New-Onset Acute Interstitial Nephritis Post-SARS-CoV-2 Infection and COVID-19 Vaccination: A Panoramic Review

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has posed a considerable challenge to global healthcare. Acute interstitial nephritis (AIN) post SARS-CoV-2 infection and vaccination has been reported, but its clinical features and pathogenesis remained unclear. We reviewed so far the largest 22 cases of AIN post SARS-CoV-2 infection and 36 cases of AIN following COVID-19 vaccination. The onset of AIN was mainly related to messenger RNA vaccines (52.8%). Apart from fever, proteinuria (45.5%) was the main manifestation of AIN post SARS-CoV-2 infection, left acute kidney injury (AKI, 63.9%) in patients post COVID-19 vaccination. The potential mechanism of vaccination induced AIN was conjugating vaccines with proteins to form a hapten, which activated dendritic cells and promoted a cascade immunological reaction leading to AIN.


Introduction
Coronavirus disease 2019 (COVID- 19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was one of the deadliest viral epidemics in human history, posing a serious threat to human health and economic development [1].Due to the wide distribution of angiotensinconverting enzyme 2 (ACE2) receptors, the gastrointestinal tract, kidney, and liver were often involved, with more severe clinical symptoms and higher mortality [2,3].COVID-19 vaccination was one of the key strategies for controlling the disease.After vaccination, the innate and adaptive immune systems would be initiated by the vaccine itself or by vaccine adjuvants, producing protective antibodies [4,5], and based on previous evidence, most adverse events following vaccination were nonserious, such as fatigue, headache, and myalgia [6].However, with widespread vaccination, acute interstitial nephritis (AIN) has been reported.AIN was characterized by the presence of inflammatory infiltrates and edema within the interstitium, usually associated with an acute deterioration in renal function.AIN was one of the common causes of acute kidney injury (AKI) from biopsy samples [7].Although the hapten formation was thought to be the key process that triggered the immune response, the exact mechanisms of AIN post SARS-CoV-2 infection and COVID-19 vaccination were unclear [8].
In the present analysis, we summarized the clinical evidence of AIN following the SARS-CoV-2 infection and COVID-19 vaccination published by September 9, 2023, with the largest sample size, and analyzed the clinical characteristics of the included cases.
We reported medians and ranges for continuous data and numbers and percentages for categorical data.We used descriptive statistics in this report and performed statistical analysis.The Mann-Whitney Test was used for continuous data, and the Chi-Square Test was used for categorical data to determine whether the two groups were statistically different.Since our sample size was less than 40, the Fisher's Exact Test was used for both simple four-table and R × C table data.All statistical analyses were performed using SPSS 25.0 software, and P value < 0.05 was considered to be statistically significant.

Baseline Demographic and Clinical Characteristics of Patients with AIN Post-COVID-19 Vaccination
A total of 36 patients were diagnosed with AIN following COVID-19 vaccination  (  4).There were 12 patients with clinical symptoms after the first dose of vaccines, of which 2 patients with a history of cancer were treated with an immune checkpoint inhibitor [35].Case 4 [28] had a history of Sjogren's syndrome and rheumatoid arthritis.Case 6 [30] had a history of on-demand lansoprazole administration.Case 11 [35] had a history of taking non-steroid anti-inflammation drugs (NSAIDs) for muscle pain.In addition to leukocyturia and proteinuria, case 8 [32] had a symptom of vascular purpura, with multiple necrotic lesions involving the hands, arms, thighs, and feet and a skin biopsy suggesting leukocytoclastic vasculitis.Follow-up data were obtained for all patients, and 9 of them responded well to treatment.Case 12 [35] was admitted to the hospital with pneumonia-infected shock at month 5 of follow-up and died of multiorgan failure.Case 5 [29] developed AKI and nephrotic proteinuria after the first dose of the Moderna vaccine and went on to receive the second dose of the vaccine.Kidney biopsy was diagnosed as AIN with IgA nephropathy, and he was treated with steroid pulse therapy, but the disease progressed without responding.Case 4 [28] relapsed after one month of steroid discontinuation, but symptoms were quickly controlled with the reintroduction of steroids.
Twenty-one patients developed clinical symptoms after the second dose of the vaccines, with a median onset time of 7 (1-82) days.Of the 21 patients, three had a history of neoplastic disease, including hepatocellular carcinoma, prostate cancer, and diffuse large B-cell lymphoma [34,36,42].Three cases had a history of autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus [36,42].Follow-up data were obtained for all patients, and they responded well to treatments.
In contrast, only 3 patients developed clinical symptoms after the third dose of the vaccines, with a median onset time of 21 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) days.Case 35 [35] had a history of invasive bladder neoplasm and responded well to conservative treatment after discontinuation of Pembrolizumab.The other two patients were treated with immunotherapy and responded well.

AIN and COVID-19 Vaccination
It was well known that drugs were the most common cause of AIN, especially NSAIDs [47], and currently, the most widely accepted mechanism of drug-induced AIN was the cell-mediated type IV hypersensitivity theory.However, the exact pathophysiological mechanism remained to be elucidated [48].
The manufacturing process of inactivated SARS-CoV-2 vaccine is traditionally used for various vaccines such as influenza vaccine, hepatitis A, and hepatitis B, which suggested some similarities in potential side effects.Of the 35 cases we collected, case 8 presented with leukocytoclastic vasculitis after inactivated COVID-19 vaccination, and leukocytoclastic vasculitis with or without renal symptoms have been described as a side effect of several vaccines, such as influenza virus, hepatitis B virus (HBV), Bacillus Calmette-Guerin (BCG), and human papillomavirus (HPV) [49][50][51][52], which strongly supported a causal relationship between vaccines and symptomatology, although these observations were poorly documented and the causal relationship remained to be verified.In the reported patients, almost all started days or weeks after vaccination and showed infiltration of monocytes, neutrophils, and eosinophils on renal biopsy and negative immune fluorescence staining for immune deposits, suggesting that they had a predominantly cell-mediated immune response.54.3% received the BNT162b2 (Pfizer) vaccine, and a meta-analysis demonstrated that anaphylaxis with the Pfizer-BioNTech vaccine was approximately 10 times higher than that associated with all other vaccines [53].Components in the SARS-CoV-2 vaccines, such as polyethylene glycol, are also known to be immunogenic and can trigger hypersensitivity-like reactions [54].Eight patients [25,27,31,32,35,37,38,45] developed   [27,28] had peripheral eosinophilia.Therefore, we suspected AIN was an allergic reaction triggered by the vaccines.Case 24 [38] was evaluated 2 months after hospital discharge in the Department of Allergy and Clinical Immunology.The lymphocyte transformation test (LTT) was positive, which supported the involvement of T cells and pointed to a type IV hypersensitivity reaction according to the classification of Gell and Coombs [55,56].
The COVID-19 vaccine caused AIN in the form of hapten via a type IV hypersensitivity reaction (Fig. 1).We speculated that vaccines could bind to proteins like drugs to produce immunogenic hapten filtered and endocytosed by peritubular mesangial or tubular epithelial cells [57][58][59][60].These cells acted as antigen presenters, presenting antigenic stimuli to dendritic cells in direct contact with the basal surface of the renal tubular epithelium [61][62][63].Once exposed to the antigen or injury signal, normally quiescent dendritic cells were activated and expressed the antigenic compound MHC II molecules in the form of peptides.After that, dendritic cells migrate through the renal lymphatics to regional lymph nodes, where they present antigens to naive T cells, which are activated and migrate to the source of antigenic injury [64][65][66][67].The renal interstitium also contains dormant macrophages and fibroblasts, which are activated and contribute to this initial inflammatory response.This inflammatory response was further amplified by the recruitment of neutrophils, including eosinophils, and was further amplified by bidirectional crosstalk between dendritic cells and T cells or neutrophils [68].

AIN and SARS-CoV-2 Infection
Infections were known to be a common cause of AIN.Many cases of AIN were caused by infections of the distal kidney, such as hepatitis C virus (HCV) [69], Epstein-Barr virus (EBV) [70], and cytomegalovirus (CMV) [71], which supported a possible causal relationship between SARS-CoV-2 infection and AIN.SARS-CoV-2 has been detected in a kidney allograft associated with a monocyte cell infiltration [17], which suggested that the virus could enter the renal parenchyma and may cause AIN.These findings were supported by recent postmortem histopathological analysis showing positive SARS-CoV nucleoprotein antibody immunostaining in the tubules [72].In addition, medications were the most common cause of AIN [73,74].However, although severely ill COVID-19 patients in intensive care units may be treated with multiple medications, drug-induced AIN was still uncommon in these cases.
Viral infections can disrupt immune tolerance by exposing antigenic epitopes and triggering cross-reactive antibodies [75].There were numerous reports of antigenic mimicry between viral and human proteins.For example, lupus patients could have immune responses to EBV [76].Some epitopes of SARS-CoV-2 have been found to exhibit crossreactivity with autoantigens.Such as respiratory failure [77] and Green-Barre syndrome [78] associated with COVID-19 may be associated with molecular mimicry mechanisms.Similarly, the emergence of Guillain-Barre syndrome (GBS) after influenza vaccination and demyelinating neuropathy after HBV vaccination have been reported [79][80][81].Despite the lack of specific evidence for any significant homology between the molecular components of influenza viruses and those in human myelin, molecular mimicry was considered the most likely mechanism.Therefore, we hypothesized that COVID-19 vaccination could induce AIN by the same mechanism.
SARS-CoV-2 infection may also trigger hypersensitivity reactions just as it does after vaccination.Viral and bacterial antigens may trigger cell-mediated injury where they were filtered, concentrated, and secreted in the kidney, accompanied by high blood flow, increasing their exposure and making them targets of immune responses [82,83].For example, respiratory viruses can trigger Kawasaki disease [84], while bacterial superantigens of Staphylococcus aureus or Streptococcus pyogenes may lead to toxic shock syndrome [85].
Most patients in the data we collected responded well to steroid therapy, and clinicians should be aware of this renal side effect of SARS-CoV-2 infection.AIN in this condition may be caused not only by the pathogen directly invading the kidney but through different immune mechanisms [86].Timely diagnosis, including biopsy evaluation, was essential for correct treatment, a good prognosis, and preservation of renal function.

Conclusion
AIN post SARS-CoV-2 infection and COVID-19 vaccination was rare but with potentially serious complications and satisfactory response to steroid therapy.The pathogenesis, treatment, and long-term prognosis of AIN following SARS-CoV-2 infection and COVID-19 vaccination still need to be further explored.

Limitations
This review has some limitations.First, the association between AIN and COVID-19 vaccination can only be based on timing and excluding other predisposing factors, such as a history of NSAIDs use in some patients and a history of connective tissue disease (CTD) in others.Second, some reports did not describe a complete etiological study of other causes of AIN.Third, there may be many unreported cases of vaccine-associated AIN, and epidemiological investigations were lacking to determine the true incidence of AIN after vaccination.Fourth, the mechanisms we elucidated need further confirmation.And fifth, due to the small sample size, there may be errors in our statistical analysis.

Fig. 1
Fig. 1 The assumed mechanisms of AIN post COVID-19 vaccination.Hypothesis of AIN caused by COVID-19 vaccination.Haptens:The vaccine may bind to proteins to form protein complexes called "hapten", which are recognized and presented by DCs, causing a subsequent T-cell-mediated toxic response, as well as activation of intrinsic immune cells in the renal stroma, and further amplification of the inflammatory response by crosstalk between different immune cells.P-i concept: some specific structures of the vaccine may stimulate T

Table 2
Clinical characteristics of patients with acute interstitial nephritis post SARS-CoV-2 infection

Table 3
Summary of published cases of acute interstitial nephritis following COVID-19 vaccination

Table 4
Clinical characteristics of patients with acute interstitial nephritis post COVID-19 vaccination