Abstract
Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused significant economic and health damage worldwide. Rapid vaccination is one of the key strategies to curb severe illness and death due to SARS-CoV-2 infection. Hundreds of millions of people worldwide have received various COVID-19 vaccines, including mRNA vaccines, inactivated vaccines and adenovirus-vectored vaccines, but the side effects and efficacy of most vaccines have not been extensively studied. Recently, there have been increasing reports of immunoglobulin A nephropathy (IgAN) after COVID-19 vaccination, however, whether their relationship is causal or coincidental remains to be verified. Here, we summarize the latest clinical evidence of IgAN diagnosed by renal biopsy associated with the COVID-19 vaccine published by 10 July 2022 with the largest sample size, and propose a hypothesis for the pathogenesis between them. At the same time, the new opportunity presented by COVID-19 vaccine allows us to explore the mechanism of IgAN recurrence for the first time. Indeed, we recognize that large-scale COVID-19 vaccination has enormous benefits in preventing COVID-19 morbidity and mortality. The purpose of this review is to help guide the clinical assessment and management of IgA nephropathy post-COVID-19 vaccination and to enrich the ‘multi-hit’ theory of IgA nephropathy.
Introduction
With the ongoing pandemic of coronavirus disease 2019 (COVID-19) and the continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it has caused great harm to human health.1 The most pronounced clinical symptoms in patients with COVID-19 are severe infections due to the fact that SARS-CoV-2 usually attacks the respiratory system first. However, there is a growing evidence that the virus can also affect other organs, and gastrointestinal symptoms and kidney damage are relatively common in this infection and are associated with increased mortality.2 Rapid and large-scale SARS-CoV-2 vaccination has been one of the key strategies to contain the COVID-19 pandemic. In recent years, hundreds of millions of people around the world have been vaccinated with various COVID-19 vaccines, including mRNA vaccines (Pfizer, Moderna and CureVac), inactivated vaccines (Sinovac Life Science and CoronaVac) and adenovirus vector vaccines (Janssen and Oxford-AstraZeneca). The mRNA vaccine is a novel vaccine consisting of lipid nanoparticles surrounding the mRNA encoding the SARS-CoV-2 spike protein. Once injected, the mRNA is translated into the target protein, resulting in a robust cellular and humoral immune response by generating antigen-specific follicular T cells and germinal center B cells3 and activated CD4+ and CD8+ T cells.4 Large clinical trials have shown that vaccination against SARS-CoV-2 has high efficacy and safety in preventing COVID-19 infection. The most common adverse events include injection site tenderness, fever, fatigue, body aches and headaches, and rarely have serious reactions.5–7
However, with the widespread use of SARS-CoV-2 vaccines around the world, growing number of reports describe the pathogenesis of glomerular diseases, such as immunoglobulin A nephropathy (IgAN), minimal change disease, antineutrophil cytoplasmic antibody-associated vasculitis and so on.8 Most cases were associated with mRNA vaccines (Pfizer and Moderna) and adenoviral vector delivery.9–12 Currently, IgAN is the most common glomerular disease after COVID-19 vaccination, which is characterized by mesangial immunodeposits of IgA1 with mesangial proliferation.13 However, it is unclear whether the COVID-19 vaccine can cause an immune response to trigger IgA antibodies production or form pathogenic IgA and form new immune deposits in the kidneys, or whether the immune response to the vaccine simply reveals pre-existing deposits. In this review, we summarized the most recent clinical evidence of IgA nephropathy diagnosed by renal biopsy associated with COVID-19 vaccines published by 10 July 2022 with the largest sample size, and elaborate the hypothesis of pathogenesis between them.
Materials and methods
In this review, we searched relevant literatures published before 10 July 2022 through electronic databases, including PubMed, EMBASE and Web of Science, using the following keywords: (‘immunoglobulin A nephropathy’ OR ‘IgA nephropathy’ OR ‘glomerulonephritis’ OR ‘nephropathies’ OR ‘hematuria’) AND (‘COVID-19’ OR ‘2019-nCoV’ OR ‘SARS-CoV-2’ OR ‘novel corona virus’ OR ‘coronavirus’) AND (‘vaccine’ OR ‘vaccination’). Then, we extracted baseline characteristics, experimental data about presentations, treatments and responses.
We report medians and ranges for continuous data and numbers and percentages for categorical data. We used descriptive statistics in this report and perform statistical analysis. The Kolmogorov–Smirnov test was used to evaluate the distribution of the variable. Mann–Whitney test was used for continuous data and Chi-Square test was used for categorical data to determine whether the two groups were statistically different. Because our sample size is small and there are data with a theoretical frequency T-value <5, the continuity correction is used for the simple four-table data, and the Fisher's Exact test is used for the R × C table data. All statistical analyses were carried out by SPSS24.0 software and P-values <0.05 were considered to be statistically significant.
Results
Baseline demographic and clinical characteristics of IgA nephropathy patients
There are 32 IgA nephropathy articles related to COVID-19 vaccines from inception to 10 July 2022. A total of 48 patients were diagnosed with IgA nephropathy by renal biopsy, including 31 newly diagnosed IgA nephropathy (64.6%)14–36 and 17 relapsed IgA nephropathy (35.4%).18,22,30,37–45 The median age was 35 (12–79) years, and 47.9% (23 of 48 cases) of patients were male. Most patients were Asians (41.7%), followed by Americans (37.5%). In addition, 62.5% of our patients received BNT162b2 (Pfizer) vaccine, 31.3% received mRNA-1273 (Moderna) vaccine and another 6.3% received AstraZeneca vaccine (Table 1).
Clinical characteristics of patients with IgAN post-COVID-19 vaccination
| Characteristics | First dose | Second dose | Total | P |
|---|---|---|---|---|
| (n = 10) | (n = 38) | (n = 48) | ||
| Age (year) | 40.5 (12–79) | 30 (13–73) | 35 (12–79) | 0.324 |
| Male sex, n (%) | 5 (50.0) | 18 (47.4) | 23 (47.9) | 1.000 |
| Geographic region, n (%) | 0.216 | |||
| Asia | 4 (40.0) | 16 (42.1) | 20 (41.7) | |
| Europe | 4 (40.0) | 6 (15.8) | 10 (20.8) | |
| USA | 2 (20.0) | 16 (42.1) | 18 (37.5) | |
| Medical history, n (%) | ||||
| Hypertension | 0 (0) | 5 (13.2) | 5 (10.4) | |
| Autoimmune disease | 2 (20.0) | 20 (52.6) | 22 (45.8) | |
| Kidney transplant | 1 (10.0) | 2 (5.3) | 3 (6.3) | |
| Abnormal urine | 3 (30.0) | 11 (28.9) | 14 (29.2) | |
| Vaccine type, n (%) | 0.127 | |||
| BNT162b2 (Pfizer) | 6 (60.0) | 24 (63.2) | 30 (62.5) | |
| mRNA-1273 (Moderna) | 2 (20.0) | 13 (34.2) | 15 (31.3) | |
| Adenovirus vector (AstraZeneca) | 2 (20.0) | 1 (2.6) | 3 (6.3) | |
| Cases, n (%) | 0.129 | |||
| New cases | 9 (90.0) | 22 (57.9) | 31 (64.6) | |
| Relapsed cases | 1 (10.0) | 16 (42.1) | 17 (35.4) | |
| Timing of symptom onset, n (%) | 0.030a | |||
| 1 day | 2 (20.0) | 18 (47.4) | 20 (41.7) | |
| 2–7 days | 2 (20.0) | 14 (36.8) | 16 (33.3) | |
| >7 days | 6 (60.0) | 6 (15.8) | 12 (25.0) | |
| Timing of symptom onset, days | ||||
| New cases | 11 (1–61) | 2 (1–42) | 2 (1–61) | 0.045 |
| Relapsed cases | 2 | 1.5 (1–79) | 2 (1–79) | 0.745 |
| Symptoms, n (%) | ||||
| GH | 7 (70.0) | 33 (86.8) | 40 (83.3) | |
| AKI | 5 (50.0) | 14 (36.8) | 19 (39.6) | |
| Proteinuria | 10 (100) | 32 (84.2) | 42 (87.5) | |
| Fever | 3 (30.0) | 17 (44.7) | 20 (41.7) | |
| Laboratory on presentation | ||||
| Serum creatinine (mg/dl) | 1.5 (0.58–3.57) | 1.23 (0.47–3.53) | 1.26 (0.47–3.57) | 0.670 |
| Treatment, n (%) | 0.065 | |||
| Conservative management | 3 (30.0) | 26 (68.4) | 29 (60.4) | |
| Steroid | 7 (70.0) | 12 (31.6) | 19 (39.6) | |
| Outcome, n (%) | 0.479 | |||
| Response | 7 (70.0) | 32 (84.2) | 39 (81.3) | |
| Not response | 1 (10.0) | 2 (5.3) | 3 (6.3) |
| Characteristics | First dose | Second dose | Total | P |
|---|---|---|---|---|
| (n = 10) | (n = 38) | (n = 48) | ||
| Age (year) | 40.5 (12–79) | 30 (13–73) | 35 (12–79) | 0.324 |
| Male sex, n (%) | 5 (50.0) | 18 (47.4) | 23 (47.9) | 1.000 |
| Geographic region, n (%) | 0.216 | |||
| Asia | 4 (40.0) | 16 (42.1) | 20 (41.7) | |
| Europe | 4 (40.0) | 6 (15.8) | 10 (20.8) | |
| USA | 2 (20.0) | 16 (42.1) | 18 (37.5) | |
| Medical history, n (%) | ||||
| Hypertension | 0 (0) | 5 (13.2) | 5 (10.4) | |
| Autoimmune disease | 2 (20.0) | 20 (52.6) | 22 (45.8) | |
| Kidney transplant | 1 (10.0) | 2 (5.3) | 3 (6.3) | |
| Abnormal urine | 3 (30.0) | 11 (28.9) | 14 (29.2) | |
| Vaccine type, n (%) | 0.127 | |||
| BNT162b2 (Pfizer) | 6 (60.0) | 24 (63.2) | 30 (62.5) | |
| mRNA-1273 (Moderna) | 2 (20.0) | 13 (34.2) | 15 (31.3) | |
| Adenovirus vector (AstraZeneca) | 2 (20.0) | 1 (2.6) | 3 (6.3) | |
| Cases, n (%) | 0.129 | |||
| New cases | 9 (90.0) | 22 (57.9) | 31 (64.6) | |
| Relapsed cases | 1 (10.0) | 16 (42.1) | 17 (35.4) | |
| Timing of symptom onset, n (%) | 0.030a | |||
| 1 day | 2 (20.0) | 18 (47.4) | 20 (41.7) | |
| 2–7 days | 2 (20.0) | 14 (36.8) | 16 (33.3) | |
| >7 days | 6 (60.0) | 6 (15.8) | 12 (25.0) | |
| Timing of symptom onset, days | ||||
| New cases | 11 (1–61) | 2 (1–42) | 2 (1–61) | 0.045 |
| Relapsed cases | 2 | 1.5 (1–79) | 2 (1–79) | 0.745 |
| Symptoms, n (%) | ||||
| GH | 7 (70.0) | 33 (86.8) | 40 (83.3) | |
| AKI | 5 (50.0) | 14 (36.8) | 19 (39.6) | |
| Proteinuria | 10 (100) | 32 (84.2) | 42 (87.5) | |
| Fever | 3 (30.0) | 17 (44.7) | 20 (41.7) | |
| Laboratory on presentation | ||||
| Serum creatinine (mg/dl) | 1.5 (0.58–3.57) | 1.23 (0.47–3.53) | 1.26 (0.47–3.57) | 0.670 |
| Treatment, n (%) | 0.065 | |||
| Conservative management | 3 (30.0) | 26 (68.4) | 29 (60.4) | |
| Steroid | 7 (70.0) | 12 (31.6) | 19 (39.6) | |
| Outcome, n (%) | 0.479 | |||
| Response | 7 (70.0) | 32 (84.2) | 39 (81.3) | |
| Not response | 1 (10.0) | 2 (5.3) | 3 (6.3) |
Patients with a history of autoimmune disease or abnormal urinalysis may have asymptomatic IgAN.
Statistically different.
Clinical characteristics of patients with IgAN post-COVID-19 vaccination
| Characteristics | First dose | Second dose | Total | P |
|---|---|---|---|---|
| (n = 10) | (n = 38) | (n = 48) | ||
| Age (year) | 40.5 (12–79) | 30 (13–73) | 35 (12–79) | 0.324 |
| Male sex, n (%) | 5 (50.0) | 18 (47.4) | 23 (47.9) | 1.000 |
| Geographic region, n (%) | 0.216 | |||
| Asia | 4 (40.0) | 16 (42.1) | 20 (41.7) | |
| Europe | 4 (40.0) | 6 (15.8) | 10 (20.8) | |
| USA | 2 (20.0) | 16 (42.1) | 18 (37.5) | |
| Medical history, n (%) | ||||
| Hypertension | 0 (0) | 5 (13.2) | 5 (10.4) | |
| Autoimmune disease | 2 (20.0) | 20 (52.6) | 22 (45.8) | |
| Kidney transplant | 1 (10.0) | 2 (5.3) | 3 (6.3) | |
| Abnormal urine | 3 (30.0) | 11 (28.9) | 14 (29.2) | |
| Vaccine type, n (%) | 0.127 | |||
| BNT162b2 (Pfizer) | 6 (60.0) | 24 (63.2) | 30 (62.5) | |
| mRNA-1273 (Moderna) | 2 (20.0) | 13 (34.2) | 15 (31.3) | |
| Adenovirus vector (AstraZeneca) | 2 (20.0) | 1 (2.6) | 3 (6.3) | |
| Cases, n (%) | 0.129 | |||
| New cases | 9 (90.0) | 22 (57.9) | 31 (64.6) | |
| Relapsed cases | 1 (10.0) | 16 (42.1) | 17 (35.4) | |
| Timing of symptom onset, n (%) | 0.030a | |||
| 1 day | 2 (20.0) | 18 (47.4) | 20 (41.7) | |
| 2–7 days | 2 (20.0) | 14 (36.8) | 16 (33.3) | |
| >7 days | 6 (60.0) | 6 (15.8) | 12 (25.0) | |
| Timing of symptom onset, days | ||||
| New cases | 11 (1–61) | 2 (1–42) | 2 (1–61) | 0.045 |
| Relapsed cases | 2 | 1.5 (1–79) | 2 (1–79) | 0.745 |
| Symptoms, n (%) | ||||
| GH | 7 (70.0) | 33 (86.8) | 40 (83.3) | |
| AKI | 5 (50.0) | 14 (36.8) | 19 (39.6) | |
| Proteinuria | 10 (100) | 32 (84.2) | 42 (87.5) | |
| Fever | 3 (30.0) | 17 (44.7) | 20 (41.7) | |
| Laboratory on presentation | ||||
| Serum creatinine (mg/dl) | 1.5 (0.58–3.57) | 1.23 (0.47–3.53) | 1.26 (0.47–3.57) | 0.670 |
| Treatment, n (%) | 0.065 | |||
| Conservative management | 3 (30.0) | 26 (68.4) | 29 (60.4) | |
| Steroid | 7 (70.0) | 12 (31.6) | 19 (39.6) | |
| Outcome, n (%) | 0.479 | |||
| Response | 7 (70.0) | 32 (84.2) | 39 (81.3) | |
| Not response | 1 (10.0) | 2 (5.3) | 3 (6.3) |
| Characteristics | First dose | Second dose | Total | P |
|---|---|---|---|---|
| (n = 10) | (n = 38) | (n = 48) | ||
| Age (year) | 40.5 (12–79) | 30 (13–73) | 35 (12–79) | 0.324 |
| Male sex, n (%) | 5 (50.0) | 18 (47.4) | 23 (47.9) | 1.000 |
| Geographic region, n (%) | 0.216 | |||
| Asia | 4 (40.0) | 16 (42.1) | 20 (41.7) | |
| Europe | 4 (40.0) | 6 (15.8) | 10 (20.8) | |
| USA | 2 (20.0) | 16 (42.1) | 18 (37.5) | |
| Medical history, n (%) | ||||
| Hypertension | 0 (0) | 5 (13.2) | 5 (10.4) | |
| Autoimmune disease | 2 (20.0) | 20 (52.6) | 22 (45.8) | |
| Kidney transplant | 1 (10.0) | 2 (5.3) | 3 (6.3) | |
| Abnormal urine | 3 (30.0) | 11 (28.9) | 14 (29.2) | |
| Vaccine type, n (%) | 0.127 | |||
| BNT162b2 (Pfizer) | 6 (60.0) | 24 (63.2) | 30 (62.5) | |
| mRNA-1273 (Moderna) | 2 (20.0) | 13 (34.2) | 15 (31.3) | |
| Adenovirus vector (AstraZeneca) | 2 (20.0) | 1 (2.6) | 3 (6.3) | |
| Cases, n (%) | 0.129 | |||
| New cases | 9 (90.0) | 22 (57.9) | 31 (64.6) | |
| Relapsed cases | 1 (10.0) | 16 (42.1) | 17 (35.4) | |
| Timing of symptom onset, n (%) | 0.030a | |||
| 1 day | 2 (20.0) | 18 (47.4) | 20 (41.7) | |
| 2–7 days | 2 (20.0) | 14 (36.8) | 16 (33.3) | |
| >7 days | 6 (60.0) | 6 (15.8) | 12 (25.0) | |
| Timing of symptom onset, days | ||||
| New cases | 11 (1–61) | 2 (1–42) | 2 (1–61) | 0.045 |
| Relapsed cases | 2 | 1.5 (1–79) | 2 (1–79) | 0.745 |
| Symptoms, n (%) | ||||
| GH | 7 (70.0) | 33 (86.8) | 40 (83.3) | |
| AKI | 5 (50.0) | 14 (36.8) | 19 (39.6) | |
| Proteinuria | 10 (100) | 32 (84.2) | 42 (87.5) | |
| Fever | 3 (30.0) | 17 (44.7) | 20 (41.7) | |
| Laboratory on presentation | ||||
| Serum creatinine (mg/dl) | 1.5 (0.58–3.57) | 1.23 (0.47–3.53) | 1.26 (0.47–3.57) | 0.670 |
| Treatment, n (%) | 0.065 | |||
| Conservative management | 3 (30.0) | 26 (68.4) | 29 (60.4) | |
| Steroid | 7 (70.0) | 12 (31.6) | 19 (39.6) | |
| Outcome, n (%) | 0.479 | |||
| Response | 7 (70.0) | 32 (84.2) | 39 (81.3) | |
| Not response | 1 (10.0) | 2 (5.3) | 3 (6.3) |
Patients with a history of autoimmune disease or abnormal urinalysis may have asymptomatic IgAN.
Statistically different.
Most patients developed symptoms after the second dose (79.2%), with a median onset time of 2 (immediate—79) days. In contrast, 10 patients (20.8%) developed clinical symptoms after the first dose (9 patients had new diagnosis and 1 patient was recurrence), with a median onset time of 10 (1–61) days. Common clinical manifestations were gross hematuria (GH), acute kidney injury (AKI), proteinuria and fever. The median serum creatinine was 1.26 (0.47–3.57) mg/dl. In most patients, GH is usually self-limited and rarely requires immunosuppressive therapy. Of 48 patients, 19 received immunosuppressive therapy, of which 13 had clinically manifested AKI and the other 29 received conservative treatment. Follow-up data were available for 42 patients, 39 patients responded well to the treatments (14 with immunotherapy and 25 with conservative treatment), and only 3 patients from the newly diagnosed group showed no respond. The median time to remission of GH in patients receiving conservative treatment was 5.5 (2–30) days. The detailed baseline clinical characteristics of each patient are shown in Table 2.
Summary of published cases of IgAN following COVID-19 vaccination
| No. | Authors | Age/sex | Country (race) | Medical history | Baseline (hhematuria/proteinuria/SCr) | Vaccine | Timing of symptom onset | Symptoms | Urinalysis | Blood test | Renal biopsy (MEST-C) | Treatments | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| New cases | |||||||||||||
| 1 | Niel14 | 13/F | Luxembourg | None | NA | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, fever, asthenia, muscle pain | proteinuria: 3.9 g/l | SCr: 3.57 mg/dl | IgAN (M1E1S0T0) | Hemodialysis + high-dose steroid |
|
| 2 | Abdel-Qader15 | 12/M | Jordanian | None | Normal | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, HTN, fever, fatigue | RBC: 1920/µl, proteinuria: 1.7 g/l | SCr: 1.77 mg/dl (D2) | IgAN | High-dose steroid |
|
| 3 | Okada16 | 17/F | Japan | Asymptomatic hematuria | Microscopic hematuria | mRNA (Pfizer) |
| GH, SRP | UPCR: 0.37 g/g |
| IgAN (M0E0S0T0) | Conservative |
|
| 4 | Fujita17 | 40/F | Japan | Occult blood | SCr: 0.76 mg/dl | mRNA (Pfizer) |
|
|
|
| IgAN (M1E0S0T0C1) | Conservative, plasma exchange, ABPC/SBT |
|
| 5 | Yokote35 | 36/F | Japan | Microscopic hematuria, proteinuria, rheumatoid arthritis | NA | mRNA (Pfizer) |
| GH, NS |
|
| DPGN, IgAN (M1E1S1T0C0) | High-dose steroid + immunosuppressive |
|
| 6 | Klomjit18 | 44/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
| AKI, NRP |
| SCr: 2.5 mg/dl | IgAN, AIN | High-dose steroid |
|
| 7 | Klomjit18 | 66/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
|
|
|
| IgAN | Prednisonea |
|
| 8 | Fenoglio19 | 74/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN | Steroid + hemodialysis |
|
| 9 | Fenoglio19 | 79/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN |
| NA |
| 10 | Anderegg20 | 39/M | Switzerland | HTN | NA | mRNA (Moderna) |
| GH, AKI, SRP, flu-like symptoms, severe fever | Numerous RBC | AKI | IgAN | High-dose steroid + immunosuppressive |
|
| 11 | Lo21 | 28/F | China | Microscopic hematuria |
| mRNA (Pfizer) |
| GH, SRP |
|
| IgAN (M1E0S0T0C0) | Conservative |
|
| 12 | Yotoke35 | 19/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH |
| SCr: 0.97 mg/dl | DPGN, IgAN (M1E1S1T0C1) | RASi |
|
| 13 | Hanna22 | 17/M |
| Foamy urine | NA | mRNA (Pfizer) | < D1 after 2nd dose | GH, AKI, SRP, HTN grade 1 | UPCR: 1.75 g/g (D9) |
| IgAN (M1E1S1T1C1) | High-dose steroid |
|
| 14 | Abramson23 | 30/M | USA (European and American ancestry) | None | NA | mRNA (Moderna) |
|
|
|
| IgAN (M1E0S1T0C0) | RASi |
|
| 15 | Tan24 | 41/F | Chinese | GDM | Normal | mRNA (Pfizer) |
| AKI, GH, SRP, HTN grade 1, headache, generalized myalgia |
|
| IgAN | High-dose steroid + immunosuppressive | NA. |
| 16 | Leong25 | 26/M | Singapore | Suspected IgAN |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever | UPCR: 174 mg/mmol, RBC: >100/HPF |
| IgAN | RASi | NA |
| 17 | Park26 | 50/M | USA |
|
| mRNA (Moderna) |
| GH, AKI, NRP |
| SCr: 1.54 mg/dl | IgAN | RASi |
|
| 18 | Lim27 | 42/F | Korea | None | NA | mRNA (Moderna) |
| GH | UTP :1.7 g/d | SCr: 0.47 mg/dl | IgAN (M0E1C1S1T0) | RASi |
|
| 19 | Uchiyama36 | 15/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, myalgia |
| SCr: 0.97 mg/dl | IgAN (M1E0S0T0C1) | Conservative |
|
| 20 | Uchiyama36 | 18/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, general malaise |
| SCr: 0.82 mg/dl | IgAN (M1E0S0T0C0) | Conservative |
|
| 21 | Kudose28 | 50/F |
|
|
| mRNA (Moderna) |
| GH, AKI, SRP, fever, body aches |
| SCr: 1.7 mg/dl | IgAN (M1E0S1T1C1) | Conservative |
|
| 22 | Kudose28 | 19/M |
| Microscopic hematuria | Normal | mRNA (Moderna) |
| GH | numerous RBC | SCr: 1.2 mg/dl | IgAN (M1E1S1T0C0) | Conservative |
|
| 23 | Horino29 | 17/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
|
|
|
| IgAN |
|
|
| 24 | Srinivasan30 | 35/M | USA (Caucasian) | Nephrolithiasis, ulcerative colitis | SCr: 1 mg/dl | mRNA (Moderna) |
| GH, AKI, SRP | UPCR: 0.656 g/g | SCr: 1.3 mg/dl | IgAN (M1E1S0T0C1) | Immunosuppressive |
|
| 25 | Morisawa31 | 16/M | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever |
|
| IgAN (M0E1S0T0C1) |
|
|
| 26 | Morisawa31 | 13/F | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, SRP, fever |
| SCr: 0.54 mg/dl | IgAN (M0E0S0T0C0) | Conservation |
|
| 27 | Nihei32 | 28/F | Japan | GH and mild proteinuria in 17 years old | NA | mRNA (Pfizer) |
| GH |
|
| IgAN (M0S0E1T0C0) | Conservative |
|
| 28 | Klomjit18 | 38/M |
| NA | SCr: 1.3 mg/dl | mRNA (Pfizer) |
| GH, SRP | RBC : 51–100/HPF UTP: 0.32 g/d | SCr: 1.6 mg/dl | IgAN | Conservative | NA |
| 29 | Alonso34 | 30/M | Spain |
|
| mRNA (Pfizer) |
| Microscopic hematuria |
|
| IgAN | Steroid |
|
| 30 | Mokos33 | 73/M | Croatia | AAN, HTN, KT | UTP: 0.25 g/d | Adenovirus vector (AstraZeneca) |
| SRP, edema of the lower legs |
| SCr: 1.67 mg/dl | IgAN (M0E1S0T0C1) | RASi |
|
| 31 | Klomjit18 | 62/M |
| NA | SCr: 1.0 mg/dl | mRNA (Pfizer) |
| AKI, SRP |
| SCr: 2.2 mg/dl | IgAN | Conservative |
|
| Relapsed cases | |||||||||||||
| 1 | Perrin37 | 41/F | France |
| Microscopic hematuria | mRNA (Pfizer) |
|
|
|
| IgAN | Conservative |
|
| 2 | Horino38 | 46/F | Japan | IgAN, tonsillectomy |
| mRNA (Pfizer) |
|
|
| SCr was normal | IgAN | Conservative |
|
| 3 | Negrea39 | 38/F |
| IgAN (2005) |
| mRNA (Moderna) | 8–24 h after 2nd dose |
| UTP: 0.82 g/d | SCr was normal | IgAN | Conservative |
|
| 4 | Negrea39 | 38/F |
| IgAN (2019) |
| mRNA (Moderna) |
|
| UTP: 0.59 g/d | SCr was normal | IgAN | Conservative |
|
| 5 | Valenzuela45 | 36/F | Spain | IgAN (2020) |
| mRNA (Moderna) | Few hours after 2nd dose | GH, AKI, fever, malaise | UTP: 1.5 g/d |
| IgAN | High-dose steroid + immunosuppressive |
|
| 6 | Rahim40 | 52/F | Asian | IgAN (2017) | ACR: <1 g/g | mRAN (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 7 | Plasse41 | NA | USA | IgAN (2020) |
| mRNA (Pfizer) | < D1 after 2nd dose |
|
| SCr: 1.16 mg/dl | IgAN | Conservative |
|
| 8 | Hanna22 | 13/M |
| IgAN, T1DM |
| mRNA (Pfizer) | < D1 after 2nd dose | GH, SRP, AKI, vomiting |
| SCr: 1.31 mg/dl (D2), ALB: 3.8 g/dl |
| Conservative |
|
| 9 | Srinivasan30 | 25/F | European | IgAN |
| mRNA (Moderna) |
| GH, AKI, NRP | UPCR: 4.76 g/g | SCr: 1.07 mg/dl | IgAN | Conservative |
|
| 10 | Perrin37 | 27/F | France |
| Normal | mRNA (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 11 | Watanabe42 | 54/F | USA (Caucasian) |
|
| mRNA (Moderna) |
| GH, AKI, SRP |
| SCr: 3.04 mg/dl (D7) | Active IgAN | Steroids |
|
| 12 | Udagawa43 | 15/F | Japan | IgAN | NA | mRNA (Pfizer) |
| GH, SRP, fever |
| SCr was normal | IgAN | Conservation |
|
| 13 | Udagawa43 | 16/F | Japan | IgAN | Normal | mRNA (Pfizer) |
|
| numerous RBC | SCr was normal | IgAN | Conservation |
|
| 14 | Plasse41 | NA | USA | IgAN (2018) |
| mRNA (Pfizer) |
|
|
| SCr: 3.53 mg/dl | IgAN | Steroids |
|
| 15 | Klomjit18 | 19/M |
| IgAN | SCr: 0.96 mg/dl | mRNA (Moderna) |
| GH, SRP |
| SCr: 0.76 mg/dl | IgAN | Conservative | NA. |
| 16 | Yokote35 | 48/F | Japan | IgAN (M0E1S1T0C1), tonsillectomy | UTP: 0.91 g/d | mRNA (Pfizer) |
| NS, GH |
|
| DPGN, IgAN (M0E1S1T0C1) | High-dose steroid |
|
| 17 | Schaubschlager44 | 35/F | USA | IgAN, psoriasis |
| mRNA (Pfizer) |
| SRP | UPCR: 2 g/g | SCr: 1.1 mg/dl | IgAN (M1E1S1T0C1) | High-dose steroid + immunosuppressive |
|
| No. | Authors | Age/sex | Country (race) | Medical history | Baseline (hhematuria/proteinuria/SCr) | Vaccine | Timing of symptom onset | Symptoms | Urinalysis | Blood test | Renal biopsy (MEST-C) | Treatments | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| New cases | |||||||||||||
| 1 | Niel14 | 13/F | Luxembourg | None | NA | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, fever, asthenia, muscle pain | proteinuria: 3.9 g/l | SCr: 3.57 mg/dl | IgAN (M1E1S0T0) | Hemodialysis + high-dose steroid |
|
| 2 | Abdel-Qader15 | 12/M | Jordanian | None | Normal | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, HTN, fever, fatigue | RBC: 1920/µl, proteinuria: 1.7 g/l | SCr: 1.77 mg/dl (D2) | IgAN | High-dose steroid |
|
| 3 | Okada16 | 17/F | Japan | Asymptomatic hematuria | Microscopic hematuria | mRNA (Pfizer) |
| GH, SRP | UPCR: 0.37 g/g |
| IgAN (M0E0S0T0) | Conservative |
|
| 4 | Fujita17 | 40/F | Japan | Occult blood | SCr: 0.76 mg/dl | mRNA (Pfizer) |
|
|
|
| IgAN (M1E0S0T0C1) | Conservative, plasma exchange, ABPC/SBT |
|
| 5 | Yokote35 | 36/F | Japan | Microscopic hematuria, proteinuria, rheumatoid arthritis | NA | mRNA (Pfizer) |
| GH, NS |
|
| DPGN, IgAN (M1E1S1T0C0) | High-dose steroid + immunosuppressive |
|
| 6 | Klomjit18 | 44/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
| AKI, NRP |
| SCr: 2.5 mg/dl | IgAN, AIN | High-dose steroid |
|
| 7 | Klomjit18 | 66/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
|
|
|
| IgAN | Prednisonea |
|
| 8 | Fenoglio19 | 74/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN | Steroid + hemodialysis |
|
| 9 | Fenoglio19 | 79/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN |
| NA |
| 10 | Anderegg20 | 39/M | Switzerland | HTN | NA | mRNA (Moderna) |
| GH, AKI, SRP, flu-like symptoms, severe fever | Numerous RBC | AKI | IgAN | High-dose steroid + immunosuppressive |
|
| 11 | Lo21 | 28/F | China | Microscopic hematuria |
| mRNA (Pfizer) |
| GH, SRP |
|
| IgAN (M1E0S0T0C0) | Conservative |
|
| 12 | Yotoke35 | 19/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH |
| SCr: 0.97 mg/dl | DPGN, IgAN (M1E1S1T0C1) | RASi |
|
| 13 | Hanna22 | 17/M |
| Foamy urine | NA | mRNA (Pfizer) | < D1 after 2nd dose | GH, AKI, SRP, HTN grade 1 | UPCR: 1.75 g/g (D9) |
| IgAN (M1E1S1T1C1) | High-dose steroid |
|
| 14 | Abramson23 | 30/M | USA (European and American ancestry) | None | NA | mRNA (Moderna) |
|
|
|
| IgAN (M1E0S1T0C0) | RASi |
|
| 15 | Tan24 | 41/F | Chinese | GDM | Normal | mRNA (Pfizer) |
| AKI, GH, SRP, HTN grade 1, headache, generalized myalgia |
|
| IgAN | High-dose steroid + immunosuppressive | NA. |
| 16 | Leong25 | 26/M | Singapore | Suspected IgAN |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever | UPCR: 174 mg/mmol, RBC: >100/HPF |
| IgAN | RASi | NA |
| 17 | Park26 | 50/M | USA |
|
| mRNA (Moderna) |
| GH, AKI, NRP |
| SCr: 1.54 mg/dl | IgAN | RASi |
|
| 18 | Lim27 | 42/F | Korea | None | NA | mRNA (Moderna) |
| GH | UTP :1.7 g/d | SCr: 0.47 mg/dl | IgAN (M0E1C1S1T0) | RASi |
|
| 19 | Uchiyama36 | 15/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, myalgia |
| SCr: 0.97 mg/dl | IgAN (M1E0S0T0C1) | Conservative |
|
| 20 | Uchiyama36 | 18/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, general malaise |
| SCr: 0.82 mg/dl | IgAN (M1E0S0T0C0) | Conservative |
|
| 21 | Kudose28 | 50/F |
|
|
| mRNA (Moderna) |
| GH, AKI, SRP, fever, body aches |
| SCr: 1.7 mg/dl | IgAN (M1E0S1T1C1) | Conservative |
|
| 22 | Kudose28 | 19/M |
| Microscopic hematuria | Normal | mRNA (Moderna) |
| GH | numerous RBC | SCr: 1.2 mg/dl | IgAN (M1E1S1T0C0) | Conservative |
|
| 23 | Horino29 | 17/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
|
|
|
| IgAN |
|
|
| 24 | Srinivasan30 | 35/M | USA (Caucasian) | Nephrolithiasis, ulcerative colitis | SCr: 1 mg/dl | mRNA (Moderna) |
| GH, AKI, SRP | UPCR: 0.656 g/g | SCr: 1.3 mg/dl | IgAN (M1E1S0T0C1) | Immunosuppressive |
|
| 25 | Morisawa31 | 16/M | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever |
|
| IgAN (M0E1S0T0C1) |
|
|
| 26 | Morisawa31 | 13/F | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, SRP, fever |
| SCr: 0.54 mg/dl | IgAN (M0E0S0T0C0) | Conservation |
|
| 27 | Nihei32 | 28/F | Japan | GH and mild proteinuria in 17 years old | NA | mRNA (Pfizer) |
| GH |
|
| IgAN (M0S0E1T0C0) | Conservative |
|
| 28 | Klomjit18 | 38/M |
| NA | SCr: 1.3 mg/dl | mRNA (Pfizer) |
| GH, SRP | RBC : 51–100/HPF UTP: 0.32 g/d | SCr: 1.6 mg/dl | IgAN | Conservative | NA |
| 29 | Alonso34 | 30/M | Spain |
|
| mRNA (Pfizer) |
| Microscopic hematuria |
|
| IgAN | Steroid |
|
| 30 | Mokos33 | 73/M | Croatia | AAN, HTN, KT | UTP: 0.25 g/d | Adenovirus vector (AstraZeneca) |
| SRP, edema of the lower legs |
| SCr: 1.67 mg/dl | IgAN (M0E1S0T0C1) | RASi |
|
| 31 | Klomjit18 | 62/M |
| NA | SCr: 1.0 mg/dl | mRNA (Pfizer) |
| AKI, SRP |
| SCr: 2.2 mg/dl | IgAN | Conservative |
|
| Relapsed cases | |||||||||||||
| 1 | Perrin37 | 41/F | France |
| Microscopic hematuria | mRNA (Pfizer) |
|
|
|
| IgAN | Conservative |
|
| 2 | Horino38 | 46/F | Japan | IgAN, tonsillectomy |
| mRNA (Pfizer) |
|
|
| SCr was normal | IgAN | Conservative |
|
| 3 | Negrea39 | 38/F |
| IgAN (2005) |
| mRNA (Moderna) | 8–24 h after 2nd dose |
| UTP: 0.82 g/d | SCr was normal | IgAN | Conservative |
|
| 4 | Negrea39 | 38/F |
| IgAN (2019) |
| mRNA (Moderna) |
|
| UTP: 0.59 g/d | SCr was normal | IgAN | Conservative |
|
| 5 | Valenzuela45 | 36/F | Spain | IgAN (2020) |
| mRNA (Moderna) | Few hours after 2nd dose | GH, AKI, fever, malaise | UTP: 1.5 g/d |
| IgAN | High-dose steroid + immunosuppressive |
|
| 6 | Rahim40 | 52/F | Asian | IgAN (2017) | ACR: <1 g/g | mRAN (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 7 | Plasse41 | NA | USA | IgAN (2020) |
| mRNA (Pfizer) | < D1 after 2nd dose |
|
| SCr: 1.16 mg/dl | IgAN | Conservative |
|
| 8 | Hanna22 | 13/M |
| IgAN, T1DM |
| mRNA (Pfizer) | < D1 after 2nd dose | GH, SRP, AKI, vomiting |
| SCr: 1.31 mg/dl (D2), ALB: 3.8 g/dl |
| Conservative |
|
| 9 | Srinivasan30 | 25/F | European | IgAN |
| mRNA (Moderna) |
| GH, AKI, NRP | UPCR: 4.76 g/g | SCr: 1.07 mg/dl | IgAN | Conservative |
|
| 10 | Perrin37 | 27/F | France |
| Normal | mRNA (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 11 | Watanabe42 | 54/F | USA (Caucasian) |
|
| mRNA (Moderna) |
| GH, AKI, SRP |
| SCr: 3.04 mg/dl (D7) | Active IgAN | Steroids |
|
| 12 | Udagawa43 | 15/F | Japan | IgAN | NA | mRNA (Pfizer) |
| GH, SRP, fever |
| SCr was normal | IgAN | Conservation |
|
| 13 | Udagawa43 | 16/F | Japan | IgAN | Normal | mRNA (Pfizer) |
|
| numerous RBC | SCr was normal | IgAN | Conservation |
|
| 14 | Plasse41 | NA | USA | IgAN (2018) |
| mRNA (Pfizer) |
|
|
| SCr: 3.53 mg/dl | IgAN | Steroids |
|
| 15 | Klomjit18 | 19/M |
| IgAN | SCr: 0.96 mg/dl | mRNA (Moderna) |
| GH, SRP |
| SCr: 0.76 mg/dl | IgAN | Conservative | NA. |
| 16 | Yokote35 | 48/F | Japan | IgAN (M0E1S1T0C1), tonsillectomy | UTP: 0.91 g/d | mRNA (Pfizer) |
| NS, GH |
|
| DPGN, IgAN (M0E1S1T0C1) | High-dose steroid |
|
| 17 | Schaubschlager44 | 35/F | USA | IgAN, psoriasis |
| mRNA (Pfizer) |
| SRP | UPCR: 2 g/g | SCr: 1.1 mg/dl | IgAN (M1E1S1T0C1) | High-dose steroid + immunosuppressive |
|
Prednisone was initiated for the treatment of pericarditis.
COVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; F, female; M, male; GH, gross hematuria; SRP, sub-nephrotic range proteinuria; NRP, nephrotic range proteinuria; SCr, serum creatinine; ANA, anti-nuclear antibody; C3, complement C3; CRP, C-reactive protein; ALB, serum albumin; RBC, red blood cell; WBC, white blood cell; HPF, high power field; UPCR, urine protein-to-creatinine ratio; UACR, urinary albumin-creatinine ratio; ACR, microalbumin-creatinine ratio; UTP, 24-h urine protein; CR, complete remission; PR, partial remission; NA, non-applicable; NR, no response; R, response; KT, kidney transplantation; HD, hemodialysis; RASi, renin–angiotensin–aldosterone system inhibition; ABPC, ampicillin; SBT, sulbactam; HTN, hypertension; T1DM, type 1 diabetes mellitus; AIN, acute interstitial nephritis; DPGN, diffuse proliferative glomerulonephritis; APS, antiphospholipid syndrome; GDM, gestational diabetes; AAN, aristolochic acid nephropathy; RF, renal failure; NS, nephrotic syndrome; AKI, acute tubular injury; GERD, gastroesophageal reflux disease; CKD, chronic kidney disease; MEST-C, M = mesangial hypercellularity, E = endocapillary proliferation, S = segmental glomerulosclerosis, T = tubular atrophy/interstitial fibrosis, C = crescents.
Summary of published cases of IgAN following COVID-19 vaccination
| No. | Authors | Age/sex | Country (race) | Medical history | Baseline (hhematuria/proteinuria/SCr) | Vaccine | Timing of symptom onset | Symptoms | Urinalysis | Blood test | Renal biopsy (MEST-C) | Treatments | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| New cases | |||||||||||||
| 1 | Niel14 | 13/F | Luxembourg | None | NA | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, fever, asthenia, muscle pain | proteinuria: 3.9 g/l | SCr: 3.57 mg/dl | IgAN (M1E1S0T0) | Hemodialysis + high-dose steroid |
|
| 2 | Abdel-Qader15 | 12/M | Jordanian | None | Normal | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, HTN, fever, fatigue | RBC: 1920/µl, proteinuria: 1.7 g/l | SCr: 1.77 mg/dl (D2) | IgAN | High-dose steroid |
|
| 3 | Okada16 | 17/F | Japan | Asymptomatic hematuria | Microscopic hematuria | mRNA (Pfizer) |
| GH, SRP | UPCR: 0.37 g/g |
| IgAN (M0E0S0T0) | Conservative |
|
| 4 | Fujita17 | 40/F | Japan | Occult blood | SCr: 0.76 mg/dl | mRNA (Pfizer) |
|
|
|
| IgAN (M1E0S0T0C1) | Conservative, plasma exchange, ABPC/SBT |
|
| 5 | Yokote35 | 36/F | Japan | Microscopic hematuria, proteinuria, rheumatoid arthritis | NA | mRNA (Pfizer) |
| GH, NS |
|
| DPGN, IgAN (M1E1S1T0C0) | High-dose steroid + immunosuppressive |
|
| 6 | Klomjit18 | 44/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
| AKI, NRP |
| SCr: 2.5 mg/dl | IgAN, AIN | High-dose steroid |
|
| 7 | Klomjit18 | 66/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
|
|
|
| IgAN | Prednisonea |
|
| 8 | Fenoglio19 | 74/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN | Steroid + hemodialysis |
|
| 9 | Fenoglio19 | 79/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN |
| NA |
| 10 | Anderegg20 | 39/M | Switzerland | HTN | NA | mRNA (Moderna) |
| GH, AKI, SRP, flu-like symptoms, severe fever | Numerous RBC | AKI | IgAN | High-dose steroid + immunosuppressive |
|
| 11 | Lo21 | 28/F | China | Microscopic hematuria |
| mRNA (Pfizer) |
| GH, SRP |
|
| IgAN (M1E0S0T0C0) | Conservative |
|
| 12 | Yotoke35 | 19/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH |
| SCr: 0.97 mg/dl | DPGN, IgAN (M1E1S1T0C1) | RASi |
|
| 13 | Hanna22 | 17/M |
| Foamy urine | NA | mRNA (Pfizer) | < D1 after 2nd dose | GH, AKI, SRP, HTN grade 1 | UPCR: 1.75 g/g (D9) |
| IgAN (M1E1S1T1C1) | High-dose steroid |
|
| 14 | Abramson23 | 30/M | USA (European and American ancestry) | None | NA | mRNA (Moderna) |
|
|
|
| IgAN (M1E0S1T0C0) | RASi |
|
| 15 | Tan24 | 41/F | Chinese | GDM | Normal | mRNA (Pfizer) |
| AKI, GH, SRP, HTN grade 1, headache, generalized myalgia |
|
| IgAN | High-dose steroid + immunosuppressive | NA. |
| 16 | Leong25 | 26/M | Singapore | Suspected IgAN |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever | UPCR: 174 mg/mmol, RBC: >100/HPF |
| IgAN | RASi | NA |
| 17 | Park26 | 50/M | USA |
|
| mRNA (Moderna) |
| GH, AKI, NRP |
| SCr: 1.54 mg/dl | IgAN | RASi |
|
| 18 | Lim27 | 42/F | Korea | None | NA | mRNA (Moderna) |
| GH | UTP :1.7 g/d | SCr: 0.47 mg/dl | IgAN (M0E1C1S1T0) | RASi |
|
| 19 | Uchiyama36 | 15/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, myalgia |
| SCr: 0.97 mg/dl | IgAN (M1E0S0T0C1) | Conservative |
|
| 20 | Uchiyama36 | 18/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, general malaise |
| SCr: 0.82 mg/dl | IgAN (M1E0S0T0C0) | Conservative |
|
| 21 | Kudose28 | 50/F |
|
|
| mRNA (Moderna) |
| GH, AKI, SRP, fever, body aches |
| SCr: 1.7 mg/dl | IgAN (M1E0S1T1C1) | Conservative |
|
| 22 | Kudose28 | 19/M |
| Microscopic hematuria | Normal | mRNA (Moderna) |
| GH | numerous RBC | SCr: 1.2 mg/dl | IgAN (M1E1S1T0C0) | Conservative |
|
| 23 | Horino29 | 17/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
|
|
|
| IgAN |
|
|
| 24 | Srinivasan30 | 35/M | USA (Caucasian) | Nephrolithiasis, ulcerative colitis | SCr: 1 mg/dl | mRNA (Moderna) |
| GH, AKI, SRP | UPCR: 0.656 g/g | SCr: 1.3 mg/dl | IgAN (M1E1S0T0C1) | Immunosuppressive |
|
| 25 | Morisawa31 | 16/M | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever |
|
| IgAN (M0E1S0T0C1) |
|
|
| 26 | Morisawa31 | 13/F | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, SRP, fever |
| SCr: 0.54 mg/dl | IgAN (M0E0S0T0C0) | Conservation |
|
| 27 | Nihei32 | 28/F | Japan | GH and mild proteinuria in 17 years old | NA | mRNA (Pfizer) |
| GH |
|
| IgAN (M0S0E1T0C0) | Conservative |
|
| 28 | Klomjit18 | 38/M |
| NA | SCr: 1.3 mg/dl | mRNA (Pfizer) |
| GH, SRP | RBC : 51–100/HPF UTP: 0.32 g/d | SCr: 1.6 mg/dl | IgAN | Conservative | NA |
| 29 | Alonso34 | 30/M | Spain |
|
| mRNA (Pfizer) |
| Microscopic hematuria |
|
| IgAN | Steroid |
|
| 30 | Mokos33 | 73/M | Croatia | AAN, HTN, KT | UTP: 0.25 g/d | Adenovirus vector (AstraZeneca) |
| SRP, edema of the lower legs |
| SCr: 1.67 mg/dl | IgAN (M0E1S0T0C1) | RASi |
|
| 31 | Klomjit18 | 62/M |
| NA | SCr: 1.0 mg/dl | mRNA (Pfizer) |
| AKI, SRP |
| SCr: 2.2 mg/dl | IgAN | Conservative |
|
| Relapsed cases | |||||||||||||
| 1 | Perrin37 | 41/F | France |
| Microscopic hematuria | mRNA (Pfizer) |
|
|
|
| IgAN | Conservative |
|
| 2 | Horino38 | 46/F | Japan | IgAN, tonsillectomy |
| mRNA (Pfizer) |
|
|
| SCr was normal | IgAN | Conservative |
|
| 3 | Negrea39 | 38/F |
| IgAN (2005) |
| mRNA (Moderna) | 8–24 h after 2nd dose |
| UTP: 0.82 g/d | SCr was normal | IgAN | Conservative |
|
| 4 | Negrea39 | 38/F |
| IgAN (2019) |
| mRNA (Moderna) |
|
| UTP: 0.59 g/d | SCr was normal | IgAN | Conservative |
|
| 5 | Valenzuela45 | 36/F | Spain | IgAN (2020) |
| mRNA (Moderna) | Few hours after 2nd dose | GH, AKI, fever, malaise | UTP: 1.5 g/d |
| IgAN | High-dose steroid + immunosuppressive |
|
| 6 | Rahim40 | 52/F | Asian | IgAN (2017) | ACR: <1 g/g | mRAN (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 7 | Plasse41 | NA | USA | IgAN (2020) |
| mRNA (Pfizer) | < D1 after 2nd dose |
|
| SCr: 1.16 mg/dl | IgAN | Conservative |
|
| 8 | Hanna22 | 13/M |
| IgAN, T1DM |
| mRNA (Pfizer) | < D1 after 2nd dose | GH, SRP, AKI, vomiting |
| SCr: 1.31 mg/dl (D2), ALB: 3.8 g/dl |
| Conservative |
|
| 9 | Srinivasan30 | 25/F | European | IgAN |
| mRNA (Moderna) |
| GH, AKI, NRP | UPCR: 4.76 g/g | SCr: 1.07 mg/dl | IgAN | Conservative |
|
| 10 | Perrin37 | 27/F | France |
| Normal | mRNA (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 11 | Watanabe42 | 54/F | USA (Caucasian) |
|
| mRNA (Moderna) |
| GH, AKI, SRP |
| SCr: 3.04 mg/dl (D7) | Active IgAN | Steroids |
|
| 12 | Udagawa43 | 15/F | Japan | IgAN | NA | mRNA (Pfizer) |
| GH, SRP, fever |
| SCr was normal | IgAN | Conservation |
|
| 13 | Udagawa43 | 16/F | Japan | IgAN | Normal | mRNA (Pfizer) |
|
| numerous RBC | SCr was normal | IgAN | Conservation |
|
| 14 | Plasse41 | NA | USA | IgAN (2018) |
| mRNA (Pfizer) |
|
|
| SCr: 3.53 mg/dl | IgAN | Steroids |
|
| 15 | Klomjit18 | 19/M |
| IgAN | SCr: 0.96 mg/dl | mRNA (Moderna) |
| GH, SRP |
| SCr: 0.76 mg/dl | IgAN | Conservative | NA. |
| 16 | Yokote35 | 48/F | Japan | IgAN (M0E1S1T0C1), tonsillectomy | UTP: 0.91 g/d | mRNA (Pfizer) |
| NS, GH |
|
| DPGN, IgAN (M0E1S1T0C1) | High-dose steroid |
|
| 17 | Schaubschlager44 | 35/F | USA | IgAN, psoriasis |
| mRNA (Pfizer) |
| SRP | UPCR: 2 g/g | SCr: 1.1 mg/dl | IgAN (M1E1S1T0C1) | High-dose steroid + immunosuppressive |
|
| No. | Authors | Age/sex | Country (race) | Medical history | Baseline (hhematuria/proteinuria/SCr) | Vaccine | Timing of symptom onset | Symptoms | Urinalysis | Blood test | Renal biopsy (MEST-C) | Treatments | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| New cases | |||||||||||||
| 1 | Niel14 | 13/F | Luxembourg | None | NA | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, fever, asthenia, muscle pain | proteinuria: 3.9 g/l | SCr: 3.57 mg/dl | IgAN (M1E1S0T0) | Hemodialysis + high-dose steroid |
|
| 2 | Abdel-Qader15 | 12/M | Jordanian | None | Normal | mRNA (Pfizer) | < D1 after 1st dose | GH, AKI, NRP, HTN, fever, fatigue | RBC: 1920/µl, proteinuria: 1.7 g/l | SCr: 1.77 mg/dl (D2) | IgAN | High-dose steroid |
|
| 3 | Okada16 | 17/F | Japan | Asymptomatic hematuria | Microscopic hematuria | mRNA (Pfizer) |
| GH, SRP | UPCR: 0.37 g/g |
| IgAN (M0E0S0T0) | Conservative |
|
| 4 | Fujita17 | 40/F | Japan | Occult blood | SCr: 0.76 mg/dl | mRNA (Pfizer) |
|
|
|
| IgAN (M1E0S0T0C1) | Conservative, plasma exchange, ABPC/SBT |
|
| 5 | Yokote35 | 36/F | Japan | Microscopic hematuria, proteinuria, rheumatoid arthritis | NA | mRNA (Pfizer) |
| GH, NS |
|
| DPGN, IgAN (M1E1S1T0C0) | High-dose steroid + immunosuppressive |
|
| 6 | Klomjit18 | 44/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
| AKI, NRP |
| SCr: 2.5 mg/dl | IgAN, AIN | High-dose steroid |
|
| 7 | Klomjit18 | 66/M |
| NA | SCr: 1.1 mg/dl | mRNA (Moderna) |
|
|
|
| IgAN | Prednisonea |
|
| 8 | Fenoglio19 | 74/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN | Steroid + hemodialysis |
|
| 9 | Fenoglio19 | 79/M | Italy | NA | Normal | Adenovirus vector (AstraZeneca) |
| RF, NS | NA | NA | IgAN |
| NA |
| 10 | Anderegg20 | 39/M | Switzerland | HTN | NA | mRNA (Moderna) |
| GH, AKI, SRP, flu-like symptoms, severe fever | Numerous RBC | AKI | IgAN | High-dose steroid + immunosuppressive |
|
| 11 | Lo21 | 28/F | China | Microscopic hematuria |
| mRNA (Pfizer) |
| GH, SRP |
|
| IgAN (M1E0S0T0C0) | Conservative |
|
| 12 | Yotoke35 | 19/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH |
| SCr: 0.97 mg/dl | DPGN, IgAN (M1E1S1T0C1) | RASi |
|
| 13 | Hanna22 | 17/M |
| Foamy urine | NA | mRNA (Pfizer) | < D1 after 2nd dose | GH, AKI, SRP, HTN grade 1 | UPCR: 1.75 g/g (D9) |
| IgAN (M1E1S1T1C1) | High-dose steroid |
|
| 14 | Abramson23 | 30/M | USA (European and American ancestry) | None | NA | mRNA (Moderna) |
|
|
|
| IgAN (M1E0S1T0C0) | RASi |
|
| 15 | Tan24 | 41/F | Chinese | GDM | Normal | mRNA (Pfizer) |
| AKI, GH, SRP, HTN grade 1, headache, generalized myalgia |
|
| IgAN | High-dose steroid + immunosuppressive | NA. |
| 16 | Leong25 | 26/M | Singapore | Suspected IgAN |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever | UPCR: 174 mg/mmol, RBC: >100/HPF |
| IgAN | RASi | NA |
| 17 | Park26 | 50/M | USA |
|
| mRNA (Moderna) |
| GH, AKI, NRP |
| SCr: 1.54 mg/dl | IgAN | RASi |
|
| 18 | Lim27 | 42/F | Korea | None | NA | mRNA (Moderna) |
| GH | UTP :1.7 g/d | SCr: 0.47 mg/dl | IgAN (M0E1C1S1T0) | RASi |
|
| 19 | Uchiyama36 | 15/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, myalgia |
| SCr: 0.97 mg/dl | IgAN (M1E0S0T0C1) | Conservative |
|
| 20 | Uchiyama36 | 18/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
| GH, fever, general malaise |
| SCr: 0.82 mg/dl | IgAN (M1E0S0T0C0) | Conservative |
|
| 21 | Kudose28 | 50/F |
|
|
| mRNA (Moderna) |
| GH, AKI, SRP, fever, body aches |
| SCr: 1.7 mg/dl | IgAN (M1E0S1T1C1) | Conservative |
|
| 22 | Kudose28 | 19/M |
| Microscopic hematuria | Normal | mRNA (Moderna) |
| GH | numerous RBC | SCr: 1.2 mg/dl | IgAN (M1E1S1T0C0) | Conservative |
|
| 23 | Horino29 | 17/M | Japan | Microscopic hematuria | NA | mRNA (Pfizer) |
|
|
|
| IgAN |
|
|
| 24 | Srinivasan30 | 35/M | USA (Caucasian) | Nephrolithiasis, ulcerative colitis | SCr: 1 mg/dl | mRNA (Moderna) |
| GH, AKI, SRP | UPCR: 0.656 g/g | SCr: 1.3 mg/dl | IgAN (M1E1S0T0C1) | Immunosuppressive |
|
| 25 | Morisawa31 | 16/M | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, AKI, SRP, fever |
|
| IgAN (M0E1S0T0C1) |
|
|
| 26 | Morisawa31 | 13/F | Japan | Asymptomatic hematuria |
| mRNA (Pfizer) |
| GH, SRP, fever |
| SCr: 0.54 mg/dl | IgAN (M0E0S0T0C0) | Conservation |
|
| 27 | Nihei32 | 28/F | Japan | GH and mild proteinuria in 17 years old | NA | mRNA (Pfizer) |
| GH |
|
| IgAN (M0S0E1T0C0) | Conservative |
|
| 28 | Klomjit18 | 38/M |
| NA | SCr: 1.3 mg/dl | mRNA (Pfizer) |
| GH, SRP | RBC : 51–100/HPF UTP: 0.32 g/d | SCr: 1.6 mg/dl | IgAN | Conservative | NA |
| 29 | Alonso34 | 30/M | Spain |
|
| mRNA (Pfizer) |
| Microscopic hematuria |
|
| IgAN | Steroid |
|
| 30 | Mokos33 | 73/M | Croatia | AAN, HTN, KT | UTP: 0.25 g/d | Adenovirus vector (AstraZeneca) |
| SRP, edema of the lower legs |
| SCr: 1.67 mg/dl | IgAN (M0E1S0T0C1) | RASi |
|
| 31 | Klomjit18 | 62/M |
| NA | SCr: 1.0 mg/dl | mRNA (Pfizer) |
| AKI, SRP |
| SCr: 2.2 mg/dl | IgAN | Conservative |
|
| Relapsed cases | |||||||||||||
| 1 | Perrin37 | 41/F | France |
| Microscopic hematuria | mRNA (Pfizer) |
|
|
|
| IgAN | Conservative |
|
| 2 | Horino38 | 46/F | Japan | IgAN, tonsillectomy |
| mRNA (Pfizer) |
|
|
| SCr was normal | IgAN | Conservative |
|
| 3 | Negrea39 | 38/F |
| IgAN (2005) |
| mRNA (Moderna) | 8–24 h after 2nd dose |
| UTP: 0.82 g/d | SCr was normal | IgAN | Conservative |
|
| 4 | Negrea39 | 38/F |
| IgAN (2019) |
| mRNA (Moderna) |
|
| UTP: 0.59 g/d | SCr was normal | IgAN | Conservative |
|
| 5 | Valenzuela45 | 36/F | Spain | IgAN (2020) |
| mRNA (Moderna) | Few hours after 2nd dose | GH, AKI, fever, malaise | UTP: 1.5 g/d |
| IgAN | High-dose steroid + immunosuppressive |
|
| 6 | Rahim40 | 52/F | Asian | IgAN (2017) | ACR: <1 g/g | mRAN (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 7 | Plasse41 | NA | USA | IgAN (2020) |
| mRNA (Pfizer) | < D1 after 2nd dose |
|
| SCr: 1.16 mg/dl | IgAN | Conservative |
|
| 8 | Hanna22 | 13/M |
| IgAN, T1DM |
| mRNA (Pfizer) | < D1 after 2nd dose | GH, SRP, AKI, vomiting |
| SCr: 1.31 mg/dl (D2), ALB: 3.8 g/dl |
| Conservative |
|
| 9 | Srinivasan30 | 25/F | European | IgAN |
| mRNA (Moderna) |
| GH, AKI, NRP | UPCR: 4.76 g/g | SCr: 1.07 mg/dl | IgAN | Conservative |
|
| 10 | Perrin37 | 27/F | France |
| Normal | mRNA (Pfizer) |
|
|
| NA | IgAN | Conservative |
|
| 11 | Watanabe42 | 54/F | USA (Caucasian) |
|
| mRNA (Moderna) |
| GH, AKI, SRP |
| SCr: 3.04 mg/dl (D7) | Active IgAN | Steroids |
|
| 12 | Udagawa43 | 15/F | Japan | IgAN | NA | mRNA (Pfizer) |
| GH, SRP, fever |
| SCr was normal | IgAN | Conservation |
|
| 13 | Udagawa43 | 16/F | Japan | IgAN | Normal | mRNA (Pfizer) |
|
| numerous RBC | SCr was normal | IgAN | Conservation |
|
| 14 | Plasse41 | NA | USA | IgAN (2018) |
| mRNA (Pfizer) |
|
|
| SCr: 3.53 mg/dl | IgAN | Steroids |
|
| 15 | Klomjit18 | 19/M |
| IgAN | SCr: 0.96 mg/dl | mRNA (Moderna) |
| GH, SRP |
| SCr: 0.76 mg/dl | IgAN | Conservative | NA. |
| 16 | Yokote35 | 48/F | Japan | IgAN (M0E1S1T0C1), tonsillectomy | UTP: 0.91 g/d | mRNA (Pfizer) |
| NS, GH |
|
| DPGN, IgAN (M0E1S1T0C1) | High-dose steroid |
|
| 17 | Schaubschlager44 | 35/F | USA | IgAN, psoriasis |
| mRNA (Pfizer) |
| SRP | UPCR: 2 g/g | SCr: 1.1 mg/dl | IgAN (M1E1S1T0C1) | High-dose steroid + immunosuppressive |
|
Prednisone was initiated for the treatment of pericarditis.
COVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; F, female; M, male; GH, gross hematuria; SRP, sub-nephrotic range proteinuria; NRP, nephrotic range proteinuria; SCr, serum creatinine; ANA, anti-nuclear antibody; C3, complement C3; CRP, C-reactive protein; ALB, serum albumin; RBC, red blood cell; WBC, white blood cell; HPF, high power field; UPCR, urine protein-to-creatinine ratio; UACR, urinary albumin-creatinine ratio; ACR, microalbumin-creatinine ratio; UTP, 24-h urine protein; CR, complete remission; PR, partial remission; NA, non-applicable; NR, no response; R, response; KT, kidney transplantation; HD, hemodialysis; RASi, renin–angiotensin–aldosterone system inhibition; ABPC, ampicillin; SBT, sulbactam; HTN, hypertension; T1DM, type 1 diabetes mellitus; AIN, acute interstitial nephritis; DPGN, diffuse proliferative glomerulonephritis; APS, antiphospholipid syndrome; GDM, gestational diabetes; AAN, aristolochic acid nephropathy; RF, renal failure; NS, nephrotic syndrome; AKI, acute tubular injury; GERD, gastroesophageal reflux disease; CKD, chronic kidney disease; MEST-C, M = mesangial hypercellularity, E = endocapillary proliferation, S = segmental glomerulosclerosis, T = tubular atrophy/interstitial fibrosis, C = crescents.
Clinical characteristics and treatment of IgAN patients with new symptoms after the first dose of COVID-19 vaccination
There were 10 patients with clinical symptoms after the first dose of vaccine, of which 9 were new cases and 1 was a relapse, with a median onset time of 10 (1–61) days. Patients with Cases 3, 4 and 5 had a history of asymptomatic hematuria. Case 6 patient had history of inflammatory bowel disease and renal cell carcinoma. He underwent partial nephrectomy 7 years before vaccination, and in order to assess the presence of IgA deposits prior to vaccination, nephrectomy samples were retrieved for further examination. There were unremarkable in the glomeruli under the light microscope. Immunofluorescence detection of pronase-digested paraffin tissue revealed segmental mesangial staining for IgA, kappa and lambda. Electron microscopy showed the presence of mesangial deposits.
Of the 10 patients, 7 received immunotherapy and 3 received conservative treatment. Among the 7 patients receiving immunotherapy, 5 patients presented with clinical AKI, and 2 patients (Cases 1 and 8) received hemodialysis. The Case 7 patient had pericarditis symptoms in addition to GH and was treated with prednisone. Case 4 underwent two plasma exchanges to rule out thrombotic thrombocytopenic purpura because of thrombocytopenia and pyuria after vaccination, and antibiotics therapy for possible pyelonephritis.
Of the 10 patients, 9 had received follow-up data from 1 week to 5 months, of which 6 patients responded well to the treatment. Case 8 died of sudden acute heart attack during the 2-month follow-up. Case 6 developed AKI and nephrotic-rang proteinuria after the first dose of Moderna vaccine and went on to receive the second dose of the vaccine. Kidney biopsy was diagnosed as IgA nephropathy with acute interstitial nephritis, and he treated with steroid pulse therapy, but the disease has progressed without responding. Relapsed Case 1 patient37 was a 41-year-old woman with a previous diagnosis of IgAN who underwent kidney transplantation in 2013. The patient developed GH, proteinuria, slightly elevated creatinine and marked leukocytosis 2 days after receiving the first dose of mRNA vaccine, and the symptoms subsided spontaneously within a few days of observation.
Clinical characteristics and treatment of IgAN patients with new symptoms after the second dose of COVID-19 vaccination
There were 38 patients with clinical symptoms after the second dose of vaccine, of which 22 were new cases and 16 were recurrent cases, with a median onset time of 2 (immediate—79) days. Case 17 patient in the recurrence group relapsed after receiving the second dose of the vaccine and was found to have worsening proteinuria on Day 79, resulting in a delayed diagnosis of IgA nephropathy. Pathology showed the presence of mixed cells and fibrocytic crescents, indicating that disease reactivation occurred several weeks before the biopsy time, which may be closer to the time of vaccination. Of the 22 newly diagnosed patients, 9 had a previous history of hematuria and 4 had autoimmune diseases. Autoimmune disorders include a history of inflammatory bowel disease, antiphospholipid syndrome and glomerulonephritis. Case 17 had a history of chronic kidney disease and mild proteinuria. Case 13 had a history of foamy urine and a renal biopsy with cellular glomerular crescents and moderate to severe renal tubulointerstitial scarring. Case 15 had a history of gestational diabetes mellitus, and histopathology suggested chronic disease. Renal biopsy in Cases 21 and 22 showed focal glomerular and tubulointerstitial scarring.
Of the 38 patients, 12 received immunotherapy and 26 received conservative treatment. Among the 12 patients receiving immunotherapy, 8 patients presented with clinical AKI. Case 23 had persistent proteinuria and microhematuria and underwent tonsillectomy and steroid pulse therapy.
Of the 38 patients, 34 had access follow-up data from 2 days to 5 months, of which 32 patients responded well to the treatment. Case 30 patient,33 a 73-year-old man with previous aristolochic acid nephropathy (AAN) and hypertension, underwent bilateral nephrectomy and kidney transplantation. The patient developed edema of the lower legs, proteinuria and hematuria 5 weeks after the second adenoviral vector vaccine, and was treated with angiotensin-converting enzyme inhibitor to optimize antihypertensive therapy, and the disease progressed 3 weeks later. Case 31 patient34 was a 30-year-old man with a previous diagnosis of membranous proliferative glomerulonephritis type 1 who received a kidney transplant in 2019. Thirty-four days after receiving the second dose of mRNA vaccine, the patient developed microhematuria and proteinuria, and his creatinine progressed to 2.4 mg/dl. He received oral prednisone, and his condition did not improve after 1 month.
Discussion
‘Multi-hit’ hypothesis of IgA nephropathy
IgA nephropathy, the most common primary glomerulonephritis worldwide, is characterized by mesangial immunodeposits of IgA1 with mesangial proliferation.46 Several studies have shown that IgA nephropathy is an autoimmune disease with multiple pathogenic mechanisms involving genetically susceptible variants encoding galactosylation, aberrant mucosal immune responses and environmental triggers such as infection, alteration of microbiota and food antigen.47 At present, the pathogenesis of IgAN is still unclear, and the most widely accepted mechanism is the ‘multi-hit’ theory.13,48 Specifically, hit 1 is an increase in circulating IgA1 deficient in O-glycosylation of the hinge region. Hit 2 is the formation of antiglycan-specific IgG and/or IgA1 autoantibodies. Hit 3 is the formation of circulating immune complexes of galactose-deficient IgA1 (Gd-IgA1) and antiglycan IgG autoantibodies. Hit 4 is the deposition of circulating immune complexes in the mesangial area of the glomerulus, and complement activation causes multicellular damage to mesangial cells, podocytes and tubular epithelial cells (Figure 1).49 IgA nephropathy patients usually present with asymptomatic microscopic hematuria or proteinuria. However, some patients have prodromal symptoms such as upper respiratory (tonsillitis or pharyngitis) and gastrointestinal infections with hours or days before the onset, and dimeric IgA1 is usually produced on the mucosal surface.50 Therefore, aberrant mucosal immune response is considered to be involved in the pathogenesis of IgAN.51
Mucosal immune anatomy of IgA responses and the ‘multi-hit’ model of IgAN. IgA is the most abundant antibody isotype in the body, with the majority of IgA found in mucosal secretions. Mucosal IgA production is induced by T-cell-dependent and T-cell-independent mechanisms. In individuals with a genetic predisposition to IgA nephropathy, chronic bacterial infection and gut dysbiosis initiate T-cell-independent pathways that trigger the expression of TLRs on antigen-presenting cells that recognize pathogens and release a variety of lymphocyte inflammatory cytokines, such as IL-6, IL-10, IL-21, BAFF, TGF-β and APRIL, stimulate B-cell differentiation and proliferation, have class switching from IgM to IgA1. IgA-secreting plasma cells migrate to lamina propria, where they release dimeric IgA1 (dIgA1). The dimers are formed through an interaction of two IgA1 molecules with a joining chain (J-chain), which is synthesized by plasma cells. IgA1 dimers can bind to the polymeric Ig receptor (pIgR) on the basolateral surface of the mucosal epithelium and undergo transcytosis to the apical surface, where they dissociate from pIgR and are secreted into the lumen carrying the secretory component of the receptor. In the T-cell-dependent pathway, B-cell type switching occurs after antigen-specific T-cell activation. The level of IgA1 bearing galactose-deficient O-glycans (Gd-IgA1) is increased in the circulation of patients with IgA nephropathy (hit 1). These IgA1 glycoforms are recognized as autoantigens by antiglycan autoantibodies (anti-Gd-IgA1 autoantibodies; hit 2), resulting in the formation of nephritogenic immune complexes (hit 3), some of which deposit in the kidney and activate mesangial cells (hit 4). Mesangial cells start to proliferate and overproduce components of extracellular matrix, cytokines and chemokines. Some of these cytokines can then cause podocyte injury and induce proteinuria. The figure refers to the pathogenesis of IgAN by Gesualdo et al.51
Mucosal origin of hypogalactosylated IgA1 in IgAN
Chronic bacterial infection and gut dysbiosis initiate T-cell-independent pathways that trigger the expression of Toll-like receptors (TLR) on antigen-presenting cells (e.g. monocytes/macrophages, dendritic cells, neutrophils) that recognize pathogens and release a variety of lymphocyte inflammatory cytokines, such as interleukin (IL)-6, IL-10, IL-21, B-cell-activating factor (BAFF), transforming growth factor (TGF)-B and aproliferation inducing ligand (APRIL), especially BAFF and APRIL may bind to tumor necrosis factor (TNF) receptor homologous transmembrane activator,52 stimulate B-cell differentiation and proliferation, have class switching from IgM to IgA1 and promote IgA overproduction.53–55 In the T-cell-dependent pathway, B-cell type switching occurs after antigen-specific T-cell activation.56 In the tonsil-renal axis, recent data show increased expression of TLR9 in tonsillar B cells of IgAN patients, which has specific activity to recognize bacterial and viral unmethylated deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN). CpG-DON activates TLR9, increases the expression of APRIL,57 BAFF58 and IL-6, which induces the overproduction of aberrantly glycosylated IgA via T-cell-independent pathway.59 In the gut-renal axis, TLRs are highly expressed on mucosal epithelial cells, and they recognize molecular patterns of microorganisms and their products, such as lipopolysaccharide (LPS). Microbiota signaling through activation of TLRs may affect intestinal repair and damage, as well as increased intestinal permeability, which promotes the absorption and blood circulation of the bacterial product LPS. LPS is a ligand for TLR4. One study showed that LPS cultured by B lymphocytes activates TLR4, methylates the cosmc gene, reduces galactosyltransferase activity and leads to a decrease in the level of galactosylation modification of IgA1 molecules.60,61 The innovative drug NEFECON is an oral targeted delayed-release preparation of budesonide. It can precisely deliver budesonide to the enrichment area of Peyer's patches in the terminal ileum for release and play a role in the source of intestinal mucosa immunity producing galactose-deficient IgA1, thereby inhibiting the occurrence and development of IgAN, reducing proteinuria and stabilizing renal function in patients.62,63
Hypothesis of IgAN caused by COVID-19 vaccination
Among reported patients with new cases, five patients showed chronic characteristic changes or moderate to severe tubulointerstitial scarring on renal biopsy,17,22,24,28 suggesting that they had potential pre-existing IgAN, exacerbated by vaccination. Abnormal urinalysis performed before vaccination in 10 patients showed a history of hematuria,16,21,29,31,32,36 1 patient had a history of chronic kidney disease and mild proteinuria26 and 1 patient was suspected of IgA nephropathy,25 therefore, we suspect that IgA nephropathy is pre-existing and exacerbated by vaccination. One patient had a history of ulcerative colitis, and another patient had a history of rheumatoid arthritis in addition to hematuria and proteinuria, and this potential immune dysregulation raised the possibility that he might have had IgA deposits in his kidney and possibly asymptomatic IgAN before vaccination.30 One patient had a history of inflammatory bowel disease and renal cell carcinoma.18 He underwent partial nephrectomy 7 years before vaccination, and a review of the sample confirmed IgA deposition. These cases demonstrate that some of the new cases are ‘relapses’ of occult IgAN.
IgAN is the most common glomerular disease after COVID-19 vaccination, but the explanation for their association has not been fully established. One possible explanation for the development of IgAN in patients is the production of excess antiglycan antibodies following the COVID-19 vaccine, which cross-react with pre-existing Gd-IgA1.23 Of the reported cases, 13 patients21,22,24,26–28,30,37,41,42 developed GH, proteinuria and AKI within 2 days of the second dose. In patients with genetic predisposition, the disease may be in a latent state or in remission before COVID-19 vaccination, and there is a small amount of Gd-IgA1 or anti-glycan antibodies in the body, which does not cause clinical symptoms. Studies had shown that the COVID-19 mRNA vaccine in healthy adults was effective in inducing exponential increases in spike antigen-specific IgA and IgG serum levels, and further increases in IgA and IgG levels after the second vaccination,64 while vaccination also stimulates spike-specific T-cell responses that were more readily detectable 7 days after secondary immunization.65–67 The CD4+ T-cell response is primarily directed against helper T-cell type 1, which produces interferon-c (IFN-c), TNF-α and IL-2. The main responses of CD8+ T cells are IFN-γ and TNF.65 After vaccination against COVID-19, the antibody titers in patients increases exponentially, leading to disease outbreaks. Therefore, we hypothesized that one possible explanation for the development of IgA nephropathy after COVID-19 vaccination is the production of excess antiglycan antibodies (Figure 2).
Hypothesis of IgAN caused by COVID-19 vaccination. The most common systemic symptoms in IgAN patients caused by COVID-19 vaccination were fever, fatigue and pain, and renal symptoms were GH, proteinuria and AKI. COVID-19 vaccination stimulates antigen-presenting cells (APCs), eliciting innate and subsequent adaptive immune responses. The first hypothesis for the development of IgAN in patients is the production of multiple antiglycan antibodies that cross-react with pre-existing galactose-deficient O-glycans (Gd-IgA1, A). The second hypothesis is an increase in pathogenic IgA production similar to influenza vaccine (B). The third hypothesis is that the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (S) acts as a superantigen, causing cytokine storms (C). The data indicated that the COVID-19 mRNA vaccine was effective in inducing spike antigen-specific IgA and IgG production and, after the second vaccination, elicited strong CD4+ T-cell and CD8+ T-cell responses and a strong antibody response. The CD4+ T-cell response is mainly of helper T-cell type 1, producing IFN-c, TNF-α and IL-2. The main responses of CD8+ T cells are IFN-γ and TNF.
The second possible explanation, given elevated IgA levels, is an increase in pathogenic IgA production similar to the influenza vaccine. Of the reported cases, 17 patients developed new symptoms 3 days after vaccination. One patient had an episode of GH on Day 7 after the second dose of COVID-19 vaccine and a renal biopsy performed an additional 14 days showed the deposition of Gd-IgA1 and complement 3 in the mesangial region, and the author also found elevated urinary Gd-IgA1 levels.32 Although the correlation between serum Gd-IgA1 levels and disease activity could not be detected. This case also suggests that an enhanced immune response to the mRNA vaccine may transiently increase Gd-IgA1 production, resulting in GH. The study had shown strong spike antigen-specific IgA and IgG responses in healthy individuals following mRNA vaccination. Serum levels of spike antigen-specific IgA were significantly lower than IgG levels, with spike-specific IgA decreasing to an average of 50% of peak levels between 1 and 2 vaccine injections, and decreased to 18% of peak levels during a follow-up period of more than 100 days after the second injection.64 Although SARS-CoV-2 spike-specific serum IgA levels decline rapidly after infection, local concentrations on mucosal surfaces persist for longer, including dimeric subtype with strong neutralizing capacity, which was 15-fold higher than monomeric IgA.68,69 Pathogenic IgA in IgAN patients is derived from dimeric IgA1. Therefore, we hypothesized that mRNA vaccination might result in increased serum Gd-IgA1 production. Parenteral influenza vaccines that do not activate mucosal immune responses are known to increase IgA levels.70 Intramuscular inactivated influenza vaccine induced hyper-responsiveness of IgA1 monomers in a cohort of pre-existing IgAN patients.71 Recurrence of IgAN following influenza vaccination has also been reported in kidney transplant recipients.72
The third possible explanation is that cytokine storm is involved in the development of disease. In addition to GH, AKI and proteinuria, 20 patients also showed systemic symptoms such as fever and pain. Two patients14,15 developed symptoms within 24 h after the first dose of vaccine, 15 patients developed symptoms within 2 days after the second dose and 1 patient20 had an attack immediately after administration. The rapidly developing clinical manifestations suggest systemic cytokine-mediated attack, possibly through the induction of enhanced IgA1 antiglycan immune response. These reports are similar to how infection with SARS-CoV-2 itself may be associated with the onset of potential autoimmune glomerular disease.73 The receptor-binding domain of the SARS-CoV-2 spike protein is an immunodominant target for neutralizing antibodies in infected patients74 and vaccinators.75 It itself may act as a superantigen, causing the over-activation of the immune system, and the sharp rise of inflammatory factors such as IL-6, IL-10 and GM-CSF in the body, while GM-CSF will further activate CD14+ and CD16+ inflammatory monocytes cells, which produce a greater amount of IL-6 and other inflammatory factors, thus inducing systemic severe reaction and cytokine storm.76,77 Among the reported cases of IgAN, three patients underwent kidney transplantation. Some studies have shown that the humoral and cellular immunity of kidney transplant patients after receiving the COVID-19 vaccine is significantly lower than that of healthy people.78,79 Significant deterioration of IgAN may occur in the absence of anti-SARS-CoV-2 antibody response.
Prognosis
Currently, patients with IgA nephropathy in newly diagnosed and relapsed glomerular disease after COVID-19 vaccination have a better prognosis. Most IgAN cases with GH can spontaneously recover in a short period of time without intervention or with renin–angiotensin–aldosterone system inhibition intervention. The Gd-IgA1 and antibody titers in the patients decreased, returning the disease to a silent state. The median remission time was 6 (2–45) days. In contrast to such cases, most patients with IgA nephropathy who presented with AKI after vaccination required steroid therapy, with a median duration of remission of 30 (7–150) days. Le et al. assessed risk factors for progression to renal failure in 1155 Chinese adult patients with IgAN and reported that patients with a history of GH had better renal outcomes than those without such history, AKI and proteinuria affecting kidneys and life prognosis80.
Limitations
The new opportunity presented by COVID-19 vaccine is very good for us to explore the mechanism of IgAN reflare for the first time. This review has certain limitations. First, the patients we reported are from a single case study, and there is only a temporal association between symptom onset and COVID-19 vaccination in IgAN patients, and we are unable to infer a causal relationship between vaccine and IgAN. Second, there may be many unreported vaccine-related IgAN cases, and epidemiological investigations are lacking, so we cannot determine the true incidence of IgAN after vaccination. Third, the mechanisms that we have elucidated about the vaccine-IgAN-related association only combine hypotheses from case reports and the literature, which has not been proven. Fourth, due to the small sample size, there may be errors in our statistical analysis.
Conclusions
Although these reported cases of IgA nephropathy, the COVID-19 vaccine has already produced enormous benefits in preventing COVID-19 morbidity and mortality, and its protection far outweighs any side effects identified so far. In conclusion, the occurrence of IgAN after COVID-19 vaccination is relatively rare. If urine is routinely checked and symptoms such as hematuria and foamy urine can be detected early after vaccination, patients will benefit from timely treatment of the primary disease. Further studies are required to determine the pathogenesis, incidence of induction or recurrence, treatment response and long-term clinical outcomes IgA nephropathy after COVID-19 vaccination.
Authors’ contributions
Y.M. performed data collection and wrote the manuscript. G.X. was responsible for the idea, funds and paper revision. The authors have all read and approved the final version of the manuscript.
Funding
This study was supported by the National Natural Science Foundation of China (No. 81970583 and 82060138), the Nature Science Foundation of Jiangxi Province (No. 20202BABL206025) and the Projects in the Second Affiliated Hospital of Nanchang University (No. 2019YNLZ12008).
Conflict of interest: The authors declare that they have no conflict of interest.
References
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 2020; 383:1920–31.
