Khalid Saad Alharbi, PhD; Fahad A. Al-Abbasi, PhD; Gopal Prasad Agrawal, PhD; Ajay Sharma, PhD; Rajesh Kowti, M.Pharm; Imran Kazmi, PhD
Context • Some research has indicated that SARS-CoV-2 has had effects on the various functions of the renal system. Acute kidney injury (AKI) is a dangerous and broadly spread pathological illness.
Objective • In this review, we emphasize that AKI can be a severe complication of COVID-19 and highlight the importance of assessing, defining, and reporting the course of AKI.
Design • The research team performed a literature review, searching relevant literature databases. We searched four databases, PubMed, EMBASE, Web of Science and CNKI (Chinese Database), to identify studies reporting COVID-19. Articles published on or before May 10, 2020 were eligible for inclusion. We used the following search terms: “Coronavirus” or “2019-nCoV” or “COVID-19” or “AKI” or “renal failure” or “nephrology”.
Setting • This study was take place at Jouf University, Sakaka, Al-Jouf, Saudi Arabia.
Results • The review showed that AKI patients, who were susceptible to a cytokine storm, showed clinical deterioration. This result allowed the current research team to develop a hypothesis of a set of adverse events in COVID-19 that proposes the modification of inflammatory pathways by stimulation of nAChRα7. The stimulation could occur by way of IL-6 / JAK2 / STAT3 / SOCS3 and NF-κB (p65)/IL-18, which work together to induce AKI and increase overall renal-related diagnostic markers, such as plasma creatinine and tubular cell damage. In addition, the functioning of the cholinergic anti-inflammatory pathway may be determined by nicotine. Pharmacological nicotine products are widely available, and their role in COVID-19-mediated AKI can be further evaluated.
Conclusions • The research team concluded that the dysregulation of the cholinergic anti-inflammatory system could explain most of the clinical features of severe COVID-19. (Altern Ther Health Med. 2020;26(S2):66-71)
Khalid Alharbi, PhD, Assistant Professor, Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia. Fahad A. Al-Abbasi, PhD, Professor, and Imran Kazmi, PhD, Associate Professor, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. Gopal Prasad Agrawal, PhD, Assistant professor, Institute of Pharmaceutical Research, GLA University, Mathura-Delhi Road, Chaumuhan, Mathura, India. Ajay Sharma, PhD, Professor, Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India. Rajesh Kowti, M.Pharm, Assistant professor Department of Pharmacology, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B.G. Nagara, Mandya, India.
Corresponding author: Imran Kazmi, PhD
E-mail address: [email protected]
The year 2020 will linger in our memory as marked by the catastrophic COVID-19 pandemic and the global freeze, when our daily practices were significantly altered and curtailed.
In December 2019, a COVID-19 outbreak occurred in Wuhan, China and spread worldwide rapidly. As of May 21, 2020, the World Health Organization (WHO) Status Report showed 4 789 205 confirmed infections and 318 789 deaths as a result of COVID-19, which is caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2. WHO identified COVID-19 as the third recorded release, within just the past two decades, of a human-animal coronavirus resulting in a major outbreak.1
Unlike other coronavirus diseases, aerosolized droplets are the primary transmission mechanism for SARS-CoV-2. Alternative pathways for transmission to children have been suggested, such as direct, oral and maternal transmission, but further research on these paths is necessary.2
At the start of the pandemic, a randomized trial estimated a period of incubation of 5-14 days for SARS-CoV-2; however, a more recent estimate suggests the incubation period could extend to 24 days.3-4 At the beginning of the COVID-19 pandemic, patients’ major symptoms were fever (98%), cough (76%), and myalgia, or weakness (44%). Other effects in those early days included: (1) acute respiratory syndromes—61.1%, (2) arrhythmia—44.4%, (3) shock—30.6%, (4) hemoptysis-3.2%, (5) diarrhea—3%, (6) occurrence of stroke—5%, (7) acute cardiac event—12%, (8) AKI—36.6%, (9) maculopapular exanthetic dermatology—36.1%, and (10) fatalities in certain instances.3-7
In addition to identifying 138 confirmed cases of COVID-19 hospitalization in Wuhan in December 2019, Wang et al found that 41% of the participants in their study—116 hospitalized COVID-19 patients—had suspected hospital transmission of SARS-CoV-2. Of them, 26% were admitted to the intensive care unit (ICU), and 4.3% died.
Wang et al’s study assessed the clinical data for those patients and examined the effects of SARS-CoV-2 on various functions of the renal system.10
Therefore, the current review intended to examine the factors that might determine the clinical features of severe COVID-19, particularly those related to the pathogenesis of acute kidney injury (AKI).
The research team searched the relevant literature databases. We searched four databases, PubMed, EMBASE, Web of Science and CNKI (Chinese Database), to identify studies reporting COVID-19. Articles published on or before May 10, 2020 were eligible for inclusion. We used the following search terms: “Coronavirus” or “2019-nCoV” or “COVID-19” or “AKI” or “renal failure” or “nephrology”. References of all retrieved studies were screened for additional eligible publications. Primary studies were eligible if they reported any information on COVID-19 patients without restriction on study type or study design. We excluded studies that focused on infection in infants, did not report original data or clear diagnostic criteria, and no reliable clinical data.
Two independent reviewers screened the literature search and assessed each study for inclusion. Any disagreement was solved by consulting a senior investigator.
Pathogenesis of AKI
Research by Gupta et al10 found that AKI was triggered by renal hypoperfusion due to dehydration and/or hypotension in 13 participants in their study or by drug-induced nephrotoxicity from high-dose fluoroquinolones administered before hospitalization in 2 cases. It was related in 3 cases to myocardial infarction or heart failure.
Hanley et al found in their study that 11 participants experienced sepsis or septic shock (13%)—from E. coli in
3 cases, Staphylococcus aureus in 6 cases, and Streptococcus viridans and Enterococcus faecalis in 2 cases.11 The researchers also found that one patient had symptoms of stroke, and 6 participants (7.3%)—3 with normal kidney function and 3 with chronic kidney disease in stages 3 to 5 (CKD 3-5)—showed impaired consciousness. In the first 72 hours after admission, 2 participants in the study developed a myocardial infarction and died as a consequence.
Cardiorenal syndromes can lead to kidney dysfunction following AKI. These syndromes, especially right-hand ventricular insufficiency, have resulted from COVID-19 pneumonia, because lower cardiac output, low arterial fill, and hypoperfusion of kidneys can contribute to left ventricular dysfunction.12 An effective strategy is to change the fluid equilibrium by volume responsiveness and tolerance test, which helps to maintain the usual volume status, prevent overload, and reduce the risk of pulmonary edema, right ventricular overload, and consecutive AKI swelling.13
AKI is a dangerous and broadly spread pathological illness, which has been unpredictably treated as a nosocomial disease in the developed world, with simultaneous spikes in community-based cases.14 This has resulted in high morbidity and death levels, not only because of hemodynamic modification in AKI pathophysiology but also because of the impact on patients’ immune cells and inflammatory response, which plays an important role in the dysregulation of renal-system function.15,16
Recent research published in the European Respiratory Journal concluded that nicotine use is a risk factor for COVID-19.17 Russo et al showed that angiotensin-converting enzyme 2 (ACE-2) is upregulated through the nicotinic acetylcholine receptor alpha 7 (nAChR-α7) and is present in neuronal and non-neuronal cells.17
It’s important to examine potential interactions between the virus and other cell receptors. Huang et al found that the ACE-2 receptor (ACE-2R) was the targeted receptor used by SARS-CoV-2 to enter host cells, based on clinical investigation of smoking prevalence in hospitalized patients with COVID-19.16
Some animal studies have found that the inhibitors of the renin-angiotensin-aldosterone system (RAAS)—a group that includes ACE inhibitors and angiotensin receptor blockers—can increase ACE-2 expression.18,19 Such results prompted researchers to conclude that the use of such drugs may strengthen SARS-CoV-2 cells and increase patients’ vulnerability to infection or increase COVID-19 intensity.20-22
More recent research has now revealed that the use of RAAS inhibitors isn’t linked to a higher risk of patients with COVID-19 who require hospital admission.23 In addition, the analysis revealed comparative data relating to various classes of antihypertensive drugs used for diabetic hypertensives.24 The data suggested that their use can almost halve the risk of adverse reactions in COVID-19 patients.
Leung et al have proposed that RAAS inhibitors may have more protective effects against complications and death in patients with COVID-19 relative to those of other antihypertensive medications, although these findings weren’t limited to patients with diabetes.25 In addition, Leung et al, Liu et al, and Lu et al have hypothesized that the nicotinic cholinergic system could be involved in increased COVID-19 infection on the basis of the malfunction of the cholinergic anti-inflammatory pathways, which could explain some of the clinical signs and symptoms of COVID-19, together with the cytokine storms.25-27
COVID-19 and the Cytokine Storm
The Coronaviridae family of viruses has a positive-sense, single-stranded RNA genome range that runs between 26 and 32 kilobases in length. Coronavirus has been also been identified in a number of avian hosts and mammals, including camels, bats, masked palm civets, mice, dogs, and cats. Novel mammalian coronaviruses are identified continuously.27
The novel SARS-CoV-2 is a β-coronavirus, and its genome is partly correlated with the known genomes of the genomically sequenced SARS-CoVs (~79%) and Middle East respiratory syndrome coroavirus or MERS-CoVs (~50%). In creating its effects, SARS-CoV-2 uses the major receptor of angiotensin converting enzyme 2 (ACE2), commonly found in the vascular endothelium, respiratory epithelium, alveolar monocytes, and macrophages, as does SARS-CoV.28,29
SARS-CoV-2 can actively replicate in the upper respiratory tissue and live viruses have been successfully isolated in throat swabs and identified by viral subgenomic RNA (sgRNA) messenger in the cells of the upper respiratory tract.30,31 Later during an infection, COVID-19 resembles SARS with its viral replication in the lower respiratory tract, and secondary viremia precedes severe assaults on ACE2 target organs, such as alveolar pulmonary cells, upper and stratified epithelial cells, ileum and colon absorptive enterocytes, cholangiocytes, myocardial cells, and proximal renal tubules.32
The first line of defense against the virus is innate immunity. Viral mammal infection triggers intracellular pattern-recognition receptors that recognize pathogen-associated molecular structures like double-stranded RNA or uncoated mRNA. Cytokines have proven to induce sepsis-like clinical manifestations such as hemodynamic instability, fever, and localized inflammation.33,34
The immune system’s identification of a pathogen-related molecular pattern contributes to subsequent cytolytic immune responses, primarily by type 1 interferons (IFNs) and natural killer cells. Adaptive immunity is also a crucial factor in viral removal by cytotoxic T cells that kill virus-infected cells and by antibodies that create B cells that target virus-specific antigens.
A rare pattern of hypercoagulation has been observed in serious and critical patients with COVID-19, together with a gradual rise in inflammation.17 This inflammation is characterized: (1) by the presence of high serum CD4+ and CD8+ circulating lymphocytes that were hyperactivated, (2) by an increased quantity of pro-inflammatory CCR6+T helper 17 (Th17) in CD4+ T cells and interleukin-6 (IL-6)-producing CD14+, CD16+ inflammatory monocytes, (3) by increased levels of ferritin, tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), IL-2, IL-7, IL-8, IL-9, IL-10, IL17, monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein 1 alpha (MIP1α), macrophage inflammatory protein 1 beta (MIP1β), macrophage inflammatory protein 3 alpha (MIP3α), D-dimer, and C-reactive protein, and (4) by activation of the Janus kinase / signal transducer and activator of transcription (JAK/STAT) protein, which is associated with cytokine complications.35,36
In addition, hyperactivated T helper type 1 (Th1) cells produce granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon alpha (IFN-α), which actually stimulates IL-6-producing monocytes.37 In addition to G-CSF, responsible for granulopoiesis and neutrophil recruitment, other cytokines that have been found during complicated COVID-19 infection further contribute to the cytokine storm that is responsible for the destruction of tissue.38
Certain cytokines, including IL-6, can stimulate the system of coagulation and counteract the fibrinolytic system. Pulmonary and peripheral endothelial damage induced by a viral attack directly can be an equally significant hypercoagulation inducer in the configuration of COVID-19. Endothelial cell damage can stimulate the coagulation mechanism strongly by tissue factor penetration and other routes. In addition, dysfunctional coagulation can also increase the aggressiveness of the immune response (Figure 1).
Figure 1. Factors Associated with Acute Kidney Disease
Abbreviations: RAAS, renin-angiotensin-aldosterone system.
Although the concept of inflammatory storms remains unclear, immune-mediated inflammation has a role in the pathogenesis of COVID-19, similarly to SARS. Different experimental models of pro-inflammatory cytokines—such as sepsis, ischemia-reperfusion, and pancreatitis—have shown that vagus stimulation can be used for specific interventions. This effect is regulated by the nicotinic acetylcholine receptor alpha 7 (nAChR-α7) subunit on macrophages.38,39 This activates the cholinergic anti-inflammatory pathway through the nAChR-α7 subunit, affecting the innate immune system and proinflammatory cytokine secretion and abolishing the cytokine storm.40,41
In addition, mice deficient in the α7 subunit have been found to have a higher production of endotoxin-induced TNF, and electrical innervation of the vagus didn’t reduce TNF serum levels.42 Other clinical aspects of COVID-19, such as anosmia and thromboembolic complications, may also be correlated significantly with the dysfunction of the nicotine cholinergic system.43
Janus kinase 2 (JAK2) / signal transducer and activator of transcription (STAT3), as well as the cytokine signal suppression regulator 3 (SOCS3) [JAK2 / STAT3 / SOCS3] are key mechanical ports by which these receptors exert their anti-inflammatory efficacy. Such a process plays a part in the regulation of IL-6 and nuclear transcription factor kappa B (NF-kB).44 Activation of the cholinergic anti-inflammatory pathway in galactose’s (GAL’s) renoprotective response to the ZYM-induced kidney-damage model has been shown to occur by triggering the nAChR-α7 subunit.45
In concurrence with the findings of various studies, the activated / phosphorylated JAK2 / STAT3 axis is capable of producing potentially harmful effects from various AKI insults.46 In comparison, another GAL-inhibited, inflammatory cytokine is IL-18, which is an essential intermediator of renal tubular epithelial cell injury and which has been by bolstered by the ZYM model.18 In addition, the current review showed that the activation of nAChR-α7 on antigen presenting cells (APCs) suppresses antigen-specific, antigen-dependent CD4+ T cell production by limiting antigen processing.30
Conversely, the activation of nAChR-α7 expressed on CD4+ T cells upregulates antigen-specific, antigen-independent processing of CD4+ T cells into Tregs and effector T cells, most likely by the activation of the JAK2 / STAT pathways. Therefore, both inborn and adoptive immunities necessary to sustain COVID-19 AKI-mediated infection are decisively impaired by nAChR-α7-expressing immune cells.47
A number of recent studies have concentrated on the adverse effects of inflammation due to JAK2 / STAT3 / SOCS3 signal activation.48 However, data from various cardiac and diabetic studies have shown that the JAK2 / STAT3 anti-inflammation pathway may initiate a cardioprotective effect by promoting cell survival via the suppressor of cytokine signaling 3 (SOCS3), which is rapidly induced by STAT3’s activation of cytokines or growth factors and which act using a negative feedback loop.49,50
In addition, the noncanonical role of STAT3 in normal physiology, together with the phosphorylation of STAT3 monomers on Ser727, is responsible for the translocation into mitochondria without dimerization. Mitochondrial (mt) STAT3 enhances stress-promoting cell survival, such as cardiac ischemia and Ras-mediated transformation. Serine phosphorylated (pS)-STAT3 interacts with the electron transport chain (ETC) complex I (I) and electron transport chain II (ETCII) to promote appropriate ETC activity, boost the polarization of membranes and the production of adenosine triphosphate (ATP), and increase lactate dehydrogenase activity, thus further enhancing aerobic glycolysis and reducing reactive oxygen species (ROS) production.
The mtSTAT3 also protects against apoptosis by blocking mitochondrial permeability of the transition pore, apparently by interacting with cyclophilin D, which increases the demand for calcium inflow from the endoplasmic reticulum (ER). While enhancing ETC activity, mtSTAT3 lessens ROS production, usually through the production of ETC supercomplexes. These are known to reduce electron leakage by optimizing coupling and/or through increased synthesis of ROS scavengers, such as glutathione. Its basic and stress-related adaptive functions should therefore be considered, and it would be advisable to avoid the use of STAT3 inhibitors immediately prior to traumatic injury until the wound healing is complete (Figure 2).51
Figure 2. Impact of SARSCoV-2-mediated Pathogenesis of Acute Kidney Injury
Abbreviations: ACE-2R, angiotensin converting enzyme 2 receptor; TMPRSS2, transmembrane serine protease 2; TNFα, tumor necrosis factor alpha; IL, interleukin; TH17, T helper 17 cells; MCP1, monocyte chemoattractant protein-1; MIP1A, macrophage inflammatory protein 1 alpha; MIP1B, macrophage inflammatory protein 1 beta; MIP3A, macrophage inflammatory protein 3 alpha; Ach, acetylcholine; nAChR-α7, nicotinic acetylcholine receptor alpha 7; JAK2/ STAT3/ SOCS3, Janus kinase 2 / signal transducer and activator of transcription / cytokine signal suppression regulator 3.
The current review showed that AKI patients, who were susceptible to a cytokine storm, showed clinical deterioration. Preliminary findings have shown that acute renal failure may represent an independent risk factor for morbidity and mortality in hospitalized individuals with established COVID-19 infection.52 More recent studies support the evidence that coronavirus gains entry into the human body through involving the epithelial cells by binding to (ACE2) receptors located on the cell surface of a variety of host cells including the renal tubular epithelial cells.53 However, the major cellular targets for COVID-19 agent are type II pneumocytes and enterocytes. Thus, AKI related to COVID-19 infection, most probably is multifactorial, including a major role of immune activation, though a rise in the level of inflammatory chemokines and mediators, pro-inflammatory cytokines, inducible nitric oxide synthetase by M1 subtype of macrophages to form cytotoxic peroxynitrite, all of which mediate kidney damage. This result allowed the current research team to develop a hypothesis that proposes a set of adverse events in COVID-19 causing a modification of inflammatory pathways by stimulation of nAChRα7. The stimulation could occur by way of IL-6 / JAK2 / STAT3 / SOCS3 and NF-κB (p65)/IL-18, which work together to induce AKI and increase overall renal-related diagnostic markers, such as plasma creatinine and tubular cell damage59. In addition, the functioning of the cholinergic anti-inflammatory pathway may be determined by nicotine. Pharmacological nicotine products are widely available, and their role in COVID-19-mediated acute kidney injury can be further evaluated.
The research team concluded that the dysregulation of the cholinergic anti-inflammatory system could explain most of the clinical features of severe COVID-19.
The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research grant no (CV-21-41).
Authors’ disclosure statement
The authors declare that they have no conflicts of interest related to the current review.
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