Is COVID-19 vaccination unmasking glomerulonephritis?

To the editor:

We read with great interest the reports of macroscopic hematuria occurring hours following coronavirus disease 2019 (COVID-19) vaccination in patients with known IgA nephropathy (IgAN).^{1 , 2} We report 2 previously healthy individuals who presented with macroscopic hematuria shortly after COVID-19 vaccination and were diagnosed with IgAN and crescentic glomerulonephritis, respectively.

A 41-year-old woman presented with headache, generalized myalgia, and new-onset macroscopic hematuria 1 day after the second dose of tozinameran (Pfizer-BioNtech COVID-19 vaccine). Her medical history was unremarkable except for gestational diabetes. She had no prior history of macroscopic or synpharyngitic hematuria, and urine analysis during pregnancy did not show any proteinuria. She was found to have subnephrotic range proteinuria, hypertension, and elevated serum creatinine on admission (Table 1 ). Renal biopsy performed showed IgAN with fibrocellular and fibrous crescents (Supplementary Figure S1). The chronic features on histopathology suggest preexisting undiagnosed IgAN that may have been unmasked after the vaccination.

Table 1.

Patient demographics and clinical characteristics

	Patient 1	Patient 2	Reference range
Clinical presentation
Age, yr/race/sex	41/Chinese/female	60/Malay/female
Medical history	Gestational diabetes mellitus	Hyperlipidemia
Date of vaccination
First dose	March 3, 2021	January 29, 2021
Second dose	March 26, 2021	February 19, 2021
Date of hematuria	March 27, 2021	February 20, 2021
Date of presentation to nephrology	March 28, 2021	March 31, 2021
Blood pressure at presentation, mm Hg	153/99	188/95
Significant laboratory resultsa
Serum creatinine, μmol/L	153	541
Urine dysmorphic red blood cells/μl	>200	>200
Urine protein-to-creatinine ratio, g/g	2.03	7.58
Serum Ig
Serum IgG, g/L	12.90	9.95	5.49–17.11
Serum IgA, g/L	6.40	1.62	0.47–3.59
Serum IgM, g/L	1.10	0.35	0.15–2.59
Complement C3, g/L	0.83	1.11	0.90–1.80
Complement C4, g/L	0.20	0.24	0.10–0.40
Anti-nuclear antibody	1:320; Homogeneous	Negative
Anti-GBM antibody (ELISA)	<1.5	10.0	<7 U/ml = negative; 7–10 U/ml = indeterminate; >10 U/ml = positive
Anti-GBM antibody (IF)	Not done	Positive
Histopathology report
Glomeruli	36 Glomeruli; 5 globally sclerosed. Focal proliferative glomerulonephritis with focal segment glomerulosclerosis; 6% cellular and 8% fibrocellular crescents	22 Glomeruli; 6 segmentally sclerosed. Diffuse crescentic glomerulonephritis with segmental sclerosis; 59% cellular, 14% fibrocellular, and 5% fibrous crescents
Tubules and interstitium	Mild tubulointerstitial inflammation. Mild tubular atrophy and interstitial fibrosis	Acute tubular injury Mild tubular atrophy
Vessels	Mild hyalinosis. No vasculitis or thrombotic microangiopathy	Mild intimal fibrosis
IF	Dominant glomerular IgA staining	Trace to 1+ linear IgG staining of glomerular basement membrane
Electron microscopy	Electron-dense deposits mostly in mesangial and paramesangial locations	No electron-dense deposits
Treatment	Pulse methylprednisolone, followed by oral prednisolone; i.v. cyclophosphamide	Pulse methylprednisolone, followed by oral prednisolone; oral cyclophosphamide; plasma exchange

ELISA, enzyme-linked immunosorbent assay; GBM, glomerular basement membrane; IF, immunofluorescence.

^aOther autoantibodies, such as anti–streptomycin O titer (ASOT), anti–double-stranded DNA (anti-dsDNA), anti–neutrophil cytoplasmic antibody (ANCA) by IF, anti-myeloperoxidase, and anti–proteinase 3 antibodies, were not detected.

A 60-year-old woman developed macroscopic hematuria 1 day after receiving the second dose of tozinameran. She was treated empirically for urinary tract infection, but presented 6 weeks later with persistent macroscopic hematuria, nephrotic-range proteinuria, hypertension, and acute kidney injury (Table 1). She had been well before her vaccination and did not have any respiratory, gastrointestinal, or constitutional symptoms, such as fever, chills, or myalgia, before and after vaccination. Kidney biopsy revealed crescentic glomerulonephritis with features consistent with anti–glomerular basement membrane nephritis (Supplementary Figure S2). Chest radiography showed no pulmonary involvement. Both patients did not have COVID-19 infection before vaccination, and the community transmission and infection rates were low during the time of vaccination. Seroconversion after vaccination was not evaluated in both patients.

Although there is insufficient evidence to postulate causality as it may be coincidental that COVID-19 vaccination closely preceded macroscopic hematuria, these cases emphasize the need for pharmacovigilance. Vigilance should be exercised in patients presenting with new-onset urinary abnormalities and hypertension following COVID-19 vaccination. Besides urinary tract infection and urological causes, glomerulonephritis should be considered in patients with unresolving macroscopic hematuria. Meanwhile, these isolated reports should not lead to vaccine hesitation during this pandemic as the benefits of vaccination strongly outweigh potential risks.