New-Onset Acute Kidney Disease Post COVID-19 Vaccination: Comparison
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The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an exceptional setback to the global economy and health. Vaccination is one of the most effective interventions to markedly decrease severe illness and death from COVID-19. Acute kidney disease (AKD) is defined as a condition of acute or subacute damage and/or loss of renal function between 7 and 90 days after exposure to an AKI initiating event

  • acute kidney disease
  • acute kidney injury
  • COVID-19

1. Introduction

With the ongoing coronavirus disease 2019 (COVID-19) pandemic and the emergence of new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the rapid development of effective and safe preventive vaccines is urgently required to control disease outbreaks [1][2]. Over the past 2 years, hundreds of COVID-19 vaccine candidates have been developed, tested, and finally rolled out, including protein-based vaccines (Novavax), inactivated vaccines (Sinovac Life Science), viral vector vaccines (Janssen, Oxford-AstraZeneca), and mRNA vaccines (Pfizer/BioNtech, Moderna, CureVac) (Figure 1) [2][3]. Among them, mRNA-based drugs are new but not unknown [4]. mRNA vaccines deliver transgenic mRNA through lipid nanoparticles, which act as carriers. Once injected, the mRNA is translated into the target protein in vivo, resulting in a strong immune response, and a 2-dose regimen confers 95% protection against COVID-19 [5]. To date, large phase III and IV trials have found these vaccines to have a good safety profile, with few serious reactions [3][6][7][8][9]. Common short-term adverse events include local injection site reactions, fever, fatigue, generalized pain, and headache [6][10].
Figure 1. SARS-CoV-2 and the main types of vaccines that may trigger AKD. SARS-CoV-2 is a positive-sense single-stranded RNA virus with a lipid bilayer consisting of the spike S protein and membrane and envelope proteins. mRNA vaccines deliver transgenic mRNA through lipid nanoparticles as carriers. Viral vector vaccines utilize adenovirus and integrate genetic material from SARS-CoV-2 into its genome. Inactivated vaccines involve SARS-CoV-2 that has been killed by physical or chemical means.
However, since mass vaccination, there have been a few case reports of acute kidney injury (AKI), acute kidney disease (AKD), proteinuria, edema, gross hematuria, and other renal side effects requiring hospitalization after COVID-19 vaccinations [11]. Serum creatinine (Scr) levels and proteinuria recovered within 3 months of treatment in most patients. The vast majority of cases occurred after mRNA vaccine and adenoviral vector injection, and a few cases of glomerulonephritis associated with inactivated virus vaccines have also been reported.

2. Inducing AKD through COVID-19 Vaccine: Hypotheses

2.1. Podocyte Damage

The temporal association between intramuscular vaccination and the development of MCD speculates that a cell-mediated immune response may be a trigger for podocyte injury [12][13]. All 12 patients with MCD reported in the literature were over 60 years of age, developed AKD within 2 weeks of vaccination, and steroids appeared to be effective in achieving rapid remission (Table 1). Typically, following vaccination, the vaccine’s antigens are taken up by dendritic cells and then presented to T cell receptors on naive T cells [14]. This leads to the activation of antigen-specific effector T cells, peaking 7 to 14 days after vaccination [15]. Studies have also confirmed that during viral infection, cellular immune responses can be observed within about 1 week after infection, but T cell activation can occur 2–3 days earlier [16][17]. This answers the question of whether it is reasonable for a COVID-19 vaccine to elicit a cell-mediated response 3–4 days after administration. Although the exact pathogenesis of MCD remains unclear, podocyte damage caused by circulating factors released by activated T lymphocytes appears to be decisive (Figure 2) [18][19]. During active stages of MCD, T cell subsets are imbalanced, and circulating CD8+ suppresses the prevalence of T cells, which is exacerbated by cytokine-induced damage [20]. Compared with conventional vaccines, mRNA vaccines are expected to provoke higher antibody responses and stronger CD8+ T and CD4+ T cell reactions, including higher chemokine and cytokine production [21][22]. The resulting irregular permeability factors can alter glomerular permeability and lead to marked proteinuria and kidney injury [13].
Figure 2. Proposed mechanisms of podocyte injury caused by COVID19 vaccination. Vaccination stimulates antigen-presenting cells (APCs) and B cells, which in turn activate T cells through antigen presentation and cytokine production. A decrease in CD4+ T helper (Th) cells is associated with the prevalence of CD8+ cytotoxic T cells, and an imbalance between Th2 and Th1 cells is associated with an increase in Th2-specific interleukin-13 (IL-13) production, and Th17. In contrast to increased cellular activity, the frequency and function of regulatory T cells (Tregs) decreased. Permeability proteins, such as cytokines and autoantibodies, can directly affect podocytes, leading to loss of foot processes and disruption of the glomerular permeability barrier. In addition, the vaccine can also affect podocytes through specific toll-like receptors (TLRs), and angiotensin conversion enzyme 2 (ACE2). The figure refers to the pathogenesis of minimal change disease by Vivarelli et al [13].
Another hypothesis researchers speculate might be relevant is that type 2 helper T cells (Th2) indirectly induce tissue cell damage through hypersensitivity reactions via nucleic acid (NA) sensors. Previous study has demonstrated that T cells sensing their own NAs can trigger and amplify allergic inflammation independent of known NA sensors in innate immunity [23]. Muscle cells presenting viral mRNA-derived products on major histocompatibility complex class I are eliminated by CD8+ T cells, and self-NA released by dead muscle cells may directly induce T cell co-stimulation. This may be followed by Th2 differentiation and Th2-mediated allergic inflammation, causing podocytopathy [24]. Nevertheless, the study by Sahin et al. found that the COVID-19 mRNA vaccine elicited a cytokine response involving Th1 T cell responses [22][25]. Furthermore, SARS-CoV-2 can penetrate proximal tubular cells through ligation with angiotensin conversion enzyme 2 (ACE2) and CD147-spike protein to cause severe AKI, and can also penetrate podocytes through ligation with ACE2, resulting in podocyte dysfunction [26][27]. In addition, SARS-CoV-2 can also unbalance renin-angiotensin-aldosterone system (RAAS) activation, promoting inflammation, glomerular dysfunction, fibrosis, and vasoconstriction [27]. However, whether the vaccine is related to ACE2 and RAAS is unclear.

2.2. Increased Production of Anti-Neutrophil Cytoplasmic Autoantibodies (ANCAs)

Influenza and rabies vaccines based on viral mRNAs have been described to possibly lead to an increase in ANCA, contributing to the development of ANCA-associated vasculitis [28]. Moreover, it was confirmed that the ANCA response was significantly reduced after the treatment of vaccinees with ribonuclease. Scientists have found that in the context of COVID-19, a host response to viral RNA can directly cause ANCA-associated vasculitis (AAV) and an autoimmune response [29][30][31]. COVID-19 mRNA vaccination induced a stronger response of the innate immune system after the second booster compared with primary immunization [32]. The heightened innate immune response observed after the second vaccination with BNT162b2 mRNA vaccine may be an inducer of MPO-ANCA and PR3 autoantibodies [33]. Toll-like receptors (TLRs) can be expressed on leukocyte membranes and play an important role in inflammatory responses, recognizing viral antigens and promoting immune system activation. In AAV, major toll-like receptor 2 (TLR2) and toll-like receptor 9 (TLR9) activation can provoke autoimmunity [34]. Interestingly, Kumar et al. suggested that TLR2 was activated by a robust and specific immune response of immunodominant cytotoxic T-lymphocyte (CTL) to the spike glycoprotein of SARS-CoV2 (also produced by the COVID-19 vaccine) [35]. Messenger RNA vaccines could act as both antigen and adjuvant due to their intrinsic immunostimulatory properties of RNA; thus, they can be recognized by endosomal TLRs and cytosolic inflammasome components [25]. Therefore, the occurrence of AAV in the context of COVID-19 mRNA is highly relevant compared with non-mRNA vaccinations, but further experiments are required to verify the mechanism of the link between autoimmunity and a COVID-19 vaccine.

2.3. Vaccine-Induced Thrombotic Thrombocytopenia (VITT)

Some scholars have speculated that antiphospholipid antibodies (APLs) may be part of the cause of thrombosis after COVID-19 vaccination, by triggering the type I interferon response associated with APLs’ production [36][37]. It binds directly to platelets by inhibiting the anticoagulant pathway of protein C, triggers the coagulation cascade, and appears to be associated with abnormal activation of immune responses involving the complement cascade [36]. Thrombocytopenia and platelet activation have been reported following the administration of adenoviral gene transfer vectors [38]. Thrombocytopenia also occurred after treatment with some anti-sense oligonucleotides [39]. Based on the above background, another hypothesis speculates that the activation of platelets by adenovirus-platelet-leukocyte complexes, mediated by von Willebrand factor (VWF) and P-selectin, may lead to accelerated clearance of platelets in the liver [37][40]. However, the virus in viral vector vaccines is replication-incomparable and the circulating virus disappears 7–14 days after vaccination, so the viral localization to the central nervous system and digestive system causing thrombosis is unlikely [41]. In addition, Greinacher et al. suggested that the rare occurrence of VITT was mediated by platelet factor 4 (PF4)-dependent platelet-activating antibodies, which in turn stimulate platelets via their Fcγ receptors [42][43]. Immune complexes containing PF4 can be recognized by C1q, which binds to the Fc portion of IgG molecules. This results in C3 activation, expansion of the complement response, and production of downstream proinflammatory mediators and effectors, ultimately leading to enhanced thrombus inflammation.

2.4. Direct Induction of Myositis

A previous case reported that a patient who presented with profound left upper arm pain after COVID-19 mRNA vaccination had an increased serum creatine kinase concentration, indicating skeletal muscle damage and inflammation (myositis) [44]. There is also evidence of renal biopsies from post-vaccination patients showing massive rhabdomyolysis-induced myoglobin casting, which may contribute to worsening renal function [33].

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