Pulmonary-Renal Syndrome

Immunopathogenesis of Immune-Mediated Pulmonary-Renal Syndromes

Pulmonary-renal syndrome is typically the result of immune-mediated disease. Rapid access to diagnosis is essential because severe cases may result in fatal pulmonary hemorrhage and oliguric kidney failure, and cases of all severities are potentially reversible with early recognition and aggressive management. The pathogenesis of immune-mediated pulmonary-renal syndrome is complex and involves either autoantibody deposition or local recognition of autoantigen peptides by autoimmune effector T cells. Tissue damage results from small vessel inflammation triggered by these humoral and cellular mechanisms in addition to their downstream activation of the complement pathway, leukocyte recruitment, and subsequent release of soluble tissue-damaging mediators, including enzymes, reactive oxygen species, arachidonic acid–derived products, cytokines, and chemokines. This cascade of immune activation results in local inflammation, tissue injury, increased capillary permeability, and loss of affected tissue structure and function. In the lung and kidney this results in necrosis, hemorrhage, and loss of effective glomerular filtration and pulmonary gas exchange, causing the clinical syndromes of respiratory failure and oliguric kidney failure.

Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

AAV is an autoimmune-mediated, necrotizing, small vessel vasculitis targeting arterioles, venules, and capillaries. Such small vessel necrosis affects glomerular filtration in the kidney and gas exchange in the lung. ANCAs are likely to be pathogenic and result from autoimmunity to leukocyte lysosomal enzymes. The two major target autoantigens in AAV are myeloperoxidase (MPO) and proteinase 3 (PR3). Although ANCAs are likely to be pathogenic, the affected tissues frequently are injured without the local deposition of ANCA. In vitro studies demonstrate that MPO and PR3 are expressed in neutrophils, and ANCA can activate these neutrophils, resulting in degranulation, release of reactive oxygen species, and increased neutrophil adhesion to endothelial cells. It is likely that ANCAs bind their target autoantigens in response to a trigger such as sepsis, which induces a translocation of PR3 and/or MPO to the neutrophil cell membrane. As neutrophils circulate freely, the impact of AAV is systemic. Those neutrophils expressing PR3 or MPO that are bound by ANCA become localized to the small vessels of glomeruli, pulmonary endothelium, and perineural microcirculation, acting as local targets for autoimmune effector T cells and leading to further recruitment of macrophages and neutrophils. In each location affected by ANCA-bound neutrophils, disease-specific manifestations arise.

In the kidney, inflammation induces acute proliferative, focal and segmental, necrotizing, crescentic glomerulonephritis with little antibody deposition, hence the term “pauci-immune crescentic glomerulonephritis.” In the lung, interstitial infiltrates and hemorrhage are major features. The inflammation may include granulomas, which are typically a feature of PR3-ANCA autoimmunity in GPA. Pulmonary infiltrates, glomerulonephritis, and/or other organ involvement without the presence of granulomas is present in MPA and typically is associated with MPO-ANCA autoimmunity.

Anti–glomerular Basement Membrane Disease (Goodpasture Disease)

Anti–GBM disease is an immune complex–mediated condition affecting the lung and kidney. The autoimmune target in anti–GBM disease is the noncollagenous domain of the alpha-3 chain of type IV collagen. This target antigen is expressed in the glomerular basement membrane and alveolar capillaries. It is a cryptic epitope, and case studies implicate hydrocarbons, infections, cigarette smoking, and lithotripsy in the onset of disease, perhaps through revealing the epitope to the systemic autoimmune process.

In vitro, anti–GBM disease can be induced via development of an immune response to a peptide that is antisense or complementary to the autoantigen. The anti–GBM antibody is directly pathogenic and can induce nephritis in primates, and in the presence of circulating anti–GBM antibody, renal allografts rapidly develop recurrent nephritis. The presence of T cells and macrophages in glomerular lesions suggests cellular immunity also is involved. Histologically, strong linear deposition of IgG is seen in affected kidney and lung biopsy specimens. Interestingly, one third of patients with anti–GBM disease have concurrent circulating ANCAs. Class II major histocompatibility complex (MHC), in particular HLA-DR2, is associated with anti–GBM disease. Specifically, HLA-DRB1*1501 and 1502 alleles confer increased susceptibility, whereas DRB1*07 and 01 confer protection.

Immune Complex–Mediated Pulmonary-Renal Syndrome

The best-described immune complex–mediated cause of pulmonary-renal syndrome is systemic lupus erythematosus (SLE). Although pulmonary involvement is uncommon, it may occur and can present as pulmonary hemorrhage. Consistent with all manifestations of SLE, the target autoantigens are multiple and typically include antinuclear antigens (ANA) and anti–double-stranded DNA (anti-dsDNA). SLE-induced immune complex deposition in the kidneys and lungs has a characteristic pattern of injury with granular deposition of multiple subclasses of immunoglobulin in the affected organs. SLE-related, or lupus, nephritis may be divided into six different histopathologic patterns or classes, according to the Renal Pathology Society/International Society of Nephrology (RPS/ISN) classification system. Of these, class IV diffuse proliferative glomerulonephritis is associated most commonly with pulmonary disease and portends the worst prognosis.

Other forms of crescentic glomerulonephritis, such as mesangiocapillary glomerulonephritis, IgAV, inflammatory myopathies, and idiopathic cryoglobulinemia are likely to be immune-mediated and also can occur as pulmonary-renal syndrome.

Immune complex deposition also may be associated with several non–immune-mediated causes of rapidly progressive glomerulonephritis, which simultaneously can involve the lung. These include subacute bacterial endocarditis, in which host immunity to persistent intravascular microbiologic antigens causes immune complex–mediated vasculitis, as well as postinfectious glomerulonephritis and hepatitis C–induced cryoglobulinemia.