proinflammatory factors (IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (GSCF), interferon gammainduced protein 10 (IP10), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1 alpha (MIP1α) and TNF-α) and severity of COVID-19 infection [27]. Therefore, the cytopathic effects of the virus through the inflammatory response and the direct effect of the virus on kidney cells can be accounted as possible mechanisms of kidney damage (Figure 1) [27]. Thus, COVID-19 by inducing AKI leading to immune activation, rise in the level of inflammatory chemokines, mediators, pro-inflammatory cytokines, and inducible nitric oxide synthetase through M1 subtype of macrophages to form reactive cytotoxic peroxynitrite (ONOO), all of which mediate renal failure. Furthermore, cytokine storm syndrome has a major role in several infection-mediated multiple organ dysfunction syndromes, such as kidneys [21]. Evidence suggests that IL-6 can be can be used as a marker in cytokine storm situations which is increased in this pandemic disease [28]. Cytokine generation has been noted in cases of invasive mechanical ventilation, continuous kidney replacement therapy (CKRT) and extracorporeal membrane oxygenation (ECMO) [29]. Approximately all the patients with AKI who receive KRT are on mechanical ventilation. These findings indicate that cytokine storm and severe hypoxemia could result in AKI, without the direct invasion on the kidney by the coronavirus [30]. Recent findings based on retrospective study demonstrated alveolar damage associated with the tubular injury which called the lung-kidney axis-in ARDS [31]. IL-6 overproduction due to lung–kidney bidirectional damage positively correlates with higher alveolar-capillary permeability and pulmonary hemorrhage following AKI [32]. Multiple clinical studies have suggested that there is strong crosstalk between the kidneys and heart [33, 34]. For this reason, the reported findings suggest cardiomyopathy and acute viral myocarditis could contribute to AKI through renal vein congestion, hypotension, renal hypoperfusion and reduction in glomerular filtration rate (GFR) in COVID-19 patients. These findings are important in CKD patients who are exposed to the SARS-CoV-2 and such patients should be given appropriate treatment and protection strategies. Previous studies have shown that podocytes and proximal straight tubule cells act as host cells. Podocytes and proximal cells play an important role in urinary filtration, reabsorption, and secretion. Podocytes are significantly susceptible to bacterial and viral attacks, and damage to podocytes easily induces severe proteinuria. According to previous reports regarding other types of coronavirus, namely Middle East respiratory syndrome coronavirus (MERS-CoV), renal failure was induced by kidney cell apoptosis through increasing the fibroblast growth factor-2 (FGF2) and Smad7 expression [35]. Interestingly, inhibiting Smad7 by antisense oligonucleotide targeting Smad7 efficiently decreased MERS-CoV replication and resulted in renal protection against virus assault [35]. Thus, it should be considered that kidney injury in COVID-19 patients might be associated with renal cell apoptosis induced through the higher expression of FGF2 and Smad7. Dehydration may be another possible mechanism by which the SARS-CoV-2 induces AKI. Dehydration is associated with fever in COVID-19 patients who often suffer from increased sweating. Fluid and electrolyte loss subsequently result in the reduction of GFR and AKI in severe cases although in mild cases dehydration can be reversed by increasing fluid intake [36]. Other potential mechanisms of AKI can be due to inappropriate use of nonsteroidal inflammatory drugs, and the presence of underlying diseases such as diabetes and hypertension (Figure 1) [37, 38]. Autopsy examinations revealed that SARS-CoV-2 contaminates renal tubules directly and causes severe kidney injury through cytopathogenic action or by infiltration CD68 þ macrophages into interstitial compartment, along with tubular accumulation of complement membrane attack complex (C5b-9) [39, 40]. In addition to the direct virulence of SARS-CoV-2, many factors contributing to AKI include drug-induced rhabdomyolysis, hypoxia, and aberrant coagulation [41]. Figure 1. Renal insufficiency following SARS-COV-2 infections, causes and potential mechanisms. Kidney infections by viruses can be caused in a variety of ways. Excessive activation of Toll-like receptors results in renal dysfunction. Abbreviations: SARS-COV-2: Severe acute respiratory syndrome coronavirus 2; GFR: Glomerular filtration rate; ESRD: End-stage renal disease; AKI: Acute kidney injury. H. Askari et al. Heliyon 7 (2021) e06008 4 Recently, SARS-CoV-2 was also shown to penetrate target cells through CD147, a receptor on host cells with interaction with diverse components such as cyclophilins, caveolin-1, and integrins. CD147 has also been found to play a key role in various kidney diseases by immune-inflammatory responses and aberrant cell cycle. Apparently, targeting the CD147-cyclophilins axis could be a potentially promising strategy to treat COVID-19 [42, 43]. 5. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and COVID-19 Recently, ACEIs