Abstract
Rationale & Objective
New-onset IgA nephropathy (IgAN) and thrombotic microangiopathy (TMA) cases were reported after COVID-19 pandemic. This study investigated the prevalence and characteristics of IgAN-MA lesions in IgAN after the COVID-19 pandemic in China.
Study Design
A cross-sectional study.
Setting & Participants
A total of 22,123 biopsied patients, mainly in northern China from June 1, 2018, to May 31, 2024 were enrolled.
Exposure
COVID-19 pandemic in China.
Analytical Approach
Cochran-Armitage trend test was used to detect trends of IgAN and MA lesions after COVID-19 pandemic. Stage 1 represented no COVID-19 infection (including Stage 1A); Stage 2 represented possible COVID-19 infection and vaccination implemented; Stage 3 represented COVID-19 infection (including Stage 3A and Stage 3B). Multivariate logistic regression was used to analyze risk factors of MA lesions.
Results
The proportion of IgAN in total biopsies and MA lesions in IgAN showed an increasing trend over time. In Stage 1, IgAN comprised 22.6% of total biopsies, significantly lower than the proportion in Stage 3 (24.5%; P = 0.01) after bias adjusted. The MA lesions increased notably from 3.6% in Stage 1 to 10.1% in Stage 2 and continued to increase to 15.4% in Stage 3 (P < 0.001). Immunofluorescence showed a progressive increase in C3 deposition in patients with IgAN and patients with MA in Stage 1A, Stage 3A, and Stage 3B (all P < 0.05). Multivariable logistic regression identified pandemic exposure, increased mean arterial pressure, lower estimated glomerular filtration rate, S1 lesions, and T1/T2 lesions as risk factors for the development of MA lesions.
Limitations
Proportion based on patients in northern China, diagnosis from medical records without re-evaluation, lack of exact data on vaccination status and COVID-19 infection, lack of prognosis.
Conclusions
COVID-19 may promote the proportion of IgAN in total biopsy and MA lesions in IgAN. Complement activation may play an important role in the development of IgAN and MA lesions.
Index Words: IgA nephropathy, microangiopathic lesions, COVID-19, complement activation
Plain-Language Summary
This study was inspired by concerns that COVID-19 might influence kidney health, particularly in relation to IgA nephropathy and its vascular lesions. The research examined numerous kidney biopsy cases over several years in China to compare how IgA nephropathy behaved before, during, and after the COVID-19 pandemic. The findings revealed that IgA nephropathy and kidney vascular lesions increased after the COVID-19 outbreak. The study further indicated that the immune system’s complement activation could play a significant role in these changes. Overall, the research suggests that COVID-19, microangiopathic lesions in IgA nephropathy, and complement activation are closely linked, emphasizing the importance of monitoring kidney health after COVID-19 exposure. These insights will help inform patient care and further research in kidney health.
IgA nephropathy (IgAN) is widely recognized as the most common primary glomerular disease globally,1 with a notably higher incidence in Asian populations compared to Caucasian and African populations.2 The key diagnostic feature is the predominant deposition of IgA immune complex in the glomerular mesangium, identified via kidney biopsy, with over 90% of patients exhibiting co-dominant C3 deposition. Microangiopathy (MA) lesions, characterized by arteriolar thrombosis, endothelial swelling, subintimal edema, fibrinoid necrosis, and onion-skin lesions, are present in 2%-53% of patients with IgAN3, 4, 5, 6 and are associated with severe clinicopathological features, which may be related to overactivation of complement. These lesions are considered to be an independent risk factor for poor prognosis of IgAN.5,7
After the initial outbreak of COVID-19 since December 2019,8 COVID-19 cases surged nationwide in December 2022. Reports and systematic reviews have documented new-onset IgAN and thrombotic microangiopathy associated with COVID-19 vaccination or infection.9, 10, 11, 12, 13, 14, 15, 16 This may be attributed to the over activation of the complement system and endothelial cell injury, as kidney endothelial cells are particularly susceptible to COVID-19 due to their high expression of angiotensin-converting enzyme 2.17, 18, 19 However, it remains unclear whether there has been a definitive increase in the proportion of IgAN in total biopsy and MA lesions in IgAN. To address this, a cross-sectional study was conducted to examine changes in the proportion of IgAN, particularly MA lesions, after the pandemic across China.
Methods
Study Design and Population
This cross-sectional study was conducted at Peking University First Hospital, the largest renal center in northern China. A total of 22,123 patients who underwent kidney biopsies at the hospital from June 1, 2018, to May 31, 2024, were initially included. The selection of this whole period is mainly based on the emergence of COVID-19 in December 2019 in China and the nationwide pandemic in December 2022.20 To establish a comparable baseline as a control, the study period extended one and a half years before and after these 2 time points.
Our study included 2 sections. The primary objective of the first section was to evaluate the impact of the COVID-19 pandemic on the proportion of IgAN in total biopsy and MA lesions in patients with IgAN. As shown in Fig 1, 5,756 patients with pathological diagnosis of IgAN were eligible for inclusion, whereas 526 were excluded mainly to eliminate bias caused by secondary IgAN and secondary thrombotic microangiopathy based on the following criteria: (1) co-diagnosis with other glomerular diseases, such as membranous nephropathy (n = 130), minimal change disease (n = 28), IgA vasculitis (n = 45), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 21), diabetic kidney disease (n = 164), or podocyte injury (n = 99); (2) concurrent diagnoses of viral hepatitis (n = 2) or malignant hypertension (n = 16); and (3) history of kidney transplantation (n = 17) or pregnancy (n = 4); repeated biopsy was excluded. Ultimately, 5,230 patients with IgAN were included for the Cochran-Armitage trend test of IgAN and MA lesions based on semi-annual statistics (Fig 2; Table 1). Additionally, we divided the whole period (June 2018 to May 2024) into 3 stages according to the emergence and nationwide prevalence of COVID-19: Stage 1 represented June 2018 to November 2019, a period when there was no COVID-19;Stage 2 represented December 2019 to November 2022, a period when COVID-19 infections began and vaccination was implemented; and Stage 3 represented December 2022 to May 2024, a period when majority of the Chinese population was infected with the COVID-19. In this way, the study compared the proportion of IgAN and MA in 3 continuous stages to ensure the change.
Figure 1.
Flowchart of patient selection and analysis for IgAN and MA lesions across pandemic phases. aDefined as time from December 1, 2018, to May 31, 2019, when there was no COVID-19 in China. bDefined as time from December 1, 2022 to May 31, 2023, when COVID-19 was prevailing across China. cDefined as time from December 1, 2023 to May 31, 2024 after COVID-19 pandemic in China.
Figure 2.
Trends of newly diagnosed IgAN and MA each half year in northern China, from June 2018 to May 2024. The half-year period division was mainly based on the global emergence of COVID-19 in December 2019 and the pandemic timeline, beginning in December 2022 and concluding in May 2023. aRe-analyzed proportion of IgAN in total biopsy and MA in IgAN after excluding data from December 1, 2022, to February 31, 2023 because of an unusual medical activity to respond to pandemic.
Table 1.
Trends of newly diagnosed IgAN and MA each half year in northern China, from June 2018, to May 2024
| Year Indexa | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total biopsy, n | 1,984 | 1,987 | 1,862 | 1,136 | 1,447 | 1,895 | 1,988 | 1,647 | 1,665 | 1,626 (1,101b) | 2,297 | 2,589 |
| IgAN cases, n | 434 | 468 | 416 | 242 | 298 | 496 | 497 | 415 | 423 | 332 (260b) | 592 | 617 |
| MA cases, n | 14 | 15 | 18 | 17 | 25 | 44 | 59 | 44 | 51 | 47 (40b) | 88 | 102 |
Note: Cochran-Armitage trend test: ZIgAN = 2.5412, PIgAN = 0.01; ZMA = 10.738, PMA < 0.001.
Abbreviations: IgAN, immunoglobulin A nephropathy; MA, microangiopathy.
Number was used to represent each half year. “1” represented time from June 2018 to November 2018, “2” represented time from December 2018 to May 2019, and etc.
Re-analyzed case numbers of Total biopsies, IgAN biopsies and MA biopsies after excluding data from December 1, 2022, to February 31, 2023, because of an unusual medical activity in order to response to pandemic.
To analyze the clinicopathological characteristics of patients with MA with COVID-19 infection, some patients from Stage 1 and Stage 3 were selected. Because the majority of the Chinese got infected with the COVID-19 after December 2022 and the end of this Public Health Emergency of International Concern was announced in May 2023,21 so patients in Stage 3 from December 1, 2022, to May 31, 2023 (n = 332) were enrolled as Stage 3A, patients from December 1, 2023, to May 31, 2024 (n = 617) as Stage 3B, while patients in Stage 1 from December 1, 2018, to May 31, 2019 (n = 468), as Stage 1A were enrolled as control groups. The clinical and pathological baseline characteristics of these 1,417 patients in these 3 periods were then analyzed separately.
The study got approval from the Ethics Committee of Peking University First Hospital (2017 [1280]), and all patients involved in this study signed the informed consent.
Clinical and Pathological Data Collection
The clinical and laboratory data at the time of kidney biopsy were obtained retrospectively from the medical records including age, sex, blood pressure, mean arterial pressure (MAP) (calculated as DBP + 1/3(SBP − DBP) or SBP/3 + 2/3 DBP, where SBP and DBP represent systolic and diastolic blood pressures, respectively); 24-hour proteinuria, estimated glomerular filtration rate (eGFR) (according to the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation).22 All kidney biopsy specimens were processed routinely for immunofluorescence microscopy, light microscopy, and electron microscopy. Sections were stained for direct immunofluorescence with FITC-conjugated antibodies specific for human IgG, IgM, IgA, C1q, C3, and fibrinogen. Intensities of these complement components in the section were scored as follows: −(negative), + (weak), ++(moderate), +++(strong), or ++++ (very strong). Sections used for light microscopy were stained with hematoxylin and eosin, Masson’s trichrome, periodic acid-Schiff, and periodic acid-Schiff together with silver methenamine. The biopsies were evaluated under the light microscopy outlined in the MEST-C criteria in Oxford classification for IgAN, conducted by qualified pathologists who were blind to the design of this study.23,24 The diagnosis of IgAN was based on the predominant deposition of IgA in the glomerular mesangium indicated by immunofluorescence. The MA lesion was diagnosed as what was described in previous study,5,7 including endothelial cell swelling and subintimal edema and arteriolar thrombosis or fibrinoid necrosis were considered acute, whereas lesions with arterial onion-skin lesions (fibrous intimal thickening with concentric lamination) were considered chronic.
Statistical Analysis
Continuous variables were presented as mean ± standard deviation for normally distributed variables or as median with interquartile range for non-normally distributed variables. Categorical variables and ordinal variables were summarized as frequency with percentage. The Cochran-Armitage trend test (Z-value) was performed to analyze the proportional trend of MA lesions in patients with IgAN and IgAN in total biopsies. For the comparison among multiple groups, One-way ANOVA is used for normally distributed variables, whereas the Kruskal-Wallis test was performed for non-normally distributed continuous variables and ordinal variables. For categorical variables, the χ2 or the Fisher exact test was used. Further comparisons between each 2 groups were carried out by Bonferroni Test (α = 0.0167 per comparison) and post hoc test. Potential correlations were analyzed by univariate and multivariate logistic regression models, with outcome (presence or absence of MA lesions) modeled as a binary variable. All potential factors associated with MA lesion occurrence were included as independent variables. Generally, P < 0.05 was considered statistically significant. Data were recorded and cleaned by Excel 2021 and statistical analyses were performed with the statistical software Statistical Program for Social Sciences (IBM SPSS version 26.0) and R software 4.4.1.
Results
Proportion of IgAN and MA Lesions Before and Throughout the Entire Pandemic Period
The proportion of IgAN in total biopsies showed a significant upward trend (Z = 2.5412; P = 0.01) (Table1). When comparing the proportion of IgAN in total biopsy in specific stages, we found there was more IgAN in Stage 2 (2,371/9,778, 24.2%) and Stage 3 (1,541/6,512, 23.7%) than in Stage 1 (1,318/5,833, 22.6%) though it was not statistically significant (Table 2). After patients from December 2022 to February 2023 were excluded for reducing the bias from epidemic control policy, a marked increase in IgAN cases after the pandemic outbreak in China was revealed (1,469/5,987, 24.5% in Stage 3 vs 1,318/5,833, 22.6% in Stage 1; P = 0.01) (Table S1). Similarly, MA lesions demonstrated a significant upward trend (Z = 10.738; P < 0.001) (Table1). In Stage 1 without COVID-19, only 3.6% (48/1,318) patients with IgAN exhibited MA lesions, while this proportion rose sharply after COVID-19 emerged and continued to increase after the pandemic outbreak in China (237/1,541,15.4% in Stage 3; 240/2,371, 10.1% in Stage 2; and 48/1,318, 3.6% in Stage 1; P < 0.001) (Table 2), with the same marked increase after excluding patients from December 2022 to February 2023 (Table S1).
Table 2.
Proportion of newly diagnosed IgAN and MA in different stages in northern China, from June 2018, to May 2024
| Variable | Stage 1a | Stage 2b | Stage 3c | P | Pa,b | Pa,c | Pb,c |
|---|---|---|---|---|---|---|---|
| IgAN/total, n (%) | 1,318 (22.6) | 2,371 (24.2) | 1,541 (23.7) | 0.06 | 0.19d | 0.17d | 0.39d |
| MA/IgAN, n (%) | 48 (3.6) | 240 (10.1) | 237 (15.4) | < 0.001 | < 0.001 | < 0.001 | < 0.001 |
Abbreviations: IgAN, immunoglobulin A nephropathy; MA, microangiopathy.
Represented June 2018 to November 2019, a period when there was no COVID-19.
Represented December 2019 to November 2022, a period when possible COVID-19 infection and vaccination implemented.
Represented December 2022 to May 2024, a period during and after COVID-19 prevailed across China.
Bonferroni-adjusted P-values (α = 0.0167 per comparison).
Furthermore, the results of Table 3 indicated that a total of 165 patients with IgAN exhibited MA lesions across the 3 cross-sectional periods. Specifically, the proportion of newly diagnosed patients with IgAN with concurrent MA lesions was comparable between the Stage 3A and Stage 3B periods, yet significantly higher than that observed in Stage 1A (15/468, 3.2% in Stage 1A; 47/332, 14.2% in Stage 3A; and 102/617, 16.5% in Stage 3B; P < 0.001).
Table 3.
Clinicopathologic Baseline Characteristics of IgAN Patients Among Groups Before, During, and After COVID-19 Pandemic
| Variables | Stage 1A n = 468 |
Stage 3A n = 332 |
Stage 3B n = 617 |
P | Pa,b | Pa,c | Pb,c |
|---|---|---|---|---|---|---|---|
| Clinical information | |||||||
| Sex | 0.64 | 0.85 | 0.37 | 0.55 | |||
| Male, n (%) | 252 (53.8) | 181 (54.5) | 349 (56.6) | ||||
| Female, n (%) | 216 (46.2) | 151 (45.5) | 268 (43.4) | ||||
| Age (y) | 39 ± 14 | 40 ± 13 | 40 ± 13 | 0.57 | 0.79 | 0.76 | 0.99 |
| Systolic BP, mm Hg | 132 ± 18 | 131 ± 17 | 130 ± 17 | 0.11 | 0.28 | 0.04e | 0.44 |
| Diastolic BP, mm Hg | 84 ± 13 | 82 ± 11 | 83 ± 12 | 0.06 | 0.02e | 0.16 | 0.24 |
| MAP, mm Hg | 100 ± 13 | 98 ± 13 | 97 ± 18 | 0.006e | 0.05 | 0.001e | 0.37 |
| Proteinuria g/24 h | 2.06 (0.98-3.83) | 1.95 (1.01-3.33) | 1.59 (0.81-3.00) | 0.004e | 1 | 0.006e | 0.006e |
| eGFR, mL/min/1.73 m2 | 67.9 (38.73-96.31) | 60.55 (34.21-86.2) | 59.1 (36.8-88.07) | 0.02e | 0.03e | 0.05 | 1 |
| Pathological features | |||||||
| MA, n (%) | 15 (3.2) | 47 (14.2) | 102 (16.5) | < 0.001e | < 0.001d,e | < 0.001d,e | 0.34d |
| Oxford classification, n (%) | |||||||
| M1 | 271 (60.6) | 162 (50.2) | 252 (41.7) | < 0.001e | 0.004d,e | < 0.001d,e | 0.01d,e |
| E1 | 156 (34.9) | 230 (71.2) | 350 (57.9) | < 0.001e | < 0.001d,e | < 0.001d,e | < 0.001d,e |
| S1 | 275 (61.5) | 244 (75.5) | 452 (74.7) | < 0.001e | < 0.001d,e | < 0.001d,e | 0.81d |
| T1/T2 | 129/54 (28.9/12.1) | 99/42 (30.7/13) | 157/68 (26/11.3) | 0.13 | 0.45d | 0.23d | 0.06d |
| C1/C2 | 254/26 (56.8/5.8) | 180/18 (55.7/5.6) | 332/23 (54.9/3.8) | 0.41 | 0.71d | 0.21d | 0.46d |
Abbreviations: BP, blood pressure; MAP, mean arterial pressure; eGFR, estimated glomerular filtration rate; MA, microangiopathy; C, crescents; E, endocapillary hypercellularity; M, mesangial hypercellularity; S, segmental glomerulosclerosis; T, interstitial fibrosis and tubular atrophy.
Defined as time from December 1, 2018, to May 31, 2019, when there was no COVID-19 in China.
Defined as time from December 1, 2022, to May 31, 2023,when COVID-19 was prevailing across China.
Defined as time from December 1, 2023, to May 31, 2024 after COVID-19 pandemic in China.
Bonferroni-adjusted P-values (α = 0.0167 per comparison).
Statistically significant.
Clinicopathologic Baseline Characteristics of Patients With IgAN and Patients With MA Among Groups Before, During, and After COVID-19 Pandemic
The clinical and pathological baseline characteristics of 1,417 patients with IgAN in 3 cross-sectional periods were analyzed in detail in Table 3. In Stage 3A during the pandemic, the mean age of patients was 40 ± 13 years, with men accounting for 54.50% of the population. The baseline MBP was 98 ± 13 mm Hg. By the time of kidney biopsy, the median proteinuria was 1.95g/d (interquartile range, 1.01-3.33) and eGFR was 60.55 mL/min/1.73 m2 (interquartile range, 34.21-86.20), which was significantly lower compared with patients in Stage 1A (67.90 mL/min/1.73 m2; interquartile range, 38.73-96.31; P = 0.03). According to the Oxford classification, patients who experienced COVID-19 prevalence exhibited a lower proportion of M1 lesion but significantly higher fractions of E1 and S1. The MA lesions in patients with IgAN were predominantly located in arterioles, with only a very small proportion accompanied by glomerular endothelial cell injury. Both acute and chronic MA lesions were present. Total of 82.3% patients presented with endothelial cell swelling and subintimal edema, 8.8% with arteriolar thrombosis or fibrinoid necrosis, and 56.3% with onion-skin lesion. This has been added in the result section. The clinicopathological characteristics of MA lesion patients across the 3 cross-sectional periods are presented in Table S2. Overall, no significant differences were observed among the 3 groups in terms of age, sex, MAP, proteinuria, eGFR, or Oxford METT-C Score (MEST-C).
Pathological Deposit of C3 and IgA on Kidney Tissue of Patients With IgAN and Patients With MA Among Groups Before, During, and After COVID-19 Pandemic
Regarding immunofluorescence staining, we observed a progressive increase over time in the C3 positive proportion in patients with IgAN and patients with MA, with a significant increase in Stage 3B compared with that in Stage 1A in patients with IgAN (446/466, 95.7% in Stage 1A; 314/324, 96.9% in Stage 3A; and 589/597, 98.7% in Stage 3B; P = 0.01) and in patients with MA (12/15, 80% in Stage 1A; 45/47, 95.7% in Stage 3A; and 97/102, 98% in Stage 3B; P = 0.02) (Figs 3A and D; Tables S3 and S4).
Figure 3.
Pathological deposit of C3 and IgA on kidney tissue of IgAN patients and MA patients among groups before, during, and after COVID-19 pandemic. Intensities of these complement components in the section were scored as follows: -(negative), + (weak), ++(moderate), +++(strong), or ++++ (very strong). ∗Statistically significant. (A) Represent the proportion of C3 deposition on kidney tissue of IgAN patients among groups before, during and after COVID-19 pandemic. (B) Represent the intensity of C3 deposition on kidney tissue of IgAN patients among groups before, during and after COVID-19 pandemic. (C) Represent the intensity of IgA deposition on kidney tissue of IgAN patients among groups before, during and after COVID-19 pandemic. (D) Represent the proportion of C3 deposition on kidney tissue of IgAN-MA patients among groups before, during and after COVID-19 pandemic. (E) Represent the intensity of C3 deposition on kidney tissue of IgAN-MA patients among groups before, during and after COVID-19 pandemic. (F) Represent the intensity of IgA deposition on kidney tissue of IgAN-MA patients among groups before, during and after COVID-19 pandemic.
The intensity of C3 deposition (≧++) in patients with IgAN was also higher in Stage 3B compared with that in Stage 1A and Stage 3A (506/597, 84.8% in Stage 3B vs 365/466, 78.3% in Stage 1A; P = 0.007; vs 251/324, 77.5% in Stage 3A; P = 0.006) and the IgA deposition intensities (≧+++) of patients with IgAN (523/612, 85.5% in Stage 3B vs 364/466, 78.1%in Stage 1A; P = 0.002; vs 252/331, 76.1%, in Stage 3A; P < 0.001) (Figs 3B and C; Table S3). However, among patients with MA across all 3 phases, the intensity of C3 deposition (≧++) and IgA deposition (≧+++) demonstrated a gradual increasing trend, with patients in Stage 3B showing the most increased deposition compared with patients in Stage 1A (Figs 3E and F; Table S4). Notably, 4% (4/99) of patients in the Stage 3B period were diagnosed at the strongest C3 intensity (++++) level, which was absent in the Stage 1A group. The proportion of patients with the strongest IgA deposition intensity (++++) was also much higher in the Stage 3B group compared with the Stage 1A and Stage 3A groups (0% in Stage 1A; 1/47, 2.1% in Stage 3A; 17/102, 16.7% in Stage 3B; P = 0.02) (Fig 3).
Risk Factors of MA Lesions in IgAN
Results of logistic regression models for the risk factors of MA lesions in patients with IgAN were presented in Table 4. Pandemic, sex, MAP, eGFR, M, E, S, and T were enrolled in the multivariable analysis. Stage 3A (possible with COVID-19 infection) (vs Stage 1A [no COVID-19 infection]; odds ratio [OR], 6.275; 95% CI, 3.021-13.034; P < 0.001), Stage 3B (possible with previous COVID-19 infection) (vs Stage 1A [no COVID-19 infection]; OR, 10.271; 95% CI, 5.236-20.144; P < 0.001), MAP (OR per 1 mm Hg higher, 1.026; 95% CI, 1.011-1.041; P < 0.001), eGFR (OR per 1 mL/min/1.73m2 higher, 0.979; 95% CI, 0.969-0.989; P < 0.001), S1 (OR, 2.194; 95% CI, 1.183-4.072; P = 0.01), T1 (vs T0; OR, 3.151; 95% CI, 1.729-5.543; P < 0.001), and T2 (vs T0; OR, 8.728; 95% CI, 4.257-17.893; P < 0.001) are the possible risk factors for the subsequent development of MA lesions.
Table 4.
Univariate and Multivariate Logistic Regression Analysis for Risk Factors of MA Lesions in IgAN
| Variable | Univariate logistic regression |
Multivariate logistic regression |
||||
|---|---|---|---|---|---|---|
| OR | OR (95% CI) | P | aOR | OR (95% CI) | P | |
| Clinical information | ||||||
| Pandemic periods | ||||||
| Stage 1Aa | Reference | Reference | ||||
| Stage 3Ab | 4.98 | 2.734-9.073 | < 0.001 | 6.275 | 3.021-13.034 | < 0.001 |
| Stage 3Bc | 5.981 | 3.429-10.435 | < 0.001 | 10.271 | 5.236-20.144 | < 0.001 |
| Sex | ||||||
| Male | Reference | |||||
| Female | 0.622 | 0.443-0.874 | 0.006 | 0.667 | 0.437-1.017 | 0.06 |
| Age, (y) | 1.006 | 0.994-1.018 | 0.32 | |||
| MAP,mm Hg | 1.033 | 1.022-1.045 | < 0.001 | 1.026 | 1.011-1.041 | < 0.001 |
| Proteinuria, g/24 h | 1.003 | 0.996-1.011 | 0.38 | |||
| eGFR, mL/min/1.73m2 | 0.961 | 0.953-0968 | < 0.001 | 0.979 | 0.969-0.989 | < 0.001 |
| Pathological features | ||||||
| Oxford classification | ||||||
| M 0 | Reference | Reference | ||||
| 1 | 1.712 | 1.210-2.421 | 0.002 | 1.119 | 0.717-1.745 | 0.62 |
| E 0 | Reference | Reference | ||||
| 1 | 1.754 | 1.231-2.499 | 0.002 | 0.726 | 0.462-1.141 | 0.17 |
| S 0 | Reference | Reference | ||||
| 1 | 4.224 | 2.445-7.297 | <0.001 | 2.194 | 1.183-4.072 | 0.01 |
| T 0 | Reference | Reference | ||||
| 1 | 5.92 | 3.616-9.69 | <0.001 | 3.151 | 1.729-5.543 | <0.001 |
| 2 | 24.241 | 14.544-40.402 | <0.001 | 8.728 | 4.257-17.893 | <0.001 |
| C 0 | Reference | |||||
| 1 | 0.818 | 0.577-1.158 | 0.26 | |||
| 2 | 0.841 | 0.369-1.918 | 0.68 | |||
Abbreviations: BP, blood pressure; MAP, mean arterial pressure; eGFR, estimated glomerular filtration rate; MA, microangiopathy; C, crescents; E, endocapillary hypercellularity; M, mesangial hypercellularity; S, segmental glomerulosclerosis; T, interstitial fibrosis and tubular atrophy.
Defined as time from December 1, 2018, to May 31, 2019, when there was no COVID-19 in China.
Defined as time from December 1, 2022, to May 31, 2023, when COVID-19 was prevailing across China.
Defined as time from December 1, 2023, to May 31, 2024, after COVID-19 pandemic in China.
Discussion
This study identified a significantly increased proportion of IgAN in total biopsy and a pronounced increase in MA lesions in IgAN, after the COVID-19 pandemic in northern China. The MA lesions became particularly pronounced after the COVID-19 pandemic spread across the country at the end of 2022. Patients with IgAN with MA lesions in postpandemic year exhibited significantly greater C3 deposition in kidney tissues than those in prepandemic and pandemic period.
Since COVID-19 emerged in December 2019, an increasing number of IgAN associated with the virus have been reported.16 Our study revealed a significant upward trend in the proportion of IgAN in biopsies, with a marked surge after December 2020 (Fig 2), coinciding with the start of China’s vaccination campaign.25 By the end of 2021, China had administered over 2.8 billion vaccine doses, achieving ∼90% first-dose coverage, whereas the proportion of positive COVID-19 nucleic acid tests remained low.25, 26, 27 In response to frequent reports of new-onset or relapsed IgAN after vaccination, we stratified Stage 2 into 2 periods, before and after the vaccination campaign, and conducted a comparative analysis. Our results showed a significant increase in biopsy-diagnosed IgAN cases after the campaign commenced (prevaccination 540/2,583, 20.9%; postvaccination, 1,831/7,195, 25.4%; P < 0.001) (Table S5).
However, a retrospective cohort study conducted by Diebold et al reported no increase in the incidence of new-onset IgAN after SARS-CoV-2 mRNA vaccination in Switzerland.28 Their study used a Bayesian model to compare observed and expected IgAN incidence over an 8-month period during the vaccination campaign, while we compared the proportion of IgAN in total biopsy over a 2-year observation period to that before the campaign. These contrasting findings suggest that methodology and study design may all play significant roles in determining the observed outcomes. Further large-scale epidemiological studies, particularly in countries with a high incidence of IgAN, are needed to clarify the impact of vaccination on the incidence of IgAN. Unlike Switzerland, where mRNA vaccines are prevalent, China has developed vaccines of different kinds, with inactivated vaccines such as Sinovac CoronaVac and BBIBP-CorV account for ∼90% of its market share because of its high efficacy with the majority of adverse reactions being mild.29,30 However, a study by Liu et al31 from China still reported an increased IgAN incidence in their center after vaccination. A prospective cohort study from Zhang et al32 in China showed that inactivated COVID-19 vaccines, predominantly 2-dose regimens, were associated with higher rates of de novo kidney diseases including IgAN, especially after the first dose compared with other vaccine types. In their study, vaccinated patients with IgAN exhibited elevated SARS-CoV-2-specific IgA and pathogenic galactose-deficient IgA1 (Gd-IgA1) levels compared with control groups, despite primarily inducing IgG/IgM responses. Proposed mechanisms might include: (1) aberrant immune activation via cross-reactivity/molecular mimicry; and (2) spike protein-induced immune complex deposition causing glomerular injury through complement activation (IL-6 and TNF-α). Although vaccine-triggered immune dysregulation may unmask renal susceptibility, experimental validation is needed.
Data from the Chinese Center for Disease Control and Prevention indicated that positive COVID-19 test numbers and positivity rates peaked on December 22, 2022, followed by a rapid decline.25 Correspondingly, we did not observe a further increase in the proportion of patients with IgAN based on the primary data we collected despite the nationwide outbreak (Table 2). However, from December 2022 to May 2023, only 20.42% (332/1,626) of patients were newly diagnosed with IgAN at our center, indicating a decline in diagnoses during the peak pandemic period (Fig 2). This trend is consistent with reports from Switzerland.28 The decline might be attributed to reduced patient mobility and health care disruptions early in the pandemic after the relaxation of national COVID-19 control measures on December 7, 2022.20,33 Many patients might have delayed seeking medical care until their conditions worsened, which could lead to potential selection bias as patients who were more sick were more likely to undergo biopsy during this period. Therefore, we excluded data from December 2022 to February 2023 and re-analyzed the proportion of IgAN cases. This analysis confirmed a significant increase in the proportion of IgAN in Stage 3 compared to that in Stage 1, with a similar proportion to Stage 2, which indicate a progressively increasing trend, leading us to hypothesize that both COVID-19 vaccination and infection have contributed to the increase in IgAN and IgAN-MA cases (Table S1). Similarly, a study by Liu et al31 from China still reported an increased IgAN incidence after infection in their center.
The proportion of MA lesions exhibited a steady upward trend over time, accompanied by progressively enhanced complement deposition. Notably, although COVID-19 was designated as a Public Health Emergency of International Concern, its status was downgraded by the World Health Organization in May 2023.21 Interestingly, our data indicated that patients with MA lesions in the Stage 3B period rather than those diagnosed in Stage 3A during the pandemic exhibited the highest proportion of C3 deposition and the strongest intensities of C3 and IgA deposition (Fig 3; Tables S3 and S4). This finding implied that the long-term influence of COVID-19 on patients with IgAN, particularly regarding the occurrence and severity of MA lesions, should not be overlooked. Mechanistically, hyperactivation of the complement system has been implicated in the pathophysiology of COVID-1934 and in the development of MA lesions.6,7,35,36 In support of this, a recent study by Guo et al17 found that patients with IgAN with COVID-19 exhibited significantly higher plasma levels of C5a and sC5b-9, and increased glomerular deposition of C4d, MAC, and Gd-IgA1, compared with those without COVID-19 infection. Therefore, we hypothesize that the pandemic may contribute to the development of MA lesions through overactivation of complement. In addition, evidence suggests that SARS-CoV-2 may infect cells expressing angiotensin-converting enzyme 2,19 including kidney endothelial cells.18 However, whether the endothelial injury in kidney was caused directly or indirectly remains unclear, as no widely accepted method exists for detecting the virus in renal tissues.37 Consequently, further investigation into the mechanisms of complement activation and the pathogenesis of MA lesions in IgAN.
This study has several limitations. First, data were collected from hospitals primarily located in northern China rather than through a nationwide analysis, limiting the generalizability of our findings to the entire country. Second, this study did not have access to exact data on COVID-19 infection and patients’ vaccination status, including the specific types of vaccines administered to patients, the number of vaccine doses they received, the COVID-19 infection status at the time of biopsy, or any antiviral therapies administered, so we are unable to differentiate the independent effects of COVID-19 infection and vaccination on the proportions of IgAN and MA lesions. Given the retrospective design, we could not systematically assess all MA lesion features or conclusively evaluate COVID-19’s impact on IgAN-MA severity (eg, acute microthrombi). Future pathological slide re-evaluations are needed. Third, the diagnosis of MA lesions was according to the pathological report without re-evaluation. Finally, prognostic data were not available in our study.
In conclusion, our study found that IgAN cases increased significantly after COVID-19 vaccination. In addition, patients exposed to vaccination and pandemic appeared to be more susceptible to developing MA lesions. Patients with MA lesions after pandemic exhibited a greater deposition of C3 in kidney tissues, suggesting a possible role for complement in the development of MA lesions, which also reminded us to pay attention to the long-time effect of COVID-19 on IgAN and MA lesions.
Article Information
Authors’ Full Names and Academic Degrees
Jing Wu, MM, Sufang Shi, MD, Xujie Zhou, MD, Lijun Liu, MD, Jicheng Lv, MD, Li Zhu, MD, Suxia Wang, MD, and Hong Zhang, MD
Author Contributions
Research idea and study design: SS; data acquisition: JW; data analysis/interpretation: JW; statistical analysis: JW; supervision or mentorship: SS, XZ, LL, JL, LZ, SW, and HZ. Each author contributed important intellectual content during article drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Support
This study was supported by the National Natural Science Foundation of China (82170710); National High Level Hospital Clinical Research Funding (State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University).
Financial Disclosure
The authors declare that they have no relevant financial interests.
Peer Review
Received January 7, 2025, as a submission to the expedited consideration track with 3 external peer reviews. Direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form April 8, 2025.
Footnotes
Complete author and article information provided before references.
Table S1: Proportion of IgAN and MA Lesions in Northern China After Excluding Data From December 2022 to February 2023.
Table S2: Clinicopathologic Baseline Characteristics of Patients with MA Lesions Among Groups Before, During, and After COVID-19 pandemic.
Table S3: Deposit of C3 and IgA in Patients with IgAN Patients Among Groups Before, During, and After COVID-19 Pandemic.
Table S4: Deposit of C3 and IgA in MA Patients Among Groups Before, During, and After COVID-19 Pandemic.
Table S5: Proportion of IgAN and MA Lesions in Northern China Before and After Vaccination in Stage 2.
Supplementary Materials
Tables S1-S5.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1-S5.