Anti-GBM disease without antibodies following H1N1 infection: A seronegative variant or an atypical entity?

Key observations

Atypical anti-GBM disease is a rare and intriguing condition characterized by linear immunoglobulin G (IgG) staining along the GBM, like classical anti-GBM disease, however, without an aggressive clinical course and/or diffuse crescentic glomerulonephritis and/or circulating anti-GBM antibodies detected by conventional assays.^[1] The present case could represent an atypical anti-GBM disease with typical kidney biopsy findings like anti-GBM disease and negative anti-GBM serology. Usually, atypical anti-GBM disease has an indolent clinical course with morphological findings of mesangial and/or endocapillary proliferative glomerulonephritis, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, mesangial sclerosis, focal crescents and/ or fibrinoid necrosis, and thrombotic microangiopathy-like glomerular endothelial changes.^[2] The present case could represent a rare manifestation of atypical anti-GBM disease presenting as crescentic glomerulonephritis with a negative anti-GBM serology. Nevertheless, given the diffuse crescents and presentation as rapidly progressive glomerulonephritis, we prefer the term “seronegative anti-GBM disease” for this case. However, it remains uncertain whether this presentation represents an extension of the phenotypic spectrum of classical anti-GBM disease, a variant of atypical anti-GBM disease, or merely a laboratory phenomenon.

The possible explanations for negative anti-GBM serology could be:

Change in the composition of epitope/antigen beyond the conventional goodpasture antigen [NC1 (non-collagenous) domain of alpha 3 subunit of type IV collagen] which could be caused by some trigger (yet to be defined, maybe infections or heavy metal exposure in this case) and resultant antibody formation which are not detected by conventional assay designed for detecting antibodies against the conventional antigen;

Immune sink phenomenon – high-affinity anti-GBM antibodies get trapped in the kidney with very low titre in circulation, not detectable by the conventional assays.

Low sensitivity of the conventional assays to detect the circulating antibodies.

The kidney biopsy findings were suggestive of crescentic glomerulonephritis secondary to anti-GBM antibodies. However, the serology for anti-GBM antibodies was negative. A prompt kidney biopsy, thorough search for the antibody (with more sensitive assays including western blot and biosensor system), categorizing the disease under an umbrella of anti-GBM disease, and quick initiation of the disease-directed treatment can be kidney/lifesaving in such cases.^[3] Negative serology for anti-GBM disease can be misleading, and the patient should not be deprived of disease-directed therapy.

Infectious association of anti-GBM disease with influenza has been a subject of rare anecdotes and should be sought in suspected cases.^[4] This case highlights a rare association with H1N1 infection.