key: cord-0307649-u3u5rej0 authors: Diebold, M.; Locher, E.; Boide, P.; Enzler-Tschudy, A.; Faivre, A.; Fischer, I.; Helmchen, B.; Hopfer, H.; Kim, M. J.; Moll, S.; Nanchen, G.; Rotman, S.; Saganas, C.; Seeger, H.; Kistler, A. D. title: Incidence of Glomerulonephritis after SARS-CoV-2 mRNA Vaccination date: 2022-05-24 journal: nan DOI: 10.1101/2022.05.18.22275112 sha: 6c393cff663cc946f8ea1da39449d765350cd3e7 doc_id: 307649 cord_uid: u3u5rej0 Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. We studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and 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. The observed incidence during the vaccination campaign (Jan to Aug 2021) was not different from the expected incidence 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 aged >18 years 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 0.97 (95% CI 0.66-1.42, P=0.95) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within 4 weeks after vaccine did not differ clinically from the rest of the cohort. Results were consistent across all types of glomerulonephritis with the possible exception of minimal change disease. In conclusion, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies. Most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis are likely coincidental. Following emergency use authorization for the first vaccines developed against 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 mRNAbased vaccines, mostly either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna). Both vaccines had been tested in large randomized controlled trials with excellent safety profiles. 1, 2 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 to SARS-CoV-2 vaccination were observed, 3 including various autoimmune phenomena. 4 Among such associations, many new-onset and recurrent cases of glomerulonephritis have been reported. 5 While mechanistically plausible, 5, 7, 11 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 to the expected incidence based on a baseline period (2015 to 2019). We further compared the vaccination 4 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. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Both studies were approved by the Ethics Committee of Eastern Switzerland. The first 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 second study, written informed consent was obtained from all participants, and the study was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. 12 We followed the STROBE Guidelines for reporting observational studies. 13 For the first study, local nephropathologists extracted relevant data from an existing database or performed a search of their electronic records. We limited our study to native kidney biopsies of persons aged >18 years with IgAN, PINGN, MCD and MN. These glomerulonephritides belong to the most frequent that can be unambiguously diagnosed by All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 14 MN was included in the analysis, because secondary MN constitutes a minority of cases, 15 but lupus nephritis class V was excluded for reasons outlined above. As information on prior kidney biopsy was not available from the records of some pathology institutes and because repeat biopsies constitute only a small fraction of all biopsies, we included both, new diagnoses and repeat biopsies in the first study. For the second study, nephropathologists provided the referring nephrologists' names for all eligible patients (>18 years old with histological diagnosis of IgAN, PINCG, MCD or MN between January 1 and August 31, 2021) to the investigators. We contacted all nephrology divisions and practices who had sent in biopsy specimens of eligible patients providing age, sex, histological diagnosis and date of biopsy to help them identify their patients and to contact them for study participation. Clinical and epidemiological data were collected in a case report form (CRF) completed by the treating nephrologist and in a questionnaire completed by the patient. All data were reviewed and the time-point of symptom onset or laboratory abnormalities attributable to the glomerular disease was adjudicated by the study investigators (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. For the first study, a Bayesian Poisson regression model was used to predict the expected incidence of glomerulonephritis cases for each month in 2021 based on data for the years 2015 to 2019, excluding 2020 because we expected underdiagnosis early in the pandemic due to lock-down measures. We calculated incidence rate ratios for the total of all four glomerulonephritides and for each diagnosis separately by dividing the observed cases in 2021 by the expected cases and expressed uncertainty using 95% credible intervals. Because the availability of serologic testing for anti-PLA2R autoantibodies may have influenced biopsy practice over time, 16 we performed a sensitivity analysis excluding MN. For the second study, we chose a control group from the general population by determining for every patient the percentage of individuals from the general population of the same age decade (the decade 20-29 was used for the few patients aged 18 or 19 years) who had received a first, second, or any vaccine dose in every one-week interval prior to (a) the calendar week of the biopsy date and (b) the calendar week of onset of symptoms or detection of laboratory abnormalities attributable to the glomerulonephritis and used 1000 controls per patient. For the comparison between controls and patients we used risk ratios by unconditional maximum likelihood estimation given that the total number of vaccinated and unvaccinated persons in Switzerland (including both, cases and non-cases) was available and assuming that a representative sample of all patients with new-onset glomerulonephritis was included in the second study. Discrete variables are expressed as counts (percentage) and continuous variables as median and interquartile range [IQR] . Comparisons between groups were made using Kruskal-Wallis' test and Pearson's X 2 test, as appropriate. Statistical analyses were performed using R software, version R version 4.0.2 (R Core Team 2020. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/). A list of the packages used for this analysis is provided in the Supplementary Methods. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Figure 1 . The observed incidence was compatible with the expected incidence for all months during the vaccination campaign ( Table 1) with an overall incidence rate ratio of 0.86 (95%-credible interval 0.73 to 1.02) for the entire study period (January to August 2021). In an additional analysis comparing the weekly incidence during the entire study period or the peak of the vaccination campaign (May to August 2021) to the corresponding calendar time of the baseline period, we also did not find any difference (Supplementary Table 1 ). Overall, 229 patients aged >18 years had a biopsy-proven diagnosis of IgAN (n = 106), PINGN (n = 62), MCD (n = 26) or MN (n = 35) between January and August 2021 in Switzerland. 125 (54.6%) of these patients could be included in the second study. Reasons for non-inclusion are shown in the study flowchart (Figure 2 ). 14 patients (11.2%) with repeat biopsies of a previously established diagnosis were not included in the analysis, and their clinical All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 2 week time period prior to kidney biopsy or prior to onset of symptoms or laboratory abnormalities, as compared to matched control groups. The analysis by type of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 24, 2022. Table 4 . Details on each individual patient are given in Supplementary Table 3 . Patients with a new diagnosis of glomerulonephritis manifesting in temporal association with vaccination were older, but otherwise did not differ from patients with a new diagnosis of glomerulonephritis temporally unrelated to SARS-CoV-2 vaccination. The sensitivity analysis excluding all MN cases showed equivalent results (Supplementary Tables 1, 4 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Postmarketing surveillance is an important means to detect rare but relevant side-effects that may have escaped detection in registration studies. However, while serving an important hypothesis-generating function, case reports and series are subject to post hoc fallacy and publication bias. In this study, which included incidence data of glomerulonephritis for 7.1 million individuals, 69% of whom had received at least one vaccine dose during the study period, we did not find evidence that mRNA-based vaccines against SARS-CoV-2 increase the risk for new-onset glomerulonephritis. On the epidemiological level, incidence of four common types of glomerulonephritis did not exceed the expected rate during any month of the SARS-CoV-2 vaccination campaign in Switzerland. Patients with new-onset glomerulonephritis did not differ from age-and calendar-time-matched controls with respect to their vaccination history, and characteristics of patients with glomerulonephritis temporally related to vaccination did not differ from those without temporal association to vaccination, except for higher age, probably due to preferential vaccination of older individuals. Glomerulonephritis is a rare disease and nationwide incidence rates have not been previously published for Switzerland. We found baseline incidence rates similar to those reported for other European countries. [17] [18] [19] An interesting finding was the significantly reduced incidence of glomerulonephritis during public lockdown measures paralleling the first infection wave. Notably, this reduction was attributable to IgAN, the most frequent of the four glomerulonephritides, which often manifests with isolated, asymptomatic urinary abnormalities not necessitating urgent evaluation and more likely to be missed with reduced use of routine medical evaluations during the first pandemic phase. Importantly, this finding demonstrates the feasibility of our study to detect true changes of incidence. Patients with a new diagnosis of histology-proven glomerulonephritis had similar vaccination histories compared to the matched population-based cohort, and the estimated risk for the development of glomerulonephritis was equal in vaccinated vs. unvaccinated persons. In the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. time-based analysis, the proportion of patients having received a vaccine dose was virtually identical for every four-week period before histological diagnosis of a glomerulonephritis, compared to the matched control cohort. A trend towards less vaccines given to patients within four weeks before histological diagnosis of glomerulonephritis is likely attributable to the fact that patients were less likely to schedule a vaccine appointment shortly before a scheduled kidney biopsy or when suffering symptoms of glomerulonephritis or vasculitis. In the two four- week-periods before symptom onset or first documented laboratory abnormalities, the percentages of patients having received a vaccine dose were nominally slightly higher compared to matched controls. However, this analysis has to be interpreted with caution, because the number of patients was relatively low and some patient-reported symptoms are unspecific and may have incorrectly been attributed to glomerulonephritis. Our findings were generally consistent across all four types of glomerulonephritis, with the possible exception of MCD. Increased numbers of newly diagnosed MCD were recently reported for 2021 in a Dutch observational cohort. 20 However, that cohort-based study could not calculate true population-based incidence, and only 5 of 11 cases had received any SARS-CoV-2 vaccine before presentation, which makes a true association with vaccination questionable. In our study, the incidence of MCD during the vaccination campaign did not cross the upper boundary of the 95% credible interval for the predicted incidence, and the risk ratio for the development of MCD in vaccinated vs. unvaccinated persons was not significantly different from one. However, both analyses showed a trend towards an increased risk, and 95% credible / confidence intervals were wide due to the overall low incidence of MCD. Thus, we cannot exclude an effect of SARS-CoV-2 mRNA vaccines on the development of MCD, but the absolute risk would be very small. We identified 15 patients with new-onset glomerulonephritis in possible temporal association to SARS-CoV-2 vaccination. While the limited number of cases precluded a detailed analysis, we did not find a distinct clinical manifestation in these patients. Macrohematuria has been All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 24, 2022. ; https://doi.org/10.1101/2022.05.18.22275112 doi: medRxiv preprint frequently reported as clinical manifestation in patients with new onset or relapsing glomerulonephritis temporally associated with SARS-CoV-2 vaccination. 21 Episodes of gross hematuria, often in association with upper respiratory tract infection, are a known manifestation of IgA nephropathy 22 and could theoretically be triggered by the systemic inflammatory response following mRNA-based SARS-CoV-2 vaccination. However, we did not find an increased rate of patient-reported gross hematuria in patients with newly diagnosed IgAN in temporal association to vaccination compared to the rest of the cohort. Furthermore, among a previously reported cohort of 88 patients with known IgA nephropathy who received at least one dose of mRNA based SARS-CoV-2 vaccine, none had developed gross hematuria. 23 Strengths of this study are the inclusion of all biopsy-proven glomerulonephritis cases diagnosed in Switzerland, which allowed to calculate true incidence rates, and the use of an unambiguous primary outcome (biopsy-proven glomerulonephritis) that limited the potential for bias. By linking the second study to the epidemiological analysis, we were able to specifically approach potential participants and achieved a considerable inclusion rate (>50% of all Swiss patients with histologically confirmed glomerulonephritis during the study period). The availability of detailed information on vaccinations administered to the general Swiss population allowed precise matching to patients with regards to age and timepoint during the vaccination campaign. Since only mRNA-based vaccines were administered in Switzerland during the study period, our study specifically addresses this type of vaccines. This study has several limitations. First, due to the limited population size of Switzerland and the low incidence of glomerulonephritis, we cannot exclude a small effect of vaccinations, in particularly for MCD, as discussed above. Second, due to the decentralized health care system in Switzerland, patients were cared for by a variety of hospital-based and private practice nephrologists. Patient evaluation and care were thus not standardized and the study relied on patient-and physician-reported data. Third, due to the retrospective design of the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 24, 2022. ; https://doi.org/10.1101/2022.05.18.22275112 doi: medRxiv preprint study, patient-reported symptoms were subject to potential recall bias and onset of symptom dates were not precise in some patient questionnaires. Therefore, we chose biopsy proven glomerulonephritis as the primary outcome. Fourth, we were not able to include all patients with biopsy-proven glomerulonephritis in the second study and cannot exclude selection bias. However, the major reason for non-inclusion of patients was non-participation of their treating nephrology divisions or practices due to time constraints, which should not introduce bias. Finally, our results are limited to new-onset glomerulonephritis and cannot answer the question, whether SARS-CoV-2 vaccination could trigger relapses in patients with previously diagnosed glomerulonephritis, because relapses are usually diagnosed clinically without repeat biopsy. In conclusion, combining two complementary approaches, we did not find an association between mRNA-based vaccination against SARS-CoV-2 and an increased incidence of the four common glomerulonephritis types IgAN, PINGN, MCD and MN. Most cases of new onset glomerulonephritis manifesting shortly after vaccination against SARS-CoV-2 are likely attributable to temporal coincidence. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Funding: This study did not receive external funding. Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. I. F. reports holding stocks from Pfizer. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. Data sharing: Data will be made available on reasonable request to the corresponding author, after approval by the local ethics committee. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 24, 2022. ; https://doi.org/10.1101/2022.05.18.22275112 doi: medRxiv preprint Tables Table 1. Observed monthly incidence of glomerulonephritis during the vaccination campaign compared to the baseline period (2015 to 2019) and the expected incidence, relative risk ratio and number of vaccine doses administered in the corresponding month. Incidence is given as the number of biopsy-proven glomerulonephritis cases (IgAN, PINGN, MCD and MN) per million population aged >18 years. Vaccine doses per population are given as doses per population. The expected incidence was calculated using a Bayesian model based on each month for the years 2015 to 2019. The relative incidence rate denotes the ratio between observed and expected cases. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Values are numbers (percentages) or median (interquantile range). To convert the creatinine values from μmol/L to mg/dL, divide by 88.4. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 24, 2022. ; https://doi.org/10.1101/2022.05.18.22275112 doi: medRxiv preprint Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting New-onset autoimmune phenomena post-COVID-19 vaccination De Novo and Relapsing Glomerular Diseases After COVID-19 Vaccination: What Do We Know So Far? Glomerular Disease in Temporal Association with SARS-CoV-2 Vaccination: A Series of 29 Cases De novo and relapsing glomerulonephritis after COVID-19 vaccination: how much do we know? 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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.