De novo and relapsing glomerulonephritis after COVID‐19 vaccination: how much do we know?

Coronavirus disease 2019 (COVID-19) is one of the deadliest viral pandemic in human history. To date, over 267 million people have been infected with a death toll of over 5.2 million around the world. To curb the spread of this infection, over 8.2 billion doses of COVID-19 vaccine have been administered so far. While vaccine efficacy has become palpable in many countries with a high vaccination rate,1 there is mounting concern on the increasing incidence of vaccine-associated adverse events. De novo onset of glomerulonephritis (GN) after influenza, hepatitis B, and rabies immunization was previously reported, including minimal change disease (MCD), membranous nephropathy, IgA nephropathy (IgAN) and ANCA-associated vasculitis with variable severity and outcomes.2-5 With the ongoing massive vaccination programme worldwide, it is not surprising that reports of de novo GN after COVID-19 vaccination emerged.6-9 Clinicians often lack data to advise patients about the chance of relapse of GN after COVID19 vaccination and the current recommendation is based on case reports and clinical experience. In this issue of Nephrology, three case series are published with de novo or relapse of different glomerulonephritides after COVID-19 mRNA vaccination. Lo et al10 from Hong Kong reported two IgAN patients who developed gross haematuria within hours of receiving the BNT162b2 COVID-19 vaccine. Kidney function was preserved in both patients and there was no significant change in the level of proteinuria. Haematuria was the most common symptom in other case series and significant acute kidney injury (AKI) that requires dialysis support is uncommon.6 As a mucosal IgA response is known to trigger haematuria in IgAN, it remains unclear whether the vaccine could have stimulated muscosal immunity. However, IgAN is more common in the Asian population, and the frequency and severity of vaccine-associated GN flare may be different from other ethnic groups. This is exemplified by the markedly different prevalence of AKI among COVID-19 patients.11, 12 More data from different ethnic populations may help to inform the frequency, severity and risk of relapse of IgAN after immunization. From Australia, Baskaran et al13 reported two cases of de novo MCD following COVID-19 vaccination. The first case developed MCD disease 3 weeks after receiving the BNT162b2 mRNA COVID-19 vaccine. The patient responded well to high-dose corticosteroid. The other case was a middle-aged man with ascites and peripheral oedema 1 week after the second dose of the ChAdOx1 nCoV-19 vaccine when he took non-steroidal anti-inflammatory drug (NSAID). The clinical course was complicated by oliguric AKI and subsequent kidney biopsy showed acute tubulointerstitial nephritis (ATIN) and MCD. Proteinuria and AKI were both ameliorated after high-dose corticosteroid. Although the authors believed NSAID14 was the culprit, the association of ATIN with COVID-19 vaccine cannot be fully excluded. ATIN after COVID-19 vaccination was reported15 and use of NSAID here also complicated the clinical picture. David et al16 from Australia reported two cases of relapse of ANCA-associated vasculitis after ChAdOx1 nCoV-19 vaccination. Two elderly patients with history of microscopic polyangiitis (MPA) developed active pauci-immune crescentic glomerulonephritis after ChAdOx1 nCoV-19 vaccination. Patients had different outcome after treatment with heavy immunosuppression. De novo ANCA-associated vasculitis with pauci-immune crescentic glomerulonephritis after immunization was reported in the past17 and the underlying mechanism was unclear. The authors suggested that in elderly patients with a history of MPA, careful monitoring of kidney function and ANCA antibody titre after vaccination could detect early relapse of disease. From these case series, mRNA COVID-19 vaccine appeared to cause de novo or relapsing GN in some individuals and several mechanisms have been postulated. Patients may have subclinical immune dysregulation being unmasked by immunization. Immunogenicity can be increased after vaccination due to a surge in cell-mediated or antibody-mediated immune responses. Antibody to SARS-CoV-2 spike protein may also cross react with other self-human antigens and promote autoimmunity. Finally, direct cytotoxicity to podocytes may occur after immunization.6 Immune response after vaccination is known to be impaired in advanced chronic kidney disease, for example, Hepatitis B vaccine. A higher or booster dose or imiquimod enhanced injection was recommended in dialysis patients to improve immunogenicity.18 A third dose of COVID-19 vaccine is currently recommended in chronic kidney disease patients who are on dialysis or after kidney transplantation in some countries,14, 19, 20 which was believed to confer more benefit than harm. Nevertheless, our perception of the risk and severity of de novo or relapsing GN after COVID-19 vaccine is not fully understood. This can be a challenge during vaccination counselling to patients with a background of immune-related GN. Further research is required to delineate the relation between COVID-19 vaccination and GN, be it de novo or relapsing, which can provide a more scientific basis for patient counselling, guidance in risk stratification and monitoring for relapse. ATPC is supported by the Croucher Senior Medical Research Fellowship awarded to SCWT in 2019. The funder had no role in writing the manuscript.