Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine

To the editor:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is currently recommended for patients with chronic kidney disease and immunocompromised patients because their risk of developing severe forms of coronavirus disease 2019 (COVID-19) is higher than other patients. Several reports have highlighted the increased risk of immune disease recurrence following mRNA vaccination, including minimal change disease, membranous nephropathy, or even acute allograft rejection.^{1 , 2} We report the case of a 66-year-old man who was diagnosed with IgG4-related disease (IgG4-RD) nephritis in December 2019. At this time, he presented with asthenia associated with acute kidney injury, evaluated by serum creatininemia (SCr) at 450 μmol/L and aseptic leukocyturia (120/mm³) without proteinuria or hematuria. Although anti-DNA antibodies were negative, anti–SSA-52 antibodies were highly positive (113 UI/L; normal range, <10 UI/L) and were associated with hypocomplementemia C3 (0.51 g/L; normal range, 0.9–1.8 g/L) and C4 (<0.02 g/L; normal range, 0.1–0.4 g/L). Serum IgG4 antibodies were elevated at 6.9 g/L (normal range, 0.03–2.01 g/L). A positron emission tomographic scan revealed intense bilateral kidney fixation and fat infiltration. A kidney biopsy revealed IgG4-related nephritis with storiform fibrosis and an IgG4-to-IgG ratio >40 (Figure 1 ). Initial treatment consisted of steroids (1 mg/kg), quickly followed by 4 weekly rituximab perfusions (375 mg/m²) due to steroid resistance.³ Kidney function improved, along with a decrease in SCr to 180 μmol/L, disappearance of leukocyturia, and normalization of serum complement and IgG4 levels, permitting steroid withdrawal. Anti–SSA-52 antibodies also strongly decreased and became negative in June 2020. A positron emission tomographic scan was performed on January 18, 2021, for IgG4-RD follow-up, and showed no pathologic fixation nor renal infiltration. The patient was vaccinated with an mRNA vaccine (BNT162b2 mRNA; Pfizer BioNTech) on January 28, 2021, and February 17, 2021. Two weeks later, he presented with intense asthenia with arthralgias and myalgias. SCr was elevated at 210 μmol/L on March 5, 2021, increased to 250 μmol/L on March 22, 2021, and was associated with recurrence of aseptic leukocyturia. Anti–SSA-52 levels increased from 4 to 17 UI/L. SARS-CoV-2 serology was positive for anti–spike protein at 177 UI/L (electrochemiluminescence immunoassay, Roche Elecsys). Steroid therapy was initiated at 0.5 mg/kg and associated with rituximab perfusion (500 mg), allowing a quick improvement of the general symptoms and resolution of acute kidney injury. Anti–SSA-52 levels also decreased to 12 UI/L by May 2021 (Figure 2 ).

Figure 1.

(a)Destructive storiform interstitial fibrosis, representing >50% of the biopsy, with abundant plasma cell infiltrate (Masson trichrome stain, original magnification ×100). (b) Presence of >10 IgG4 plasma cells per large field at ×400 original magnification (immunohistochemistry with anti-IgG4 [clone ZSIGG4 Diagomics]), with a 40% IgG4-to-IgG ratio. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org.

Figure 2.

Evolution of sera creatininemia (SCr) and anti–SSA-52 antibodies, reflecting the activity of IgG4-related disease, from the diagnosis in December 2019 to the relapse in March 2021 following mRNA coronavirus disease 2019 (COVID-19) vaccine. RTX, rituximab.

Our report highlights the possibility of immune disease relapse following mRNA vaccine, a situation previously described by others. It is currently unknown if immune disease recurrence is linked to direct immune activation following vaccination, chronic immune activation following a paucisymptomatic allergic reaction, or both. Indeed, IgG4-RD pathogenesis has been linked to IgE production, as seen in late immune-mediated allergic reactions.⁴ If the benefit-to-risk ratio indisputably favors vaccination of this at-risk population, physicians should be aware of the possibility of immune disease recurrence to provide close monitoring of these patients and fast treatment of relapses to avoid long-term consequences and progression to end-stage renal disease.