Sequential studies of glomerular crescent formation in rats with antiglomerular basement membrane-induced glomerulonephritis and the role of coagulation factors

Abstract

Injection of presensitized rats with goat antiserum to rat glomerular basement membrane (GBM) results in a crescentic glomerulonephritis with typical linear deposition of goat IgG and host IgG and C3 along the GBM. Sequential renal biopsies from rats with this model of anti-GBM nephritis were studied by light, electron, and immunofluorescence microscopy to investigate the mechanisms of crescent formation. The localization of fibrin-related antigens (FRA) and factor VIII-related antigens (VIIIAGN) at different stages of disease was specifically studied since earlier studies of human glomerulonephritis had shown deposits of FRA without VIIIAGN in crescents and suggested that either a thrombin-independent mechanism might cause fibrin deposition or, alternatively, that glomerular fibrinolysis was relatively deficient within Bowman's space. Separation of the endothelium from the GBM or glomerular endothelial loss was the first change noted, a lesion that promotes intracapillary FRA deposition. Subsequently, intracapillary hypercellularity and GBM damage became progressively more severe. During the second and third weeks, coincident with early crescent formation, increasing amounts of FRA were noted within Bowman's space; FRA in crescents persisted throughout the study, whereas FRA within the glomerular tuft decreased over time. In early lesions, granular deposits of IgM and factor VIIIAGN were found diffusely within crescents. However, at later times, extracapillary deposits of these proteins and IgG were limited to the periphery of crescents within the markedly thickened and altered Bowman's capsule. Persistence of IgM and factor VIIIAGN at the periphery of older crescents appears to result from entrapment in areas less subject to cellular degradation and transport. Preferential clearance of FRA from the glomerular tuft suggests that fibrinolysis is less effective in Bowman's space than clearance mechanisms within glomerular capillaries.