<b><i>Introduction:</i></b> To date, almost 7 billion doses of the different types of vaccine against SARS-CoV-2 have been administered worldwide. Although the severity of new cases of SARS-CoV-2 has progressively decreased, and the pressure on national health systems has declined, the development of de novo glomerular injuries has been suggested. <b><i>Methods:</i></b> This study aimed to examine the patients who were hospitalized in our Unit between April and November 2021 and underwent renal biopsy for new-onset urinary abnormalities (UA) and/or renal impairment within 3 months of SARS-CoV-2 vaccination. <b><i>Results:</i></b> We identified 17 patients who developed UA and/or renal insufficiency within 3 months of vaccination. Minimal change disease was the most common disease in our cohort (5 patients, 29.4%) followed by acute tubulointerstitial nephritis (TIN; 3 patients, 17.6%), membranous nephropathy (3 patients, 17.6%), and rapidly progressive IgA nephropathy (2 patients, 11.8%). The other 4 patients had a diagnosis of membranoproliferative glomerulonephritis (1 patient), systemic lupus erythematosus (1 patient), ANCA-associated vasculitis (1 patient), and tip-variant focal segmental glomerulosclerosis (1 patient), respectively. Eight out of the 17 patients (47.1%) developed acute kidney injury. Two patients with acute TIN had to start hemodialysis that was discontinued after 1 and 2 months, respectively, due to the recovery of renal function. All patients underwent treatment with corticosteroids and/or immunosuppressants. <b><i>Discussion:</i></b> Although it is not possible to conclusively determine whether there is a causal relationship between SARS-CoV-2 vaccination and new-onset nephropathies, based on the appearance of UA and/or renal insufficiency shortly after vaccination, we hypothesize that the immune response to the COVID-19 vaccine may be a trigger of nephropathies. Therefore, our results highlight the need for pharmacovigilance. However, this report should not lead to vaccine hesitation during this pandemic as the benefits of vaccination strongly outweigh the potential risks.

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO AAV. CCX168, i.e., Avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the pro-inflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability. Summary: Avacopan was found to be safe in healthy volunteers given a wide range of doses in a Phase 1 clinical trial. The Phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the Standard of Care (SoC) therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The Phase 3 ADVOCATE study compared the ability of an Avacopan-associated regimen to induce and sustain remission in AAV patients vs a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given Avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given Avacopan and in 54.9% receiving prednisone. The Avacopan-associated regimen was non-inferior at week 26, and superior at week 52 in sustaining remission as compared to the GC-based scheme. Key point: The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of Avacopan in a routinary clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.