Anti-Glomerular Basement Membrane Disease

Abstract

Anti-glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs, although the inciting events that induce the autoimmune response are not fully understood. The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCA-associated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors.

Keywords: Anti-Glomerular Basement Membrane Disease; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoantigens; Autoimmunity; Capillaries; Glomerular Basement Membrane; Glomerulonephritis; Hereditary; Humans; Immunology and pathology; Inflammation; Membranous; Nephritis; Plasma Exchange; Plasmapheresis; Prognosis; Recurrence; Renal Insufficiency; Retrospective Studies; glomerulonephritis; kidney; kidney transplantation; renal dialysis; vasculitis.

Figure 1.

Structure of the glomerular basement membrane. In its native form, the collagen IV network in the glomerular basement membrane consists of triple-helical protomers of α3, α4, and α5 chains (shown individually in [A]). The carboxy-terminal domains of these α3 α4 α5 protomers form a trimeric “cap” (B), end-to-end association of which results in the formation of the hexameric NC1 domain (C). The quaternary structure of this hexamer is stabilized by hydrophobic and hydrophilic interactions across the planar surfaces of opposing trimers, and reinforced by sulfilimine bonds crosslinking opposing NC1 domains. Two key autoantibody epitopes within α3(IV)NC1 have been described, designated EA (incorporating residues 17–31 toward the amino terminus) and EB (residues 127–141 toward the carboxy terminus), which in the native form are sequestered at the junction with α4 and α5 chains within the triple helical structure. Binding through 7s domains (shown in orange) completes the lattice-like structure of the type IV collagen network (D). Reprinted from reference .

Figure 2.

Kidney biopsy sample immunofluorescence for IgG revealing linear deposits along the glomerular basement membrane, and weaker staining of Bowman’s capsule and tubular basement membranes.

Figure 3.

Renal histopathology in anti–glomerular basement membrane (anti-GBM) GN. (A–C) Hematoxylin and eosin–stained sections demonstrating (A) segmental fibrinoid necrotizing lesion in early anti-GBM GN; (B) small, circumscribed cellular crescent; and (C) large, circumferential cellular crescent. (D–E) Demonstrate the use of Jones methylamine silver stain to delineate glomerular and tubular basement membranes, clearly identifying a segmental area of extracapillary proliferation (D). (E) Demonstrates obliteration of the glomerular architecture and rupture of Bowman’s capsule, with extravasation of red blood cells into the urinary space, and significant peri-glomerular inflammation. (F) Adjacent glomeruli with synchronous cellular crescent formation typical of anti-GBM disease.