Risk of Glomerular Diseases, Proteinuria and Hematuria Following mRNA (BNT162b2) and Inactivated (CoronaVac) SARS-CoV-2 Vaccines

Franco Wing Tak Cheng; Carlos King HoWong; Simon Xiwen Qin; Celine Sze Ling Chui; Francisco Tsz Tsun Lai; Xue Li; Eric Yuk Fai Wan; EstherW. Chan; ChiHoAu; Xuxiao Ye; Sydney ChiWai Tang; Ian Chi KeiWong

Disclosures

Nephrol Dial Transplant. 2023;38(1):129-137.

Abstract and Introduction

Abstract

Background: With accruing case reports on de novo or relapsing glomerular diseases (GD) following different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, we evaluated the risk of GD following BNT162b2 and CoronaVac vaccines.

Methods: A modified self-controlled case series analysis was conducted using anonymized, territory-wide SARS-CoV-2 vaccination records in Hong Kong. All Hong Kong residents aged 18 years or above with outcomes of interest were included. Outcomes of interest were GD, proteinuria or hematuria within 42 days following each dose of SARS-CoV-2 vaccines. Incidence per 100 000 doses of SARS-CoV-2 vaccines administered was calculated, and incidence rate ratios (IRRs) were estimated using conditional Poisson regression with seasonality adjustment.

Results: Between 23 February 2021 and 31 March 2022, 4062 patients had an incident diagnosis of GD, proteinuria or hematuria, with 2873 of them being vaccinated during the observation period. The incidences of the composite events 1–41 days after vaccination were 3.7 (95% CI 3.1–4.4) per 100 000 doses of BNT162b2 administered, and 6.5 (95% CI 5.7–7.5) per 100 000 doses CoronaVac administered. There was no significant increase in the risks of composite events following the first (BNT162b2: IRR = 0.76, 95% CI 0.56–1.03; CoronaVac: IRR = 0.92, 95% CI 0.72–1.19), second (BNT162b2: IRR = 0.92, 95% CI 0.72–1.17; CoronaVac: IRR = 0.88. 95% CI 0.68–1.14) or third (BNT162b2: IRR = 0.39. 95% CI 0.15–1.03; CoronaVac: IRR = 1.18. 95% CI 0.53–2.63) dose of SARS-CoV-2 vaccines.

Conclusions: There was no evidence of increased risks of de novo or relapsing GD with either BNT162b2 or CoronaVac vaccines.

Introduction

Since the coronavirus disease 2019 (COVID-19) outbreak due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in early 2020, tremendous efforts have gone into preventive vaccination. Several types of vaccines are approved for emergency use for immunization against the SARS-CoV-2 virus, and population-based vaccination campaigns have been promoted across the globe within a short period since the World Health Organization's declaration of the pandemic. A nationwide safety analysis of BNT162b2 in Israel demonstrated a reduced risk of acute kidney injury (AKI) after vaccination, plausibly due to protection against undiagnosed COVID-19.^[1] On the contrary, there is an increasing number of case reports published for de novo or relapse of different glomerular diseases (GD) since the widespread rollout of SARS-CoV-2 vaccination programs across the globe. These case reports include antineutrophil cytoplasmic antibodies associated with vasculitis (AAV) and nephritis,^[2–7] crescentic glomerulonephritis,^[8] membranous nephropathy,^[6,7,9] anti-glomerular basement membrane nephritis,^[6,7,10] IgA vasculitis and nephritis,^{[6,7,11–16]} minimal change disease (MCD),^{[6,7,17–19]} IgG4-related nephritis^[20] and lupus nephritis.^[21] Furthermore, 14% of patients with urologic side effects reported hematuria post-SARS-CoV-2 mRNA vaccines in the US Vaccine Adverse Event Reporting System (VAERS).^[22] Among the published cases, BNT162b2 appeared to be the most frequent vaccine preceding GD.^[23]

In Hong Kong Special Administrative Region, China, a territory-wide vaccination program with BNT162b2 (Comirnaty, BioNTech/Pfizer/Fosun) and CoronaVac (Sinovac Life Sciences) commenced on 6 March and 23 February 2021, respectively. BNT162b2 vaccine was the first SARS-CoV-2 mRNA vaccine approved by the US Food and Drug Administration,^[24] while CoronaVac is an inactivated whole-virion SARS-CoV-2 vaccine using the adjuvant aluminium hydroxide.^[25–27] The Department of Health of Hong Kong received spontaneous reports of nephropathy following SARS-CoV-2 vaccination.^[28] Hence, the regulatory-initiated pharmacovigilance programme [The COVID-19 Vaccines Adverse Events Response and Evaluation (CARE)]^[29] conducted this population-based, retrospective study to evaluate and compare the incidences of GD, proteinuria and hematuria following SARS-CoV-2 vaccines.

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Table 1. Characteristics of patients with nephritis receiving BNT162b2 or CoronaVac vaccination during the observation period in the self-controlled case series studies.
	BNT162b2	CoronaVac
N	1133	1740
Sex, male (%)	721 (63.6)	1105 (63.5)
Age, years [mean (SD)]	61.50 (16.83)	70.57 (14.50)
Asthma (%)	7 (0.6)	19 (1.1)
Chronic pain (%)	35 (3.1)	48 (2.8)
Chronic pulmonary disease (%)	17 (1.5)	58 (3.3)
Cirrhosis (%)	2 (0.2)	7 (0.4)
Dementia (%)	9 (0.8)	47 (2.7)
Depression (%)	24 (2.1)	25 (1.4)
Type 2 diabetes (%)	161 (14.2)	311 (17.9)
Hypertension (%)	350 (30.9)	730 (42.0)
Hypothyroidism (%)	13 (1.1)	30 (1.7)
Inflammatory bowel disease (%)	0 (0.0)	0 (0.0)
Irritable bowel syndrome (%)	2 (0.2)	4 (0.2)
Parkinson's disease (%)	2 (0.2)	20 (1.1)
Peptic ulcer disease (%)	9 (0.8)	20 (1.1)
Peripheral vascular disease (%)	2 (0.2)	0 (0.0)
Psoriasis (%)	1 (0.1)	1 (0.1)
Rheumatoid arthritis (%)	10 (0.9)	3 (0.2)
Schizophrenia (%)	1 (0.1)	12 (0.7)
Malignancy (%)	27 (2.4)	62 (3.6)
Medication use in previous 90 days
Renin–angiotensin system agents	231 (20.4)	451 (25.9)
Beta blockers	147 (13.0)	275 (15.8)
Calcium channel blockers	252 (22.2)	553 (31.8)
Diuretics	63 (5.6)	153 (8.8)
Lipid-lowering agents	288 (25.4)	567 (32.6)
Insulins	30 (2.6)	69 (4.0)
Antidiabetic medications	237 (20.9)	417 (24.0)
Glucocorticoids	45 (4.0)	59 (3.4)
Immunosuppressants	47 (4.1)	36 (2.1)

Table 2. Risks of glomerular diseases, proteinuria or hematuria following the first, second and third doses of BNT162b2 or CoronaVac vaccination using the modified self-controlled case series.
	BNT162b2					CoronaVac
	Number of events	Person-years	Event/person-year	IRR (95% CI)	P-value	Number of events	Person-years	Event/person-year	IRR (95% CI)	P-value
Baseline	2172	2341.75	0.93			2735	2927.41	0.93
Day 1–41 after 1st dose	50	70.19	0.71	0.76 (0.56–1.03)	0.073	85	133.53	0.64	0.92 (0.72–1.19)	0.528
Day 1–41 after 2nd dose	89	104.03	0.86	0.92 (0.72–1.17)	0.487	88	117.81	0.75	0.88 (0.68–1.14)	0.324
Day 1–41 after 3rd dose	8	32.62	0.25	0.39 (0.15–1.03)	0.058	19	35.40	0.54	1.18 (0.53–2.63)	0.681

Table 3. Subgroup analysis of modified self-controlled case series.
	After 1st dose			After 2nd dose			After 3rd dose
	Number of events	Person-years	IRR (95% CI)	Number of events	Person-years	IRR (95% CI)	Number of events	Person-years	IRR (95% CI)
BNT162b2
Overall			0.76 (0.56–1.03)			0.92 (0.72–1.17)			0.39 (0.15–1.03)
Glomerular diseases	3	9.86		14	13.90	1.09 (0.60–2.01)	1	3.25
Proteinuria	1	4.27		2	6.41		1	1.18
Hematuria	46	56.12	0.88 (0.64–1.21)	73	83.84	0.95 (0.73–1.24)	6	28.18	0.32 (0.10–1.04)
Age
Age ≥65 years	25	33.33	0.79 (0.51–1.22)	44	46.14	1.05 (0.74–1.49)	3	14.57	0.25 (0.07–0.92)
Age <65 years	25	36.87	0.71 (0.46–1.11)	45	57.90	0.80 (0.56–1.14)	5	18.05	1.38 (0.11–17.67)
Sex
Male	35	44.71	0.76 (0.53–1.10)	55	67.01	0.83 (0.61–1.12)	7	23.20	0.37 (0.13–1.04)
Female	15	25.48	0.74 (0.42–1.31)	34	37.02	1.09 (0.71–1.66)	1	9.41
Diabetes status
Yes	8	9.66	1.35 (0.58–3.11)	15	13.95	1.44 (0.78–2.66)	0	4.62
No	42	60.53	0.70 (0.51–0.98)	74	90.08	0.86 (0.66–1.13)	8	27.99	0.38 (0.14–1.01)
CoronaVac
Overall			0.92 (0.72–1.19)			0.88 (0.68–1.14)			1.18 (0.53–2.63)
Glomerular diseases	8	13.14	0.83 (0.37–1.88)	11	11.99	1.01 (0.51–1.98)	2	2.59
Proteinuria	2	5.10		5	4.81	1.46 (0.44–4.89)	2	1.78
Hematuria	75	115.51	0.95 (0.72–1.25)	72	101.25	0.84 (0.63–1.12)	16	31.15	0.99 (0.43–2.26)
Age
Age ≥65 years	59	90.63	0.99 (0.71–1.39)	44	71.46	0.71 (0.49–1.03)	8	18.12	0.58 (0.21–1.59)
Age <65 years	26	42.91	0.76 (0.49–1.18)	44	46.34	1.07 (0.75–1.53)	11	17.28	3.75 (0.80–17.46)
Sex
Male	54	85.10	0.89 (0.64–1.24)	57	77.16	0.87 (0.63–1.19)	12	24.41	0.78 (0.34–1.81)
Female	31	48.43	0.96 (0.63–1.48)	31	40.64	0.91 (0.59–1.40)	7	10.99
Diabetes status
Yes	11	23.24	0.58 (0.26–1.27)	10	17.54	0.54 (0.23–1.27)	0	3.64
No	74	110.29	0.97 (0.74–1.28)	78	100.27	0.93 (0.71–1.22)	19	31.76	1.20 (0.54–2.70)

Table 4. Risks of relapse of glomerular diseases following the first, second and third doses of BNT162b2 or CoronaVac vaccination using the modified self-controlled case series.
	BNT162b2					CoronaVac
	Number of events	Person-years	Event/person-year	IRR (95% CI)	P-value	Number of events	Person-years	Event/person-year	IRR (95% CI)	P-value
Baseline	753	806.88	0.93			991	1050.51	0.94
Day 1–41 after 1st dose	7	15.70	0.45	0.43 (0.21–0.88)	0.020	17	39.20	0.43	0.72 (0.39–1.32)	0.289
Day 1–41 after 2nd dose	9	22.73	0.40	0.60 (0.29–1.25)	0.175	14	29.31	0.48	0.70 (0.36–1.35)	0.286
Day 1–41 after 3rd dose	6	6.11	0.98	1.09 (0.35–3.39)	0.885	3	6.50	0.46	1.53 (0.32–7.36)	0.596

Authors and Disclosures

Franco Wing Tak Cheng^1,*, Carlos King HoWong^1–3,*, Simon Xiwen Qin^1,2,*, Celine Sze Ling Chui^2,4,5, Francisco Tsz Tsun Lai^1,2, Xue Li^1,2,6, Eric Yuk Fai Wan^1–3, EstherW. Chan^1,2, ChiHoAu¹, Xuxiao Ye¹, Sydney ChiWai Tang⁶ and Ian Chi KeiWong^1,2,7

¹Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China, ²Laboratory of Data Discovery for Health (D²4H), Hong Kong Science and Technology Park, Sha Tin, Hong Kong SAR, China, ³Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China, ⁴School of Nursing, Li Ka Shing Faculty ofMedicine, The University of Hong Kong, Hong Kong SAR, China, ⁵School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China, ⁶Division of Nephrology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China and ⁷Aston Pharmacy School, Aston University, Birmingham, UK

Correspondence to
Ian Chi KeiWong; E-mail: wongick@hku.hk; Sydney ChiWai Tang; E-mail: scwtang@hku.hk

*Co-first authors
These authors contributed equally to this article.

Authors' Contributions
F.W.T.C., S.X.Q., C.K.H.W., S.C.W.T. and I.C.K.W. had the original idea for the study, contributed to the development of the study, extracted data from the source database, constructed the study design and the statistical model, reviewed the literature, and act as guarantors for the study. F.W.T.C., S.X.Q. and C.H.A. undertook the statistical analysis. F.W.T.C., S.X.Q. and C.K.H.W. wrote the first draft of the manuscript. I.C.K.W. is the principal investigator and provided oversight for all aspects of this project. C.S.L.C., F.T.T.L., X.L., E.Y.F.W., E.W.C. and S.C.W.T. provided critical input to the analyses, design and discussion. All authors contributed to the interpretation of the analysis, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. F.W.T.C., S.X.Q., C.K.H.W. and I.C.K.W. have accessed and verified the data used in the study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication

Conflict of Interest Statement
F.W.T.C., S.X.Q. and C.H.A. declare that there is no conflict of interest. C.K.H.W. reports the receipt of General Research Fund, Research Grant Council, Government of Hong Kong SAR; EuroQol Research Foundation, all outside the submitted work. C.S.L.C. has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA and Amgen; personal fees from Primevigilance Ltd; outside the submitted work. F.T.T.L. has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from Food and Health Bureau of the Government of the Hong Kong SAR, outside the submitted work. X.L. received research grants from Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council Early Career Scheme (RGC/ECS, HKSAR), Janssen and Pfizer; internal funding from the University of Hong Kong; consultancy fee from Merck Sharp & Dohme, unrelated to this work. E.Y.F.W. has received research grants from the Food and Health Bureau of the Government of the Hong Kong SAR, and the Hong Kong Research Grants Council, outside the submitted work. E.W.C. reports grants from Research Grants Council (RGC, Hong Kong), grants from Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Wellcome Trust, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, Narcotics Division of the Security Bureau of HKSAR; honorarium from Hospital Authority, outside the submitted work. S.C.W.T. reports research funding outside the submitted work from Sanofi, Research Grants Council of Hong Kong, Health and Medical Research Fund of Hong Kong, and National Natural Science Foundation of China, and also received speaker fees from AstraZeneca, Novartis and Bayer in the previous 3 years. He is also on the Executive Committee of KDIGO, Steering Committee of Eledon Pharmaceuticals, and provides scientific advice to Travere Therapeutics. I.C.K.W. reports research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong RGC, and the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, and also received speaker fees from Janssen and Medice in the previous 3 years. He is also an independent non-executive director of Jacobson Medical in Hong Kong.