Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased

Abstract

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73–1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66–1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental. Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73–1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66–1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental. Editor’s NoteThis excellent study discusses new-onset glomerular disease in the face of coronavirus disease 2019 (COVID-19) mRNA vaccination. The readership is reminded that there has been an abundance of reports suggesting activation or worsening of pre-existing glomerular diseases after receiving the vaccines, especially IgA nephropathy and minimal change disease. Although these reports do not provide mechanistic proof of causation, timing of disease exacerbation is consistent, and the association is plausible. This excellent study discusses new-onset glomerular disease in the face of coronavirus disease 2019 (COVID-19) mRNA vaccination. The readership is reminded that there has been an abundance of reports suggesting activation or worsening of pre-existing glomerular diseases after receiving the vaccines, especially IgA nephropathy and minimal change disease. Although these reports do not provide mechanistic proof of causation, timing of disease exacerbation is consistent, and the association is plausible. After emergency use authorization for the first vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries in late 2020, an unprecedented vaccination campaign was initiated worldwide in 2021. In Europe and North America, the majority of people received mRNA-based vaccines, mostly either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna). Both vaccines had been tested in large randomized controlled trials with excellent safety profiles.1Polack F.P. Thomas S.J. Kitchin N. et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (7786) Google Scholar,2Baden L.R. El Sahly H.M. Essink B. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (5255) Google Scholar However, these registration studies were not powered to detect rare vaccine side effects. During the worldwide vaccination campaign, numerous rare adverse events with a temporal association with SARS-CoV-2 vaccination were observed,3Barda N. Dagan N. Ben-Shlomo Y. et al.Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.N Engl J Med. 2021; 385: 1078-1090Crossref PubMed Scopus (503) Google Scholar including various autoimmune phenomena.4Chen Y. Xu Z. Wang P. et al.New-onset autoimmune phenomena post-COVID-19 vaccination.Immunology. 2022; 165: 386-401Crossref PubMed Scopus (128) Google Scholar Among such associations, many new-onset and recurrent cases of glomerulonephritis have been reported.5Bomback A.S. Kudose S. D'Agati V.D. De novo and relapsing glomerular diseases after COVID-19 vaccination: what do we know so far?.Am J Kidney Dis. 2021; 78: 477-480Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 6Caza T.N. Cassol C.A. Messias N. et al.Glomerular disease in temporal association with SARS-CoV-2 vaccination: a series of 29 cases.Kidney360. 2021; 2: 1770-1780Crossref PubMed Google Scholar, 7Chan A.T.P. Tang S.C.W. De novo and relapsing glomerulonephritis after COVID-19 vaccination: how much do we know?.Nephrology (Carlton). 2022; 27: 5-6Crossref PubMed Scopus (7) Google Scholar, 8Farooq H. Aemaz Ur Rehman M. Asmar A. et al.The pathogenesis of COVID-19-induced IgA nephropathy and IgA vasculitis: a systematic review.J Taibah Univ Med Sci. 2022; 17: 1-13PubMed Google Scholar, 9Klomjit N. Alexander M.P. Fervenza F.C. et al.COVID-19 vaccination and glomerulonephritis.Kidney Int Rep. 2021; 6: 2969-2978Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 10Li N.L. Coates P.T. Rovin B.H. COVID-19 vaccination followed by activation of glomerular diseases: does association equal causation?.Kidney Int. 2021; 100: 959-965Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 11Izzedine H. Bonilla M. Jhaveri K.D. Nephrotic syndrome and vasculitis following SARS-CoV-2 vaccine: true association or circumstantial?.Nephrol Dial Transplant. 2021; 36: 1565-1569Crossref PubMed Scopus (22) Google Scholar Specific types of glomerulonephritis most often reported after SARS-CoV-2 vaccination include IgA nephropathy (IgAN), minimal change disease (MCD), membranous nephropathy (MN), and pauci-immune necrotizing glomerulonephritis (PINGN), the renal manifestation of antineutrophil cytoplasmic antibody–associated vasculitis. Although mechanistically plausible,5Bomback A.S. Kudose S. D'Agati V.D. De novo and relapsing glomerular diseases after COVID-19 vaccination: what do we know so far?.Am J Kidney Dis. 2021; 78: 477-480Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,7Chan A.T.P. Tang S.C.W. De novo and relapsing glomerulonephritis after COVID-19 vaccination: how much do we know?.Nephrology (Carlton). 2022; 27: 5-6Crossref PubMed Scopus (7) Google Scholar,11Izzedine H. Bonilla M. Jhaveri K.D. Nephrotic syndrome and vasculitis following SARS-CoV-2 vaccine: true association or circumstantial?.Nephrol Dial Transplant. 2021; 36: 1565-1569Crossref PubMed Scopus (22) Google Scholar a causal link between SARS-CoV-2 vaccination and glomerulonephritis has not been formally established. Published case series lack control groups, and estimates of incidence of these glomerulonephritides before and during the vaccination campaign have not been published yet. Given the high number of vaccine doses administered, many cases of new-onset glomerulonephritis would be expected to occur in temporal proximity to vaccination by pure coincidence. Here, we tested the hypothesis that SARS-CoV-2 mRNA vaccines increase the incidence of several types of glomerulonephritis against the null hypothesis that reported temporal associations can be attributed to a by-chance-effect. We compared the observed incidence of glomerulonephritis in Switzerland during the vaccination campaign in 2021 with the expected incidence based on a baseline period (2015–2019). We further compared the vaccination history of patients with glomerulonephritis newly diagnosed during the vaccination campaign to the general population matched for age and timepoint, and we characterized patients with new-onset glomerulonephritis in temporal association with vaccination. We performed 2 complementary, interconnected studies. For the first study with a retrospective cohort design (the cohort representing the entire adult Swiss population), all Swiss pathology institutes analyzing kidney biopsies provided biopsy date, age, sex, and histologic diagnosis for all patients aged >18 years with histologic diagnosis of IgAN, PINGN, MCD, or MN from January 1, 2015, through August 31, 2021. These data, together with census data for each year (2015–2021) on the Swiss population aged >18 years, were used to calculate the incidence of all 4 types of glomerulonephritis. Notably, only the histologic diagnosis was provided by pathologists, without information on extrarenal manifestations, such as IgA vasculitis or extrarenal symptoms of antineutrophil cytoplasmic antibody vasculitis. For the second study with a case-cohort design, all of the above-mentioned patients with biopsy date between January 1, 2021, and August 31, 2021, were eligible. Clinical information was gathered and vaccination history was compared with the general Swiss population, matched for age and timepoint during the vaccination campaign. Both studies were approved by the Ethics Committee of Eastern Switzerland. The retrospective cohort study was exempt from patient consent because only minimal data were included and it would have been impossible to obtain consent from all patients, while inclusion of all cases was essential to calculate true incidence. For the case-cohort study, written informed consent was obtained from all cases, and the study was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.12World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.JAMA. 2013; 310: 2191-2194Crossref PubMed Scopus (13238) Google Scholar We followed the Strengthening the Reporting of Observational Studies in guidelines for M. et al.The Strengthening the Reporting of Observational Studies in guidelines for Full Text Full Text PDF PubMed Scopus Google Scholar For the retrospective cohort study, data from or performed a of We study to native kidney biopsies of aged >18 years with IgAN, PINGN, MCD, and These the most glomerulonephritides that can be diagnosed by and have been reported after SARS-CoV-2 vaccination. was not included because biopsies often performed for glomerulonephritis, a significant of all We did not include because most cases by and not from by A.S. 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However, while an case reports and series to and In study, included incidence data of glomerulonephritis for of had received at least vaccine dose during the study we did not that mRNA-based vaccines against SARS-CoV-2 increase the risk for new-onset glomerulonephritis. the incidence of 4 types of glomerulonephritis did not the expected rate during any of the SARS-CoV-2 vaccination campaign in Switzerland. Patients with new-onset glomerulonephritis did not differ from and with to vaccination and the of patients with glomerulonephritis temporally to vaccination did not differ from those without temporal association with for age, to vaccination of older individuals. is a rare disease, and nationwide incidence have not been published for Switzerland. We baseline incidence to those reported for A. The incidence of glomerulonephritis a systematic of the Dial Transplant. 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However, we did not an rate of in patients with newly diagnosed in temporal association with vaccination compared with the of the a reported cohort of patients with received at least dose of mRNA-based SARS-CoV-2 had developed COVID-19 vaccination in J Kidney Dis. 2021; 78: Full Text Full Text PDF PubMed Scopus (7) Google Scholar of study the inclusion of all biopsy-proven glomerulonephritis cases diagnosed in to calculate true incidence and the use of an that the for the second study to the we were to and a inclusion rate of all Swiss patients with glomerulonephritis during the study The of information on to the general Swiss population to patients with to age and timepoint during the vaccination campaign. only mRNA-based vaccines were in Switzerland during the study study of This study has several because of the population of Switzerland and the incidence of glomerulonephritis, we a of in for MCD, as because of the in patients were for by a of and and were not and the study on and because of the retrospective design of the study, symptoms were to and the of was not in patient we biopsy-proven glomerulonephritis as the we were not to include all patients with biopsy-proven glomerulonephritis in the second study, However, the for of patients was of or to not patients included in the study were to those not included in of histologic age, and timepoint of kidney has been reported in temporal association with SARS-CoV-2 we did not include patients with because the data from pathology institutes did not a between and we that cases of IgA vasculitis and antineutrophil cytoplasmic antibody–associated vasculitis have been diagnosed on or by biopsy of the or to new-onset glomerulonephritis and the SARS-CoV-2 vaccination in patients with diagnosed glomerulonephritis, because diagnosed clinically without In 2 complementary we did not an association between mRNA-based vaccination against SARS-CoV-2 and an incidence of the 4 glomerulonephritis types IgAN, PINGN, MCD, and cases of new-onset glomerulonephritis manifesting shortly after vaccination against SARS-CoV-2 likely to temporal coincidence. reports from the Data be on to the after by the We and from the of and of for and in with the Bayesian of and of and of the biopsy at the of and The following from the and to those the patients for the second study and provided S. 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