Th1 Cytokines Signature in 2 Cases of IgA Nephropathy Flare after mRNA-Based SARS-CoV-2 Vaccine: Exploring the Pathophysiology

Abstract

mRNA-based vaccines have dramatically shifted the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. IgA nephropathy (IgAN) flare is the most reported renal adverse effect after the administration of these vaccines. Unraveling the mechanistic pathways leading to these flares is necessary to confirm a causal association. Herein, we report 2 cases of IgAN flare after SARS-CoV-2 vaccination in patients previously diagnosed with IgAN. We describe and compare the clinical and analytical features of the disease at the time of the diagnostic with the post-vaccine flare. In addition, we obtained serum and urine of these patients at the moment of the flare and determined the levels of IL-2, TNF-α, and IFNγ using a multiplex bead-based assay. As diseased controls, we included <i>n</i> = 13 patients diagnosed with IgAN who had available serum and urine samples at the moment of the diagnostic stored in our biobank. We also included 6 healthy controls. Compared to the first episode, postvaccination flares were more severe in terms of peak serum creatinine, albuminuria, and urinary erythrocyte count. The histological lesions found at the biopsy performed during the post-vaccine flare were similar to those found at the diagnostic. One of the patients who suffered a post-vaccine flare showed increased serum IL-2 and TNFα compared to the IgAN-diseased controls and the healthy controls. In conclusion, although several cases of post-vaccine IgAN flares have been reported, there are no mechanistic studies on the occurrence of these flares. We here suggest that hyperactivation of the Th1 pathway may be involved, but larger studies with more refined methods for numerical and functional Th1 lymphocytes evaluation are required.

IgA nephropathy after COVID-19 vaccination and analysis of reported cases

“… 12 12 36 N/A F Relapse Moderna Second Within 24 h N/A, 0.7 g/day, 79.6 μmol/L 363/μL, 203 g/mol (albumin), 159.1 μmol/L Fever, malaise Prednisolone dose was increased to 0.5 mg/kg/body weight, mycophenolate mofetil Two months later, creatinine decreased to 97.2 μmol/L and proteinuria decreased under 0.5 g/day. 13 13 50 White F Initial onset Moderna Second 2 days 10-20/HPF, 1.3 g/gCr, 114.9 μmol/L >50/HPF, 2 g/gCr, 150.3 μmol/L Fever, generalized body aches N/A Gross hematuria resolved within 5 days. 14 14 19 White M Initial onset Moderna Second 2 days N/A, N/A, N/A Numerous red blood cells, no proteinuria, 106.1 μmol/L N/A N/A Gross hematuria resolved within 2 days.…”

“… 30 37 35 N/A F Relapse Pfizer Second N/A N/A, 0.36 g/gCr, 88.4 μmol/L Bland urine, 2 g/gCr, 99.9 μmol/L N/A Oral prednisolone, Mycophenolate Mofetil Four weeks later, proteinuria decreased to 1.143 mg/gCr and serum creatinine remained stable at 97.2 μmol/L 31 38 50 N/A M Initial onset Pfizer First None Negative hematuria by dipstick test, negative proteinuria by dipstick test, 79.6 μmol/L 10/HPF, 2+ proteinuria by dipstick test, 79.6 μmol/L Purpuric rashes RAASi After 100 days first vaccination, proteinuria decreased to 0.5 g/day. 32 39 50 N/A M Relapse Pfizer First 3 days N/A, 0.7 g/day, 88.4 μmol/L 170/μL, 329 g/mol (albumin), 106.1 μmol/L N/A N/A N/A 13 40 15 Asian M Initial onset Pfizer Second 1 day N/A, N/A, N/A 3+ hematuria by dipstick test, 3+ proteinuria by dipstick test, 85.7 μmol/L Fever None Microscopic hematuria and proteinuria persis...…”

IgA vasculitis presenting as nephrotic syndrome following COVID-19 vaccination: a case report

“…IgA nephropathy is the most common GN after receiving the mRNA COVID-19 vaccine, followed by minimal change disease [ 8 – 10 ]. In the literature, 47 cases of IgA nephropathy following mRNA COVID-19 vaccination have been reported (30 de novo and 17 flare-ups) thus far [ 3 , 9 – 40 ]. Gross hematuria within 1–2 days after vaccination was the most common initial presentation, followed by acute kidney injury.…”

“…The global COVID-19 vaccine campaign has been actively underway to overcome the COVID-19 pandemic. mRNA COVID-19 vaccines deliver lipid nanoparticle-encapsulated mRNA, which encodes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and triggers robust innate and adaptive immune responses [ 1 – 3 ]. The efficacy and safety of BNT162b2 and mRNA-1273 have been demonstrated in clinical trials and real-world studies [ 4 – 7 ].…”

Relapses or de-novo IgA nephropathy following COVID-19 vaccination; a narrative review

“…Moreover, Martinez Valenzuela et al studied two cases of IgA nephropathy flare after COVID-19 vaccination and proposed the role of hyper-activation of the Th-1 pathway in IgA nephropathy flare by the vaccine (15).…”