to induce remission. Azathioprine can be substituted once remission is achieved (2 mg/kg/d). Methotrexate (15-25 mg/wk) was not found to be safer than azathioprine.³⁷ Mycophenolate mofetil (1.5-3 g/d in divided doses) was less efficacious in maintaining remission than azathioprine.³⁸ Maintenance therapy is continued for a duration dictated by the individual patient's clinical course, though a typical course may extend 12-24 months after a stable remission has been achieved.

• In a recent study, there was no benefit with the addition of plasma exchange.³⁹ This study also reported noninferiority of a reduced dose of prednisone (0.5 mg/kg/d not exceeding a total of 40 mg/d) as compared to the standard regimen.

• 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.