Revisiting Gross Hematuria in IgA Nephropathy in the COVID-19 Era

Background: Sudden gross hematuria is occasionally observed in patients with IgA nephropathy (IgAN) after COVID-19 mRNA vaccination (v-GH), which is similar to that after acute mucosal infection as part of the natural history of IgAN (n-GH). V-GH and n-GH may share a clinical background or immune mechanism, although the relationship between the development of v-GH and n-GH is not yet clear. Therefore, we aimed to determine the effect of n-GH on the development of v-GH in patients with IgAN. Methods: Adult patients with IgAN who received COVID-19 mRNA vaccinations were enrolled from four hospitals in Japan. The incidence of v-GH in patients with n-GH was compared with that in patients without n-GH. Results: Among 459 participants, 287 (63%) did not have a history of n-GH, while 172 (37%) did. Of the patients without n-GH and with n-GH, 21 (7.3%) and 18 (10.5%), respectively, had v-GH, with no statistically significant difference between the groups (Figure 1A). Subgroup analyses demonstrated that this relationship was not changed by age and sex (Figure 1B and 1C). Multivariable analysis including previously reported related factors such as age, sex, and the presence of microscopic hematuria showed no significant association of n-GH with the development of v-GH (Odds ratio 0.89 [95% confidence interval 0.43−1.83]). Conclusion: Despite some possible similarities in pathogenesis, we failed to demonstrate a clear relationship between v-GH and n-GH, suggesting the involvement of factors specific to each condition. To better understand the pathogenesis of IgAN, further studies are warranted to elucidate the various immunological activation pathways that are commonly or differentially involved in the development of gross hematuria due to infection or vaccination.