Anti-glomerular basement membrane glomerulonephritis following COVID-19 infection without clinically evident pneumonia

To the Editor,

Anti-glomerular basement membrane (anti-GBM) glomerulonephritis is a rare autoimmune disease, usually presenting with rapidly progressing glomerulonephritis (RPGN). The inciting factor for remains elusive, although observations of spatial and temporal clustering support the hypothesis of an environmental trigger, including infections [1]. Recent reports of de-novo and relapsing anti-GBM cases occurring in close temporal association with COVID-19 infections have emerged [2–5]. We present a case of anti-GBM glomerulonephritis preceded by a mild COVID-19 infection.

A 58-year-old Chinese female presented with RPGN four weeks after a mild COVID-19 infection. She reported painless, gross hematuria one week after the infection, with prolonged pyrexia and malaise which persisted despite improving upper respiratory tract symptoms. She was initially treated for presumptive cystitis but re-presented for non-resolving symptoms. She had hypertension, gross hematuria, nephrotic range proteinuria and acute kidney injury (AKI) at presentation (Fig. 1A). Computed tomography (CT) of the lungs showed no evidence of pulmonary hemorrhage or COVID-19 pneumonitis.

Fig. 1.

A Patient demographics and clinical characteristics. B I, II. Glomerulus shows a cellular crescent that is near-circumferential, accompanied by fibrin (arrows), PAS (A), PGMT (B), original magnification × 400. III. Acute tubular damage shows tubules lined by variably flattened epithelial cells with diminished brush borders, with interstitial lymphoplasmacytic infiltrates. A glomerulus that is relatively normocellular, and another glomerulus with a circumferential crescent with disruption of the Bowman’s capsular membrane, are seen, PAS, original magnification × 200. IV. Immunofluorescence for IgG shows 1+ linear staining of glomerular capillary walls, original magnification × 400. V. Electron microscopy shows a leucocyte within the capillary lumen, without any electron densities, original magnification × 9600

A kidney biopsy performed revealed diffuse crescentic glomerulonephritis (Fig. 1B). Immunofluorescence showed linear staining for IgG, consistent with anti-GBM glomerulonephritis. Anti-GBM antibody was positive with titres of 388 U/ml. She received 20 sessions of plasmapheresis, pulsed methylprednisolone and oral cyclophosphamide. Dialysis was initiated for progressive AKI. Clinical course was complicated by cytomegalovirus viremia requiring ganciclovir treatment, but immunosuppression was continued at attenuated doses. Immunosuppression was subsequently withdrawn in view of dialysis dependency at 3 months. However, partial renal recovery was eventually observed and dialysis was successfully weaned off after 5 months.

The close temporal association of anti-GBM glomerulonephritis with the COVID-19 infection suggests a possible link, although the exact initiating mechanism(s) remains obscure. Prior such reports surfaced earlier in the pandemic before the Omicron variant became prevalent [4, 5]. It was postulated that COVID-19 virus may infect and damage alveolar endothelial cells, leading to exposure of a cryptic epitope on the non-collagenous domain of type 4 collagen, precipitating the production of autoantibodies [2]. This hypothesis was supported by documented findings of COVID-19 pneumonia in affected individuals in a case series [5]. Interestingly, the prevailing local variant at the time of our patient’s infection was the Omicron variant, which frequently spares the alveolar compartment [6]. Consistent with this understanding, our patient also reported predominantly upper respiratory symptoms and lacked radiologically evident pneumonia on CT. This may argue against the earlier proposed mechanism of disease initiation, although subclinical pulmonary injury cannot be completely excluded. The alternative mechanism of unspecific bystander activation of pre-existing autoreactive T and B lymphocytes during the COVID-infection may be a more plausible explanation for anti-GBM disease in our case.

Despite the perceived increased clustering of anti-GBM glomerulonephritis during the COVID-19 pandemic, the overall incidence in relation to the total number of COVID-19 cases globally likely indicates a relative rarity of this association. Nevertheless, awareness of the possible relationship should be raised given the potentially devastating condition and benefit of early diagnosis and treatment. New onset macro-hematuria and persistent prodromal symptoms following COVID-19 infection is a recurring observation [4], and should warrant consideration of acute glomerulonephritis as a differential.

Data Availability

All data are included in the manuscript.