The use of SARS-CoV-2 vaccines is a promising strategy to alleviate the severity of the coronavirus disease (COVID-19) pandemic. Several reports have shown that a vaccine for SARS-CoV-2 might cause relapse membranous nephropathy (MN).1,2 However, the development of de novo MN after an mRNA-1273 vaccination is rare.2,3 We report a patient who developed nephrotic syndrome as early as two weeks after the first dose of SARS-CoV-2 mRNA-1273 vaccination.
In late 2021, a 53-year-old Thai man with well-controlled type 2 diabetes developed nephrotic syndrome after receiving the SARS-CoV-2 mRNA-1273 vaccine. Two weeks following the initial vaccination, he observed pedal edema. He received a second vaccination because he was unaware that the edema may have been a side effect of the first and developed generalized edema. His most recent HbA1c level was 6.5%, and his urinalysis was normal. He had never been infected with COVID-19 before. Nephrotic syndrome was diagnosed. Serological tests were negative for secondary causes of nephrotic syndrome (antinuclear antibody, hepatitis B virus surface antigen, anti-hepatitis C virus antibody, and anti-human immunodeficiency virus antibody). Moreover, C3 and C4 complement levels were within reference ranges. Polymerase chain reaction results for SARS-CoV-2 in nasopharyngeal swabs were negative (Supplementary Fig. S1). After admission, intravenous furosemide was administered, and a percutaneous kidney biopsy was performed (Supplementary Fig. S2). Forty-eight glomeruli were found in kidney tissue without global or segmental glomerulosclerosis. All glomeruli had diffuse capillary wall thickening with small spikes and holes. The mesangial matrix was mildly increased without evidence of mesangial hypercellularity. The interstitial area and renal tubules were normal. Blood vessels were also normal without arteriolar hyalinosis. Unfortunately, immunohistochemistry staining was unsatisfactory. Serum PLA2R antibody was 68RU/mL by ELISA (reference, <20RU/mL). The diagnosis was PLA2R-positive, biopsy-proven, de novo MN. Age-appropriate cancer screening was completed with negative results. Treatment with prednisolone (1mg/kg/day) was initiated on the day of kidney biopsy (5 days after presentation). Over 3 weeks, peripheral edema gradually disappeared, spot UPCR steadily fell to 4.4mg/mg, and serum albumin reached 2.1g/dL. Two months after the diagnosis, oral cyclophosphamide was administered at a maximum of 100mg per day, along with a progressive decrease in prednisolone dosage. A partial remission was obtained after approximately six months of combination therapy. The spot UPCR result was 1.3mg/mg, whereas the serum albumin concentration was 3.8g/dL. The patient still achieved remission three months after immunosuppressive therapy was discontinued.
After searching EMBASE, MEDLINE, and SCOPUS in June 2023, this is the first report of biopsy-proven de novo PLA2R MN occurring after SARS-CoV-2 mRNA-1273 vaccination. Relapse of MN has been reported after injection with a SARS-CoV-2 mRNA vaccine and an inactivated vaccine.1,2 There have been reports of de novo MN associated with neural epidermal growth factor-like 1 (NELL1) antibodies2 or thrombospondin type-1 domain-containing 7A (TSHD7A) antibodies3 following injections of the BNT162b2 mRNA vaccine. However, de novo MN associated with anti-PLA2R antibodies after a first mRNA-1273 vaccination has not been reported.
The clinical appearance of MN in our case is interesting. Edema developed quickly: 2 weeks after the first vaccination. Patients with de novo MN usually develop edema 4–9 weeks after the second vaccination.2,4 Our case also had positive anti-PLA2R antibodies. These are well recognized as an autoantibody associated with primary MN. We propose that the mRNA-1273 vaccine aggravates the development of primary MN rather than causes MN. We base this on the rapid appearance of nephrotic syndrome symptoms and the development of anti-PLA2R antibodies.
Using the Naranjo algorithm, our patient was classified as having a possible association between mRNA-1273 vaccine and the development of PLA2R-associated MN with a score of four. It is unclear whether this is merely a coincidence or has a causal relationship. Although the temporal association between vaccination and the disease onset at 2 weeks in our case suggests vaccine-related causation of the immune process, the pathophysiological mechanisms responsible for this immune dysregulation have not yet been determined. Furthermore, the kidney biopsy showed no evidence of chronic damage; chronicity in the kidney tissue would suggest that the MN anteceded the vaccination.5 Our patient was treated with an oral combination of cyclophosphamide and prednisolone, like the treatment of patients with idiopathic primary membranous nephropathy and had comparable results.
In conclusion, this is the first report of biopsy-proven de novo PLA2R-associated MN occurring 2 weeks after a first SARS-CoV-2 mRNA-1273 vaccination. Considering our case, it appears that SARS-CoV-2 mRNA vaccines can (re)activate autoantibody-mediated kidney disease, which can be alleviated by immunosuppressive therapy.
Statement of ethicsThis study protocol was reviewed and approved by the Lampang Hospital Ethics Committee. Written informed consent was obtained from the patient for his participation in, and publication of this study and any accompanying images. A written informed consent obtained from the patient is available from the corresponding author upon reasonable request.
Funding sourceThis study was not supported financially by any public, private, or non-profit organization.
Conflict of interestNothing to disclose.
The following are the supplementary data to this article:
