To the editor:
With the worldwide rollout of coronavirus disease 2019 (COVID-19) vaccines, numerous reports of de novo or relapsing glomerular diseases have been published recently.1, 2, 3, 4 It has been stressed that associations between vaccination efforts and the onset of disease do not prove causation, but the administration of vaccines and the induction of an immune response might trigger disease activity. Of note, most cases appear to be either IgA nephropathy (IgAN) or minimal change disease,1 with around 30 cases each reported to date. Occurrence of glomerular diseases has been reported for all vaccine platforms following vaccination.
We conducted a pharmacovigilance study using the World Health Organization global database of individual case safety reports VigiBase to identify potential associations of glomerular diseases with the use of COVID-19 vaccines. A total of 143 cases with nephrotic syndrome were reported, of whom 103 (72%) received the BNT162b2 vaccine (Pfizer–BioNTech; odds ratio [OR], 1.65; 95% confidence interval [CI], 1.33–2.05). The risk to develop “minimal lesion GN [glomerulonephritis]” (as per coding) was strongly associated with the use of BNT162b2 (78.3%; OR, 2.13; 95% CI, 1.46–3.09). In contrast, IgAN was predominantly reported in individuals receiving the mRNA-1273 vaccine (Moderna–NIAID; 48.7%; OR, 3.33; 95% CI, 2.05–5.40). The risk for other glomerular diseases based on reports submitted to VigiBase was not increased (Table 1 ). VigiBase did not indicate if patients had an established diagnosis; thus, it is not possible to dissect the reported cases into de novo and relapsing glomerulonephritis.
Table 1.
Performance of a disproportionality analysis in VigiBase, summarizing the reports on de novo or relapsing GN following COVID-19 vaccination with either viral-vectored or mRNA vaccines
| Variable |
ChAdOx1 nCOV-19 (AZ/UoO) |
NRVV Ad26 JNJ 78436735 |
Elasomeran Moderna mRNA |
Tozinameran Pfizer/BioNTech mRNA |
Full database |
||||
|---|---|---|---|---|---|---|---|---|---|
| Total no. of ICSRs available |
561,214 |
73,208 |
286,467 |
770,304 |
6,052,767 |
||||
| No. of ICSRs and statics by nephrotic syndrome and various glomerulonephritis | Cases | IC/IC025 | Cases | IC/IC025 | Cases | IC/IC025 | Cases | IC/IC025 | Cases |
| Nephrotic syndrome | 22 | –1.14/–1.80 | 6 | –0.08/–1.46 | 12 | –1.03/–1.96 | 103 | 0.60/0.31 | 530a |
| MPGN | 1 | –0.18/–3.98 | 0 | NA | 0 | NA | 0 | NA | 13 |
| FSGS | 3 | –1.21/–3.26 | 0 | NA | 0 | NA | 0 | NA | 13 |
| GN, minimal lesion | 7 | –0.96/–2.22 | 1 | –0.64/–4.43 | 2 | –1.62/–4.21 | 36 | 0.88/0.37 | 152b |
| RPGN | 1 | –2.90/–6.70 | 0 | NA | 3 | –0.77/–2.82 | 6 | –1.23/–2.60 | 116 |
| C3 glomerulonephritis | 1 | –0.18/–3.98 | 1 | 1.19/–2.60 | 0 | NA | 1 | –0.52/–4.32 | 13 |
| IgA nephropathy | 5 | –1.23/–2.75 | 0 | NA | 19 | 1.51/0.79 | 15 | –0.17/–1.00 | 134c |
| Anti-GBM disease | 1 | –0.46/–4.26 | 1 | 1.09/–2.70 | 1 | 0.20/–3.59 | 4 | 0.76/–0.98 | 17 |
| GN, proliferative | 0 | NA | 1 | 1.22/–2.58 | 0 | NA | 0 | NA | 12 |
| MGN | 0 | NA | 0 | NA | 3 | –0.32/–2.37 | 5 | –1.23/–2.60 | 82 |
| Glomerulonephritis, unspecified | 2 | –2.64/–5.23 | 1 | –0.72/–4.52 | 10 | 0.35/–0.67 | 21 | 0.01/–0.66 | 116 |
AZ, AstraZeneca; CI, confidence interval; COVID-19, coronavirus disease 2019; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; IC, information component; IC025, 95% credibility interval lower end point of IC; ICSR, individual case safety report; JNJ, Johnson & Johnson; MGN, membranous glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; NA, not applicable; OR, odds ratio; RPGN, rapid-progressive glomerulonephritis; UoO, University of Oxford.
Values are n, unless otherwise indicated. IC and IC025 are given. A positive IC025 value (>0) is the traditional threshold used for statistical signal detection (in bold). For significant signals, reporting OR and its 95% CI are given (95% CIs were also calculated using the entire database from January 1, 2020, to August 18, 2021, as a comparator).
The OR of BNT162b2 (tozinameran) related nephrotic syndrome is 1.65 (95% CI, 1.33–2.05).
The OR of BNT162b2 (tozinameran) related minimal GN is 2.13 (95% CI, 1.46–3.09).
The OR of mRNA-1273 (elasomeran) related IgA nephropathy is 3.33 (95% CI, 2.05–5.40).
Until August 18, 2021, 1.8 billion people were fully vaccinated against COVID-19, and only 295 glomerulonephritis (de novo or relapsing) cases were reported to VigiBase, highlighting the relative safety of COVID-19 vaccines. On the basis of the high mortality rates of patients with underlying glomerular diseases,5 the benefits of COVID-19 vaccination outweigh risks. The higher rates of glomerular disease occurrence following mRNA vaccines may underline their higher immunogenicity, but we advise using the available vaccines and platforms and comply with national vaccination recommendations with respect to a third vaccine or booster doses. Some of these reported cases so far tend to have a mild and self-limiting disease course, especially in patients with IgAN and minimal change disease.1 Unfortunately, VigiBase did not provide follow-up data on the respective disease course.
In conclusion, our analysis revealed that both approved mRNA vaccines, BNT162b2 and mRNA-1273, have a different spectrum of association with glomerular diseases. The former associates with nephrotic syndrome, whereas the latter increases the risk of developing de novo or relapsing IgAN.
Disclosure
AK received consultancy fees from Alexion, Vifor Pharma, Otsuka, UriSalt, and Catalyst Biosciences; and grant support from Otsuka and Vifor Pharma, all outside the submitted work. All the other authors declared no competing interests.
References
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