New insights into kidney disease after COVID-19 infection and vaccination: histopathological and clinical findings

Summary

In addition to its pulmonary effects, coronavirus disease 2019 (COVID-19) has also been found to cause acute kidney injury (AKI), which has been linked to high mortality rates. In this review, we collected data from 20 clinical studies on post-COVID-19-related AKI and 97 cases of AKI associated with COVID-19 vaccination. Acute tubular injury was by far the most common finding in the kidneys of patients with COVID-19-related AKI. Among patients hospitalized for COVID-19, 34.0% developed AKI, of which 59.0%, 19.1% and 21.9% were Stages 1, 2 and 3, respectively. Though kidney disease and other adverse effects after COVID-19 vaccination overall appear rare, case reports have accumulated suggesting that COVID-19 vaccination may be associated with a risk of subsequent kidney disease. Among the patients with post-vaccination AKI, the most common pathologic findings include crescentic glomerulonephritis (29.9%), acute tubular injury (23.7%), IgA nephropathy (18.6%), antineutrophil cytoplasmic autoantibody-associated vasculitis (17.5%), minimal change disease (17.5%) and thrombotic microangiopathy (10.3%). It is important to note that crescentic glomerulonephritis appears to be more prevalent in patients who have newly diagnosed renal involvement. The proportions of patients with AKI Stages 1, 2 and 3 after COVID-19 vaccination in case reports were 30.9%, 22.7% and 46.4%, respectively. In general, clinical cases of new-onset and recurrent nephropathy with AKI after COVID-19 vaccination have a positive prognosis. In this article, we also explore the underlying pathophysiological mechanisms of AKI associated with COVID-19 infection and its vaccination by describing key renal morphological and clinical features and prognostic findings.

Introduction

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, there have been over 500 million confirmed cases of coronavirus disease 2019 (COVID-19) reported to the World Health Organization (WHO) as of May 25, 2022, with 6 million deaths. Mass vaccination has been a key strategy in containing the COVID-19 pandemic, particularly against severe COVID-19. According to multiple phase III and IV trials, the safety profile of these vaccines is good, with minimal occurrences of serious reactions.^1–3

The widespread use of vaccinations has raised concerns about adverse effects such as acute kidney injury (AKI) and the emergence of new glomerulonephritis on a global scale.^4,5 Despite this, the mechanisms, risk factors and long-term consequences of postvaccination AKI are not yet well established.⁶ This article presents a comprehensive review of the clinical features, treatment and prognosis of new-onset AKI following COVID-19 infection and vaccination. Additionally, potential mechanisms are summarized to further understand this phenomenon.

Search strategy

This narrative review was conducted following a thorough literature search of various databases, including PubMed/Medline, Embase and Web of Science (WOS), up until May 2023. Keywords are ‘glomerulonephritis’, ‘acute kidney disease’, ‘acute kidney injury’, ‘COVAN’, ‘SARS-CoV-2’, ‘COVID-19’, ‘coronavirus’, ‘novel corona virus’, ‘vaccination’ and ‘vaccine’. The definition of AKI according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines is as follows: Stage 1 is characterized by an increase in serum creatinine (Scr) by 0.3 mg/dl within 48 h or a 1.5- to 1.9-fold increase in Scr from baseline within 7 days; Stage 2 is defined as a 2- to 2.9-fold increase in Scr within 7 days and Stage 3 is marked by a 3-fold or more increase in Scr within 7 days or the initiation of renal replacement therapy (RRT).^7,8

New-onset AKI post-SARS-CoV-2 infection

Pathological types and clinical features

A literature review on natural kidney biopsy findings in the minority of patients with COVID-19 showed the following findings with their corresponding percentages in parentheses: collapsing glomerulopathy (CG) (28.4%), acute tubular injury (ATI) (13.9%), diabetic nephropathy (DN) (9.7%), focal segmental glomerulosclerosis (FSGS) (7.6%), minimal change disease (MCD) (5.4%) and membranous nephropathy (MN) (4.5%).⁹ However, most patients with AKI after COVID-19 do not undergo biopsy. Of course, most patients with suspected acute tubular necrosis (ATN) do not undergo biopsy, and therefore, any biopsy series will be enriched with patients with hematuria and/or proteinuria and thus patients with non-ATN diagnoses. Autopsy studies have demonstrated that ATI is by far the most common finding in the kidneys of patients with COVID-19-related AKI.¹⁰ Virtually all experts in the field believe that ATN is the most common renal diagnosis after COVID-19 infection.^11,12

We conducted a thorough search of various databases to identify recent large cohort studies on AKI in patients with COVID-19, as outlined in Supplementary Table S1.^13–32 Among patients hospitalized for COVID-19, 34.0% developed AKI, and among these cases of AKI, 59.0%, 19.1% and 21.9% were Stages 1, 2 and 3, respectively (Table 1). Proteinuria and hematuria were more prominent in patients with COVID-19 and ATN than in most patients with ATN.^32,33 In addition, low levels of hematuria and proteinuria were common in patients with COVID-19 without AKI, suggesting that they may not predict AKI. The most common comorbidities associated with COVID-19-related AKI were diabetes mellitus (DM) (7.4–72.1%), hypertension (HT) (15–66.8%), heart disease (30%) and chronic kidney disease (CKD) (0.7–22.6%).^13,34,35 In addition, it was found that patients in the AKI group were significantly older than those in the non-AKI group,³⁶ and patients with COVID-19 and AKI were more commonly male (67.9%) than female. Several studies have identified various factors that independently predict severe COVID-19-related AKI. These include older age, male sex, black race, CKD, DM, cardiovascular disease, an immunosuppressed state, the severity of COVID-19, apolipoprotein L1 (APOL1) variants, angiotensin-converting enzyme 2 (ACE2) polymorphism, elevated albuminuria, serum cystatin C, potassium, kidney injury molecule-1 (KIM-1) and D-dimer levels at hospital admission.^17,32,37,38

Treatment and prognosis

To prevent the patient’s condition from deteriorating rapidly, it is important to develop a comprehensive treatment plan for those with COVID-19-related AKI as soon as possible. It is recommended to follow the supportive care guidelines outlined in KDIGO for managing COVID-19-related AKI in patients.³⁹ The management of COVID-19-associated AKI is similar to that of AKI caused by septic shock and is primarily supportive. Implementing lung-protective ventilation may help reduce the risk of developing or worsening AKI by mitigating volutrauma and barotrauma.⁴⁰ Li et al.⁴¹ found that patients with COVID-19 and AKI had a 5.3-fold higher mortality risk than those without AKI, which was higher than that of patients with other chronic comorbidities. Furthermore, Xiao et al.¹⁶¹ reported that mortality rates for 7.3% AKI Stage 1 but significantly increased to 64.3% for Stages 2 and 3 after 28 days.

New-onset and relapsed kidney disease with AKI post-COVID-19 vaccination

Pathological types and clinical features

The cases of a total of 97 patients are summarized in Table 2, including 86 (88.7%) patients with newly diagnosed renal involvement and 11 (11.3%) patients with recurrent kidney disease with AKI.^{4–6,42–113} Major types of renal pathology in post-COVID-19 vaccination AKI data collected from the literature included crescentic glomerulonephritis (29.9%, 29 of 97 patients), ATI (23.7%, 23 of 97 patients), IgA nephropathy (IgAN) (18.6%, 18 of 97 patients), antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (17.5%, 17 of 97 patients), minimal change disease (17.5%, 17 of 97 patients), thrombotic microangiopathy (10.3%, 10 of 97 patients) and antiglomerular basement membrane (anti-GBM) glomerulonephritis (5.2%, 5 of 97 patients). Some other renal pathologies included anti-GBM glomerulonephritis in five patients, MN in three patients, lupus nephritis (LN) in three patients, ANCA-negative vasculitis in two patients, FSGS in one patient, podocytopathy in one patient and focal proliferative glomerulonephritis in one patient. There were 29 patients with crescentic glomerulonephritis in the new kidney involvement group and none in the relapsed group (Table 3). The mean age was 55.4 (range 12–84) years, and 56.7% (55 of 97 patients) of patients were male.

Edema, hematuria, headache and proteinuria were the four main initial signs in patients with AKI after vaccination. AKI developed after vaccination with any of the commercially available COVID-19 vaccines, but 72.2% (70/97) of patients received an mRNA vaccine, and 20.6% (20/97) received a vector vaccine. In addition, 7.2% (7/97) received an inactivated vaccine. Of these, 45.4% (44/97) of patients developed AKI after the first dose, while 48.4% (47/97) of patients developed AKI after the second dose. In addition, 5.2% (5/97) of patients developed AKI after the third dose, and 1.0% (1/97) of patients developed AKI after the fourth dose. The proportions of patients with AKI Stages 1, 2 and 3 after COVID-19 vaccination in case reports were 30.9%, 22.7% and 46.4%, respectively. Twenty-two (25.6%) patients were treated with hemodialysis (HD).

Common clinical symptoms included edema, hematuria, fever, body aches, fever, dizziness, nausea, vomiting, asthenia, headache and foamy urine. According to research, the medical conditions most commonly associated with the development of AKI after receiving COVID-19 vaccines were HT (35.4%), DM (20.7%) and thyroid dysfunction (including hypothyroidism, hyperthyroidism, total thyroidectomy, autoimmune thyroiditis and Hashimoto's thyroiditis, 13.4%) and dyslipidemia (12.2%).

Treatment and prognosis

Seventy-seven (89.5%) patients received steroid therapy, 24 (27.9%) patients received cyclophosphamide (CyC) therapy, 17 (19.8%) patients were treated with rituximab (RTX), 18 (20.9%) patients received plasma exchange (PLEX) therapy and 11 (12.8) patients received conservative treatment. A small number of patients received mycophenolate mofetil (MMF)^6,70,103 or intravenous immunoglobulins (IVIG).^77,87,91 Regarding outcomes, 49.4% of patients achieved complete remission in 3 months, 28.2% of patients achieved partial remission in 3 months, 22.4% of patients achieved no response in 3 months and 8.2% of patients were still dependent on HD after discharge. Generally, clinical cases of new-onset and relapsed kidney disease with AKI after COVID-19 vaccination had a good prognosis. Some patients, especially those with new-onset kidney disease with AKI, achieved remission through conservative treatment.

Discussion

Potential mechanisms of AKI post-SARS-CoV-2 infection

The pathophysiology of AKI in patients with COVID-19 is complex and involves various factors. There is controversy about whether COVID-19 causes AKI primarily through direct or indirect mechanisms.^10–12 What needs to be clarified is that in addition to the direct effects of the virus, indirect mechanisms also play an important role in COVID-19-related AKI.¹² Many cases appear to be clearly attributable to indirect effects, such as ischemic injury, toxic injury, cytokine storm, activation and the dysregulation of the angiotensin (Ang) II pathway and complement system, endothelial dysfunction, abnormal platelet activation, hypercoagulation and microangiopathy (Figure 1).^10,114–116

SARS-CoV-2 enters host cells mainly by binding to the ACE2 receptor. This receptor aids virus entry through two pathways: clathrin-dependent endocytosis and ACE2 receptor-mediated transmembrane protease serine 2 (TMPRSS2)-dependent membrane fusion.^117–119 Recent research findings indicate that ACE2 and TMPRSS2 are present in proximal tubular epithelial cells and renal podocytes.^120–122 These receptors are essential for the virus to enter the cells and replicate.¹²³ Once SARS-CoV-2 interacts with cells, ACE2 binds to the spike (S) protein of SARS-CoV-2,¹¹⁷ while TMPRSS2 interacts with the spike protein and promotes internalization. Additionally, a disintegrin and a metalloproteinase 17 (ADAM17) leads to ACE2 shedding by converting ACE2 to a soluble form. After binding to ACE2, SARS-CoV-2 may lead to a downregulation of ACE2, resulting in increased levels of Ang II and decreased levels of Ang (1–7) and thus causing RAS dysregulation.¹²⁴ Ang II can induce the release of cytokines, activate nuclear factor kappa B (NF-κB), trigger inflammatory reactions and lead to necrotic sequelae with the release of neutrophil extracellular traps (NETs). However, there are no human data at all that the role of Ang II matters in COVID-19. The findings of several large randomized trials examining RAS modulators of various types and in various scenarios (starting vs. stopping RAS blockade, continuing vs. discontinuing chronic RAS blockade, RCTs of novel RAS modulators) have essentially all been negative.^125–128 One possibility is that COVID-19 infection may not result in unopposed Ang II activity in the organs, as hypothesized.

In addition, an analysis of renal biopsy samples from 19 SARS-CoV-2-related AKI patients revealed evidence of complement system activation in the patients’ renal tissue after viral infection.¹²⁹ Complement components may collaborate with other factors to trigger inflammation, coagulation and endothelial damage. There is a hypothesis that Ang II may activate the terminal components of the complement system (C5a, C5b-9) in a destructive manner through the angiotensin-1 (AT1) receptor.¹³⁰ C5a can also stimulate the production of NETs in vitro,¹³¹ triggering an increase in mitochondrial oxygen species (ROS) production.

Studies have also found that viral particles exist in renal endothelial cells, and these particles mediate endothelial injury and promote vasoconstriction and a hypercoagulable state, leading to microthrombosis and renal microvasculature damage.^34,120,132 According to Wang et al.,¹³³ CD147 (extracellular matrix metalloproteinase inducer/basigin) has a high affinity for SARS-CoV-2 and is expressed within the transmembrane, which helps the virus enter renal epithelial cells. Normally, CD147 is highly expressed only on the basolateral side of renal tubular epithelial cells in healthy kidneys.¹³⁴ However, in patients with viremia, SARS-CoV-2 may invade renal proximal tubular epithelial cells through both the luminal surface and the basolateral side, leading to the production of inflammatory cytokines.¹³⁵ The innate immune system directly responds to SARS-CoV-2 by recognizing pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) and indirectly responds to the virus through damage-associated molecular patterns (DAMPs), releasing cytokines locally, recruiting inflammatory cells and stimulating adaptive immune responses.¹⁰

Although the theory of a cytokine storm being a prominent part of severe COVID-19 was popular early in the pandemic, how much of a role a true cytokine storm plays in COVID-19 or COVID-19-associated AKI remains controversial.^10–12 A meta-analysis reported that serum IL-6 levels were much lower in patients with severe COVID-19 than in patients with sepsis and non-COVID-19 acute respiratory distress syndrome (ARDS).¹³⁶ Importantly, a role for local inflammation in the pathogenicity of COVID-19 has not been ruled out. Inflammatory mediators can directly bind to their specific receptors expressed by renal endothelial cells and tubular epithelial cells to cause cellular damage, but their role in COVID-19-related AKI has not been clearly demonstrated.^136–138

Organ crosstalk among the lung, heart and kidneys has also been found in critically ill patients with COVID-19, and this process is complex.⁴⁰ Acute hypoxemia can affect renal function and increase renal vascular resistance.^139,140 Pneumonia may cause right ventricular failure, leading to renal congestion, while left ventricular dysfunction can cause reduced cardiac output and renal hypoperfusion.¹⁴¹ In patients with severe COVID-19, excessive positive pressure ventilation can have negative effects on cardiac output and renal hypoperfusion.¹⁴² Additionally, extracorporeal membrane oxygenation (ECMO) may cause AKI via venous congestion, hemolysis, bleeding, secondary infections and inflammation.^10,143 Severe COVID-19 can also cause rhabdomyolysis and myositis, resulting in tubular obstruction and toxicity.¹⁴⁴ Furthermore, exposure to certain drugs such as antibiotics, antivirals and other nephrotoxic drugs can also lead to AKI in patients.⁴⁰ In addition, patients' underlying diseases such as CKD, DM, cardiovascular disease^17,32,37,38 and genetic risk factors such as high-risk APOL1 alleles may further induce the occurrence of AKI.^145,146

Potential mechanisms of AKI post-COVID-19 vaccination

According to recent studies, the SARS-CoV-2 spike protein found in vaccines may lead to kidney damage, either directly or indirectly (Figure 2). These studies have shown that certain tissue antigens, including transglutaminase 3, antiextraction nuclear antigen and thyroid peroxidase, can strongly react with SARS-CoV-2 antibodies.¹⁴⁷ COVID-19 vaccines activate antigen-presenting cells (APCs), which, upon receiving a second vaccination, trigger robust CD4+ T-cell and CD8+ T-cell responses. This process results in the release of significant amounts of inflammatory cytokines (IFN-c, TNF-α, IL-2, IFN-γ and TNF), which can promote a cytokine storm and lead to damage to renal tissue.^148,149 The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (S) has the ability to bind to natural antibodies in the body, which can lead to the formation of circulating immune complexes and their deposition in the glomeruli.¹⁵⁰

CoronaVac is a vaccine that was developed using whole virion inactivated Vero cells that retain the antigenic components of SARS-CoV-2 to induce antiviral neutralizing immunoglobulins.¹⁵¹ Additionally, CoronaVac contains aluminum, a complex adjuvant that enhances the antigen-specific immune response, making the recognition of ‘nonself’ factors easier and more effective.¹⁵² Autoinflammatory syndrome induced by adjuvants (ASIA) can be triggered by the injection of adjuvant, which can induce the release of risk-related molecular patterns in vivo.¹⁵³ This, in turn, can activate the intracellular Nalp3 inflammasome system and caspase-1, leading to autoimmune or autoinflammatory disease (AI/AIFD). Additionally, aluminum may stimulate the production and secretion of cytokines, such as IL-1β, IL-18 and IL-33.¹⁵⁴

Elevated levels of complement markers (sC5b-9 and C5a) have been observed in COVID-19 patients, and these markers were found to be correlated with the severity of the disease.^155,156 Furthermore, in vitro studies have shown that the spike protein of SARS-CoV-2 can directly activate the alternative pathway of complement (APC) by impeding the inactivation of the cell surface APC convertase.¹⁵⁷ It is currently speculated that COVID-19 vaccines, which target the spike protein as an immunogenic target, may also activate the complement system and lead to endothelial damage.

NETs play a crucial role in the pathogenesis of complement activation and cytokine storms in COVID-19 vaccine-induced AKI.¹⁵⁸ In individuals with compromised immune systems, NET nucleic acid clearance may be reduced.¹⁵⁹ Neutrophils are activated by proinflammatory cytokines, which in turn release NETs. These NETs are crucial in local inflammatory responses, pathogen clearance and thrombus formation and play a significant role in host defense. However, NET dysregulation can lead to vasculopathy and ANCA-associated vasculitis.¹⁶⁰ NETs are often accompanied by numerous harmful proteins, such as myeloperoxidase (MPO) and antiproteinase 3 antibody. These proteins can inflict direct harm on the vascular endothelium, activate the alternative complement pathway and contribute to the onset and progression of vasculitis.

According to research, the expression of ACE2 in kidney tissue is 100 times higher than that in lung tissue.¹⁶¹ The binding of SARS-CoV-2 to ACE2 is believed to downregulate the production of ACE2, which results in an increase in Ang II levels and a decrease in Ang 1–7 levels. This increase in Ang II levels can lead to renal injury by triggering inflammation and apoptosis.¹⁶² Additionally, increased Ang II levels can also lead to endothelial and platelet activation, vasoconstriction and microthrombosis, which are all unfavorable outcomes.¹³² The prothrombotic state can increase the likelihood of microthrombosis formation in renal tissue. These factors collectively contribute to the development of ATI or ATN, as well as glomerulonephritis. Overall, all of the proposed pathogenic processes described are simply hypotheses and may not be consistently confirmed in real-world clinical studies. For example, drugs aimed at reversing elevated Ang II to Ang (1–7) ratios did not confer benefit in COVID-19 patients in large RCTs.^163,164

The risk of kidney disease after COVID-19 vaccination

Although there have been numerous case reports of glomerulonephritis and kidney injury following SARS-CoV-2 vaccination, a causal relationship between them remains to be proven. In a study that included data on the incidence of glomerulonephritis in 7.1 million people, 69% of whom received at least one dose of the vaccine during the study period, it was found that patients who developed glomerulonephritis within four weeks after receiving the mRNA vaccine showed no differences from patients with vaccination-unrelated glomerulonephritis.¹⁶⁵ Another study, a self-controlled case series of Hong Kong-wide SARS-CoV-2 vaccination records, found no evidence of an increased risk of new or recurrent glomerular diseases with vaccination with the BNT162b2 or CoronaVac vaccines.¹⁶⁶ A retrospective cohort study in Canada included 1105 adult patients with clinically stable glomerular disease (including MCD, FSGS, MN, IgAN, LN, ANCA-associated vasculitis and C3 glomerulonephritis) as confirmed by renal biopsy sample analysis. Exposure to a second or third dose of the COVID-19 vaccine in this population was associated with a 2.23-fold risk of relapse, but the absolute increase in risk of relapse remained low (1–5%).¹⁶⁷ Overall, further research is needed on the risk of kidney disease following SARS-CoV-2 vaccination. The emergence of new cases of glomerulonephritis shortly after SARS-CoV-2 vaccination may be attributed to timing coincidence. Patients with preexisting glomerular disease should be monitored more closely after receiving a second or third COVID-19 vaccine.

Limitations

This study has limitations. The literature on the relationship between vaccines and AKI is primarily based on single-case reported studies, making it difficult to establish a definitive causal relationship. Additionally, there may be potential unmeasured confounders that could impact the results. Furthermore, relying solely on electronic health information systems as data sources may lead to an underreporting of AKI cases in patients with COVID-19. On the other hand, as the data presented on AKI after COVID-19 vaccination are based primarily on case reports, our analysis provides no information on the true incidence of AKI after COVID-19 vaccination. Though these observational data suggest that COVID-19 vaccination may predispose to kidney disease, given that billions of people have received COVID-19 vaccinations worldwide, whether COVID-19 vaccination truly increases the risk of kidney disease or if these case reports represent association rather than causation remains unclear. Finally, while there are hypotheses regarding the mechanism of action, a mechanism of action has not been definitively proven and hypotheses are based on a combination of case reports and literature.

Conclusion

The associated between COVID-19 and AKI is significant, leading to increased morbidity and mortality. However, with the widespread availability of vaccines, the death toll has decreased significantly, highlighting the importance of vaccination in the battle against the outbreak. This narrative review offers fresh perspectives on AKI in relation to COVID-19 infection and vaccination. We reviewed the pathomorphological, and clinical features and the prognosis of AKI associated with COVID-19 infection and vaccination. Additionally, the study explored the underlying pathophysiological mechanisms of AKI in these cases.

Supplementary material

Supplementary material is available at QJMED online.

Author contributions

Yebei Li and Yan Gong conducted data collection and wrote the manuscript. Gaosi Xu was responsible for the idea, funds and paper revision. All authors contributed to the article and approved the submitted version.

Yebei Li (Data curation, Investigation, Methodology, Writing—original draft, Writing—review & editing [equal]), Yan Gong (Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing [equal]) and Gaosi Xu (Conceptualization, Funding acquisition, Supervision, Writing—review & editing [lead])

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81970583 and 82060138), the Key Project of Jiangxi Provincial Nature Science Foundation (No. 20224ACB206008), the Kidney Disease Engineering Technology Research Centre Foundation of Jiangxi Province (No. 20164BCD40095), Jiangxi Province introduces and trains innovative and entrepreneurial high-level talents “Thousand Talents Plan” project (JXSQ2023201030) and the Key Project of Clinical Research of the Second Affiliated Hospital of Nanchang University (2022efyB01).

Conflict of interest

None declared.

References

Author notes