Histologic correlates of gross hematuria following Moderna COVID-19 vaccine in patients with IgA nephropathy
Authors: Satoru Kudose, Paul Friedmann, Oltjon Albajrami, Vivette D. D’Agati
Journal: Kidney International (2021)

We read with interest the recent reports of gross hematuria occurring in 4 patients with IgA nephropathy shortly following the second dose of mRNA vaccine for coronavirus disease 2019 (COVID-19).1Negrea L. Rovin B.H. Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.Kidney Int. 2021; 99: 1487Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 2Rahim S.E.G. Lin J.T. Wang J.C. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination.Kidney Int. 2021; 100: 238Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 3Tan H.Z. Tan R.Y. Choo J.C.J. et al.Is COVID-19 vaccination unmasking glomerulonephritis?.Kidney Int. 2021; 100: 469-471Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar These include 2 cases following the Moderna vaccine1Negrea L. Rovin B.H. Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.Kidney Int. 2021; 99: 1487Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and 2 following the Pfizer BioNTech vaccine.2Rahim S.E.G. Lin J.T. Wang J.C. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination.Kidney Int. 2021; 100: 238Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar,3Tan H.Z. Tan R.Y. Choo J.C.J. et al.Is COVID-19 vaccination unmasking glomerulonephritis?.Kidney Int. 2021; 100: 469-471Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar As only 1 of these patients had a postvaccination biopsy performed,3Tan H.Z. Tan R.Y. Choo J.C.J. et al.Is COVID-19 vaccination unmasking glomerulonephritis?.Kidney Int. 2021; 100: 469-471Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar we report the biopsy findings in 2 additional patients who underwent their first kidney biopsy due to the development of gross hematuria shortly following the second dose of the Moderna vaccine for COVID-19. A 50-year-old White woman with hypertension since age 18 years, obesity, and anti–phospholipid syndrome presented with gross hematuria 2 days after the second dose of the Moderna vaccine for COVID-19, accompanied by low-grade fever and generalized body aches. After the first dose, the patient had experienced only generalized weakness and decreased appetite for several days. Medications included amlodipine, furosemide, and olmesartan, with the more recent addition of warfarin and enoxaparin 3 months prior to presentation. There was no past history of gross hematuria. Laboratory evaluation revealed a serum creatinine of 1.7 mg/dl and a urine protein-creatinine ratio of 2 g/g (increased from baseline values of 1.3 mg/dl and 1.3 g/g, respectively, 7 months prior to presentation). Urinalysis demonstrated >50 red blood cells per high-power field (increased from baseline 10–20 red blood cells 7 months prior to presentation). Serologies included negative or normal anti-nuclear antibody, anti-neutrophil cytoplasmic autoantibody, hepatitis B surface antigen, hepatitis C virus antibody, PLA2R antibody, C3, and C4. The biopsy, performed 19 days after the onset of macrohematuria, demonstrated IgA nephropathy (Figure 1a and b). Among 12 glomeruli sampled, 3 were globally sclerotic and 1 contained a segmental scar. The remainder had mild diffuse mesangial hypercellularity, and 1 glomerulus displayed active segmental fibrinoid necrosis with mild leukocyte infiltration, rupture of glomerular basement membrane, and an overlying segmental cellular crescent. There was 30% tubulointerstitial scarring and moderate arterio- and arteriolosclerosis. Immunofluorescence revealed global granular mesangial staining for IgA (3+), C3 (1+), kappa (2-3+), and lambda (3+). The Oxford MEST-C score (where M is mesangial hypercellularity; E is endocapillary hypercellularity; S is segmental sclerosis; T is tubular atrophy and interstitial fibrosis >25%; C is active cellular or fibrocellular crescent) was M1E0S1T1C1. The gross hematuria resolved within 5 days. A 19-year-old White man with a 6-month history of microhematuria presented with gross hematuria 2 days after receiving the second dose of the Moderna vaccine. The patient had no prior history of gross hematuria, was on no medications, and had no family history of kidney disease. Serum creatinine was 1.2 mg/dl (Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, 87 ml/min per 1.73 m2), and urinalysis revealed numerous red blood cells and no proteinuria. Kidney biopsy, performed 18 days later, demonstrated IgA nephropathy (Figure 1c and d). Among 25 glomeruli sampled, 1 was globally sclerotic. There was mild to moderate, diffuse and global, mesangial hypercellularity. Two glomeruli had segmental endocapillary hypercellularity including infiltrating monocytes and neutrophils. One glomerulus with an incipient segmental scar contained an overlying segmental fibrous crescent. Mild tubular atrophy and interstitial fibrosis involved approximately 10% of the cortex. Immunofluorescence revealed 1 to 2+ granular global mesangial staining for IgA, C3, kappa, and lambda. The Oxford MEST-C score was M1E1S1T0C0. The gross hematuria resolved within 2 days. Our 2 patients were diagnosed, for the first time, with active IgA nephropathy, including focal endocapillary hypercellularity, fibrinoid necrosis, and crescents, following a second dose of the Moderna COVID-19 vaccine. Anticoagulation with warfarin in 1 case may have potentiated the development of gross hematuria. The history of prior microhematuria, as noted in other reported cases,1Negrea L. Rovin B.H. Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.Kidney Int. 2021; 99: 1487Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 2Rahim S.E.G. Lin J.T. Wang J.C. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination.Kidney Int. 2021; 100: 238Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 3Tan H.Z. Tan R.Y. Choo J.C.J. et al.Is COVID-19 vaccination unmasking glomerulonephritis?.Kidney Int. 2021; 100: 469-471Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar and the presence of focal glomerular and tubulointerstitial scarring in both biopsies support the notion that immune response to vaccination exacerbated a preexisting IgA nephropathy. The rapid development of gross hematuria within several days of the second vaccination implicates a systemic cytokine-mediated flare, possibly via induction of heightened IgA1 anti-glycan immune responses. These reports are analogous to our previous observation that infection with severe acute respiratory syndrome coronavirus 2 itself can be associated with flares of underlying autoimmune glomerular diseases.4Kudose S. Batal I. Santoriello D. et al.Kidney biopsy findings in patients with COVID-19.J Am Soc Nephrol. 2020; 31: 1959-1968Crossref PubMed Scopus (293) Google Scholar It remains unclear how the postvaccination setting should be factored into the design of optimal therapy for these active glomerular lesions. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccinationKidney InternationalVol. 100Issue 1PreviewWe read with great interest the report of Negrea and Rovin of 2 cases of IgA nephropathy with gross hematuria following the Moderna vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 We also cared for a 52-year-old Asian female with prior biopsy-proven IgA nephropathy who developed gross hematuria within 24 hours of receiving a second dose of the Pfizer vaccine. Table 1 summarizes clinical data. Her workup was notable for proteinuria of 4.2 g/g of creatinine with serum creatinine at baseline. Full-Text PDF Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathyKidney InternationalVol. 99Issue 6PreviewSeveral of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines use a nucleoside-modified, purified mRNA lipid nanoparticle-encapsulated platform. Compared with traditional inactivated viral and adjuvanted protein vaccines, this RNA platform elicits far higher neutralizing antibody titers, stronger antigen-specific cluster of differentiation (CD) 4+ and CD8+ T-cell responses, and stronger germinal center B and TFH cell activation in experimental animals.1 The activated CD4+ and CD8+ T cells produce several proinflammatory cytokines, including interferon-γ and tumor necrosis factor-α. Full-Text PDF Is COVID-19 vaccination unmasking glomerulonephritis?Kidney InternationalVol. 100Issue 2PreviewWe 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. Full-Text PDF COVID-19 vaccination followed by activation of glomerular diseases: does association equal causation?Kidney InternationalVol. 100Issue 5PreviewTo date, >4 billion doses of the various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been administered worldwide in response to the coronavirus disease 2019 (COVID-19) pandemic. Even as widespread vaccination campaigns have contributed to declining case rates, adverse events are appearing beyond those originally reported in the clinical trials of vaccine efficacy and safety. Of particular relevance to the kidney is the increasing number of reports of de novo or reactivation of glomerular diseases (Table 11–25). Full-Text PDF