The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis

Abstract

Classic anti-glomerular basement membrane (GBM) disease presents with rapidly progressive glomerulonephritis (GN) with or without pulmonary hemorrhage. On biopsy typical disease displays bright polytypic linear GBM staining for IgG by immunofluorescence and diffuse crescentic/necrotizing GN on light microscopy. Here, we studied 20 patients with atypical anti-GBM nephritis typified by bright linear GBM staining for immunoglobulins but without a diffuse crescentic phenotype. Patients had hematuria, proteinuria, and mild renal insufficiency, without pulmonary hemorrhage. Light microscopy showed endocapillary proliferative GN in 9 patients, mesangial proliferative GN in 6, membranoproliferative GN in 3, and focal segmental glomerulosclerosis with mesangial hypercellularity in 2. Eight of the 20 showed features of microangiopathy. Crescents/necrosis were absent in 12 and were focal in 8 patients. Bright linear GBM staining for IgG was seen in 17 patients, IgM in 2, and IgA in 1 patient, which was polytypic in 10 patients and monotypic in 10 patients. No circulating α3NC1 antibodies were detected by commercial ELISA. The 1-year patient and renal survival rates were 93% and 85%, respectively. Thus, atypical anti-GBM nephritis is a rare variant of anti-GBM disease characterized clinically by an indolent course, no pulmonary involvement, and undetectable circulating α3NC1 antibodies. Further studies are needed to characterize the molecular architecture of GBM autoantigens in these patients and establish optimal therapy.

Clustering of Anti-GBM Disease: Clues to an Environmental Trigger?

“…The fact that the temporal cluster had an over-representation of ANCA suggests that a different disease mechanism may be acting in these patients or as suggested by Canney et al (10), that the disease may present variably in different subpopulations. This is perhaps in keeping with other recent reports that have identified atypical presentations of anti-GBM disease, such as those associated with IgG4 anti-GBM antibodies (13) or what might be termed idiopathic linear Ig deposition (14), and it illustrates the challenges in reliably characterizing the full phenotypic spectrum of a very rare disorder.…”

Diagnostic and management challenges in Goodpasture’s (anti-glomerular basement membrane) disease

“…Interestingly, the presence of crescent formation was more commonly associated with polytypic IgG antibody profiles (deposits staining for both kappa and lambda light chains) compared to monotypic binding. Renal recovery and patient outcomes were better than typical anti-GBM disease, likely due to the pattern of renal injury but also the absence of lung involvement in this cohort (17). Finally, a number of dual positive (ANCA and anti-GBM) patients appear to have a predominant pauciimmune glomerulonephritis with relatively good rates of renal recovery.…”

“…IgG1 and IgG3 subclass restriction is most frequently found in patients both in sera and glomeruli and is more closely associated with disease severity; IgG3 has the greatest ability to activate complement and both IgG1 and IgG3 have the greatest affinity for binding Fc receptors (15,16). However, IgG4 subclass antibodies have also been found to be pathogenic both in isolation and co-existing with other immunoglobulin subclasses in atypical anti-GBM disease and are not detected by standard ELISA (14,17). Additionally, IgA anti-GBM antibodies are also not detected by standard methods and have been shown to bind various α(IV)chains (including 1,2,5 and 6) (18,19), which may not be represented in standard assays using 3(IV) (Figure 1 ).…”

“…Additionally, IgA anti-GBM antibodies are also not detected by standard methods and have been shown to bind various α(IV)chains (including 1,2,5 and 6) (18,19), which may not be represented in standard assays using 3(IV) (Figure 1 ). Antibodies bound to glomeruli have a longer half-life than their circulating counterparts and if combined with a low level of antibody titer, may make antibody detection in serum difficult (17,20). Other factors affecting antibody detection can include low level antibody affinity and the presence of high levels of circulating polyclonal antibodies contributing to false negative or positive results.…”

“…However, indolent disease and different patterns of injury with reduced crescent formation may also occur (17).…”