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      IgA nephropathy following COVID-19 vaccination: challenges and perspectives

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          Abstract

          To the Editors: We would like to thank Morizawa and colleagues for reporting two other pediatric patients who presented with Ig A nephropathy (IgAN) flare-ups following mRNA COVID-19 vaccination [1]. Interestingly, both patients had been diagnosed with microscopic hematuria prior to COVID-19 vaccination, and already benefited from an adequate follow-up in pediatric nephrology. On the contrary, the patient we reported in a previous letter [2] had no documented microscopic hematuria prior to COVID-19 vaccination: school urinalysis routinely performed in Luxembourg was negative. This observation thus confirms that IgAN flare-ups can potentially occur after COVID-19 vaccination in previously symptomatic and asymptomatic patients alike, raising questions about the optimal COVID-19 vaccination strategy in the pediatric population. Indeed, it remains unclear whether COVID-19 vaccination should be continued after the occurrence of IgAN flare-up following the first or second dose of COVID-19 vaccine. In the patient reported previously [2], the severity of the flare-up led us to contraindicate further COVID-19 vaccination until new medical evidence are available. However, more moderate flare-ups [3] might not necessarily contraindicate further COVID-19 vaccination in patients with a high risk of severe COVID-19, but the lack of strong scientific evidence makes the decision process difficult. Another open question is the need for specific vaccination guidelines in pediatric patients with suspected or confirmed IgAN diagnosis prior to COVID-19 vaccination. On the one hand, COVID-19 vaccination could potentially trigger disease relapses; on the other hand, the SARS-CoV-2 virus itself has been reported as a likely cause of IgAN flare-ups [4], although mostly in adults. In order to better address these questions, we believe that it is particularly important that pediatric nephrologists continue to report potential side effects of COVID-19 vaccination, as well as SARS-CoV-2 related chronic kidney disease flare-ups. The implementation of an international pediatric registry, as well as prospective studies, is needed to help clinicians to better evaluate the risk–benefit ratio of COVID-19 vaccination in pediatric patients with chronic kidney diseases at risk of relapsing, in all pediatric age groups.

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          IgA Nephropathy presenting as macroscopic hematuria in 2 pediatric patients after receiving the Pfizer COVID-19 vaccine

          To the editor: With great interest, we read the recent reports of IgA nephropathy (IgAN) flare-up presenting as macroscopic hematuria, following the second dose of coronavirus disease 2019 (COVID-19) vaccination in adult patients.1,2,3,4 The United States Food and Drug Administration granted an emergency use authorization (EUA) for the Pfizer-BioNtech-COVID-19 vaccination in December 2020 for individuals 16 years of age and older; the EUA was recently expanded to include children ages 12 to 15 years on May 10, 2021. Here, we report two pediatric patients with IgAN presenting with macroscopic hematuria less than 24 hours after Pfizer COVID-19 vaccination. Neither patient had COVID-19 infection prior to vaccination nor any prior history of reactions to any vaccinations. See Table 1 for clinical information. Table 1 Clinical Characteristics of Two Pediatric Patients with IgAN Flare Following COVID-19 Vaccination Patient Age (yr) Race Gender Prior to COVID-19 Vaccination Following COVID-19 Vaccination 1 13 White Male Clinical symptoms Microscopic Hematuria and sub-nephrotic proteinuria noted on routine urine screening for diabetes leading to IgAN diagnosis New-onset gross hematuria x 2 days, vomiting x 1 day Serum creatinine (mg/dL) 0.54 Day 2: 1.31Day 6: 0.66 Serum albumin (g/dL) 3.4 Day 2: 3.8Day 6: 3.0 Urine protein-to-creatinine ratio (mg/mg) 1.6 Day 2: 1.07Day 6: 0.86 Oxford MEST-C score M0 E0 S0 T0 C0 -- Treatment Lisinopril 10 mg daily Stopped lisinopril on day 5 2 17 White Male Clinical symptoms Foamy urine for several months New-onset macroscopic hematuria x 4 days & stage I hypertension Serum Creatinine (mg/dL) -- Day 6: 1.78Day 9: 1.47Day 22: 1.20 (following corticosteroid treatment) Serum Albumin (g/dL) -- Day 9: 3.8 Urine protein-to-creatinine ratio (mg/mg) -- Day 9: 1.75 Oxford MEST-C score -- Day 9: M1 E1 S1 T1 C1 Treatment -- Day 9: 1 gram intravenous methylprednisolone daily x3 followed by oral prednisone The first patient is a 13-year-old male with a history of type 1 diabetes mellitus and known IgAN (Supplementary Figure S1). His initial IgAN diagnosis was made six months prior to this event during an evaluation for sub-nephrotic proteinuria and microscopic hematuria with normal renal function, and he was receiving treatment with lisinopril. Within twenty-four hours following the second dose of the COVID-19 vaccine, he developed new-onset gross hematuria and acute kidney injury. His gross hematuria self-resolved and his kidney function recovered without intervention within one week. The second patient is a previously healthy 17-year-old male who presented with new-onset gross hematuria, proteinuria, and acute kidney injury less than 24 hours following the second dose of the vaccine. He had no family history of autoimmune disease, and he was not taking any medications. His gross hematuria self-resolved, but his kidney insufficiency persisted. Kidney biopsy performed 9 days later was consistent with IgAN with cellular glomerular crescents and moderate to severe tubulointerstitial scarring (Supplementary Figure S2), suggesting an acute exacerbation of pre-existing IgAN. He received intravenous methylprednisolone pulses and follow up serum creatinine level showed improvement. The mechanism by which COVID-19 vaccination may be associated with IgAN flares is unclear. We concur with previous authors’ statements that patients, including children, with IgAN should be monitored closely following COVID-19 vaccine, and COVID-19 vaccination may unmask previously undiagnosed glomerulonephritis in pediatric patients.1,2,3,4 Uncited reference 1., 2., 3., 4..
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            Clinical and pathological findings of SARS-CoV-2 infection and concurrent IgA nephropathy: a case report

            Background Since the Coronavirus Disease 2019 (COVID-19) outbreak, there is accumulating data on the clinical characteristics, treatment strategies and prognosis of COVID-19 in patients with concurrent renal disease. Postmortem investigations reveal renal involvement in COVID-19, and most recently, several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy such as collapsing glomerulopathy were common histological findings. However, to our best knowledge, there is limited data regarding IgA nephropathy in the setting of COVID-19. Case presentation In the present case, we report a 65-year old Chinese woman who presented with dark-colored urine, worsening proteinuria and decreased renal function after COVID-19 infection. She received a renal biopsy during COVID-19 infection. The renal biopsy revealed IgA nephropathy without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities were a consequence of exacerbation of this patient’s underlying glomerular disease after COVID-19 infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up. Conclusions It is important to consider the underlying glomerular disease exacerbation as well as virus induced injury when dealing with renal abnormalities in patients with COVID-19. A kidney biopsy may be indicated to exclude a rapidly progressive glomerular disease.
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              IgA nephropathy presenting as rapidly progressive glomerulonephritis following first dose of COVID-19 vaccine

              To the Editors, Coronavirus disease 2019 (COVID-19) has recently been associated with kidney disease in pediatric patients [1]. Interestingly, COVID-19 vaccination has also been described as a potential trigger of acute kidney injury (AKI); in particular, IgA nephropathy (IgAN) flare-ups following mRNA COVID-19 vaccination have been reported in adult [2] and pediatric patients [3]. However, the pediatric cases published so far described patients suffering from mild IgAN flare-ups occurring after the second dose of the COVID-19 vaccine. Here, we describe the development of de novo IgAN occurring within 24 h following the first dose of mRNA COVID-19 vaccine. The patient was 13 years old, with no relevant medical history. In particular, she had no history of COVID-19 infection (SARS-CoV-2 PCR and serology were negative), and she never had reacted to any previous vaccinations. Within 24 h following the first dose of the Pfizer mRNA COVID-19 vaccine, she developed fever, asthenia, and muscle pain. Macroscopic hematuria was also reported. At admission, clinical examination showed a mild streptococcus-negative pharyngitis. Serum creatinine was 3.57 mg/dl, and blood urea nitrogen was 96 mg/dl. Macroscopic hematuria was accompanied by nephrotic range proteinuria (3.88 g/l). Other etiologic investigations came back negative, including immunological and infectious testing. Kidney biopsy performed at day 4 post-vaccination is shown in Fig. 1. The estimated Oxford score was M1E1S0T0. Kidney function rapidly deteriorated, and the patient became oliguric; as a consequence, hemodialysis was started. Treatment consisted of 3 IV methylprednisolone pulses, followed by oral prednisone. Kidney function improved progressively; hemodialysis was stopped at 5 days post-vaccination. At 11 days post-vaccination, serum creatinine was down to 1.9 mg/dl. At 30 days post-vaccination, serum creatinine had returned to almost normal values (0.86 mg/dl, leading to a GFR according to the Schwartz formula of 82 ml/min). Microscopic hematuria and a slight proteinuria persisted. Fig. 1 Pathology showing IgA nephropathy, Oxford score M1E1S0T0. a Optical microscopy (scale bar 100 µm). Mesangial and endocapillary proliferation. No constituted crescents were observed, but fibrin deposits were present in the Bowman space of most of the observed glomeruli. No evidence of renal scarring from previous kidney injury could be detected. b Immunofluorescence (scale bar 100 µm). Diffuse mesangial IgA and C3 deposits. Absence of other deposits. c Electron microscopy (scale bar 1 µm). Diffuse mesangial deposits Unlike previous observations [2, 3], this report suggests that development of IgAN following COVID-19 vaccination may occur after the first dose of vaccine, and may present as a rapidly progressive glomerulonephritis leading to severe AKI. As with other case reports, COVID-19 vaccine responsibility in the IgAN flare-up reported here remains difficult to establish. Therefore, it appears essential to precisely assess the risk–benefit ratio of COVID-19 vaccination in all pediatric age groups, and to carefully plan COVID-19 vaccination in patients with chronic kidney disease at risk of relapsing.
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                Author and article information

                Contributors
                niel.olivier@chl.lu
                Journal
                Pediatr Nephrol
                Pediatr Nephrol
                Pediatric Nephrology (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0931-041X
                1432-198X
                29 March 2022
                : 1-2
                Affiliations
                [1 ]GRID grid.418041.8, ISNI 0000 0004 0578 0421, Pediatric Nephrology, , Centre Hospitalier de Luxembourg, ; 4 rue Barblé, L1210 Luxembourg, Luxembourg
                [2 ]GRID grid.16008.3f, ISNI 0000 0001 2295 9843, Faculty of Science, Technology and Medicine, , University of Luxembourg, ; 2, Avenue de l΄Université, L4365 Esch-sur-Alzette, Luxembourg
                [3 ]GRID grid.418041.8, ISNI 0000 0004 0578 0421, Pediatric Infectious Diseases, , Centre Hospitalier de Luxembourg, ; 4 rue Barblé, L1210 Luxembourg, Luxembourg
                Author information
                http://orcid.org/0000-0003-0546-7921
                Article
                5476
                10.1007/s00467-022-05476-7
                8963394
                d0f30233-411d-471b-96dc-4053a1360da7
                © The Author(s), under exclusive licence to International Pediatric Nephrology Association 2022

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 21 January 2022
                : 21 January 2022
                : 24 January 2022
                Categories
                Letter to the Editors

                Nephrology
                Nephrology

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