Gender, IgA Nephropathy Linked to Gross Hematuria After COVID-19 Vaccination

Yusuke Suzuki, MD, PhD

Credit: Juntendo University

New research is providing clinicians with an overview of the clinicopathological characteristics of patients who develop gross hematuria after COVID-19 mRNA vaccination, suggesting female patients and patients with IgA nephropathy (IgAN) and IgA vasculitis (IgAV) are more likely to experience gross hematuria following receipt of the vaccine, especially after the second and third doses.¹

The prospective nationwide multicenter cohort study was conducted across 22 hospitals in Japan. Beyond the apparent sex and IgAN/IgAV bias, results also suggest specific galactose-deficient IgA1 (Gd-IgA1) and the adaptive immune system may be involved in the development of gross hematuria following vaccination.¹

“In the past 3 years, several cases of patients with IgAN presenting with gross hematuria after the COVID-19 mRNA vaccination have been reported. However, their detailed characteristics and long-term renal outcomes have not been evaluated,” Yusuke Suzuki, MD, PhD, a professor and chairman of the department of nephrology at Juntendo University in Japan, and colleagues wrote, later stating “To the best of our knowledge, this is the first study that investigated the change of biomarkers associated with the development of IgAN in patients with gross hematuria after the COVID-19 vaccination.”

A leading cause of glomerulonephritis and renal failure, the disease course of IgAN varies but generally progresses slowly over time and thus goes unnoticed until symptoms eventually present, the most common of which is hematuria. Cases of gross hematuria after COVID-19 vaccination have been reported but are thought to be distinct from gross hematuria after acute mucosal infection, part of the natural history of IgAN.²

To determine the postevent renal prognosis of patients who experienced gross hematuria after vaccination for COVID-19, their clinical backgrounds, and underlying mechanisms, investigators conducted a prospective nationwide multicenter cohort study of adult patients ≥ 18 years of age who presented with gross hematuria after receiving the COVID-19 vaccine at 22 hospitals in Japan between May 11, 2021, and October 31, 2022. Patients were followed up for 6 months after presenting with gross hematuria.¹

Investigators analyzed laboratory findings at the time of the first presentation at the hospital and 3 and 6 months thereafter, additionally exploring histopathological findings based on kidney biopsy specimens. Changes in pathological biomarkers of IgAN, including Gd-IgA1 and its immune complexes, were also evaluated.¹

During the study period, 127 patients with gross hematuria after COVID-19 vaccination were enrolled. Among the cohort, the median age was 39.9 (range, 18-81) years and the majority (73.2%) of patients were female. Investigators pointed out that except for the 10- to 19-year-old age group, female patients presented with gross hematuria more frequently than male patients in all age groups.¹

Results showed most patients experienced gross hematuria within 3 days after the second or third dose of the COVID-19 vaccine, and it resolved within a week in nearly all study participants. Investigators noted most patients had mild adverse events, such as fever, fatigue, or myalgia, associated with the COVID-19 mRNA vaccination, with the most frequent adverse reaction being fever (90.6%). However, none of the patients developed COVID-19 during the observational period.¹

Investigators pointed out 37 (29.1%) patients had already been diagnosed with IgAN (n = 35), IgAV (n = 1), or proliferative glomerulonephritis with monoclonal IgG deposits before the onset of gross hematuria based on kidney biopsy findings prior to vaccination. In the remaining 90 undiagnosed patients, 69 of the 70 who newly underwent kidney biopsy were diagnosed with IgAN (n = 67) or IgAV (n = 2).¹

To investigate whether certain pathological characteristics were specific to patients with IgAN and gross hematuria after COVID-19 vaccination, investigators compared the pathological findings of patients in the postvaccine gross hematuria group with those of 78 vaccine-unrelated patients with IgAN who were diagnosed at Juntendo University Hospital between May 11, 2018, and October 31, 2019, prior to the COVID-19 pandemic. Of note, no differences in clinical characteristics and serological findings were observed between the postvaccine and the nonvaccinated groups, except for differences in gender ratio.¹

Further analysis of patients with IgAN and gross hematuria revealed their histopathology did not show a high incidence of acute lesions such as endocapillary hypercellularity and crescentic lesions. According to the Oxford pathological classification of 62 cases with available results, mesangial hypercellularity was observed in 8 (12.9%) patients, endocapillary cellularity in 18 (29.0%) patients, segmental glomerulosclerosis/adhesion lesions in 32 (51.6%) patients, tubular atrophy/interstitial fibrosis in 4 (6.5%) patients, and cellular/fibrocellular crescents in 29 (46.8%) patients.¹

Among the biomarkers measured, serum Gd-IgA1 and immune complexes were comparable throughout the observation period. However, investigators pointed out only urinary Gd-IgA1 was increased at the time of gross hematuria.¹

Investigators outlined multiple limitations to these findings, including the potential lack of generalizability to patients from other racial backgrounds and/or countries; the fact that gross hematuria cases may have been biased toward mRNA vaccines more frequently administered in Japan; the exclusion of cases of severe disease or renal failure; and the inability to determine a causal relationship between vaccination and gross hematuria.¹

“Our prospective, multicenter observational cohort study reveals that GH after the vaccination is more likely to occur in patients with IgAN/IgAV and with a female bias. Moreover, among the biomarkers measured, only urinary Gd-IgA1 level significantly increased at the time of GH, suggesting that specific Gd-IgA1, not all, are carried to the glomerulus and thus may be involved in GH appearance,” investigators concluded.¹ “However, further studies are required on the causal relationship between vaccination and GH, the molecular mechanisms of disease, and gender bias.”

References

1. ^{Aoki R, Nihei Y, Matsuzaki K, et al. Gross Hematuria after the COVID-19 mRNA Vaccination: Nationwide Multicenter Prospective Cohort Study in Japan. Kidney360. doi:10.34067/KID.0000000000000498}
2. ^{Brooks, A. Vaccine-Related Hematuria in IgA Nephropathy Not Impacted by Infection-Related Hematuria. HCPLive. July 9, 2024. Accessed October 2, 2024. https://www.hcplive.com/view/vaccine-related-hematuria-iga-nephropathy-not-impacted-infection-related-hematuria}