key: cord-0872032-upyar7en authors: Ahmadian, Elham; Hosseiniyan Khatibi, Seyed Mahdi; Razi Soofiyani, Saiedeh; Abediazar, Sima; Shoja, Mohammadali M.; Ardalan, Mohammadreza; Zununi Vahed, Sepideh title: Covid‐19 and kidney injury: Pathophysiology and molecular mechanisms date: 2020-10-06 journal: Rev Med Virol DOI: 10.1002/rmv.2176 sha: 8aac8930eb72f24f2b1c262e42932c56bcfdecab doc_id: 872032 cord_uid: upyar7en The novel coronavirus (SARS‐CoV‐2) has turned into a life‐threatening pandemic disease (Covid‐19). About 5% of patients with Covid‐19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS‐CoV‐2‐induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin‐converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS‐CoV‐2‐driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid‐19 is necessary to develop management strategies and design effective therapies. The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease . Acute respiratory distress syndrome (ARDS) and diffuse alveolar haemorrhage are the principal manifestations of Covid-19. 1 Although the respiratory system is the major target of COVID-19, other organs in the body might be infected by the virus via the circulating system, including scanty information regarding the renal system. Reports indicate that kidney involvement is frequent and ranges from mild proteinuria to an advanced acute kidney injury (AKI). 2 Clinical evidence has shown the increment of serum creatinine and blood urea nitrogen as well as the appearance of haematuria and proteinuria in 701 Covid-19 cases in a large prospective study in China. 3 These patients showed a lower platelet and lymphocyte count, higher leucocyte count, a higher rate of comorbidities, and an intensive care need compared to patients with normal kidney function. About 5% of the patients were diagnosed with AKI during hospitalization. 3 Studies in Europe and the USA reveal that Covid-19 induces AKI in 20-40% of the patients admitted to intensive care unit (ICU) and AKI is deemed as a negative prognostic factor and an indicator of disease severity. [3] [4] [5] Multiple factors could be involved in the pathogenesis of kidney damage in patients with Covid-19. 6, 7 The initial impact might be the direct role of the virus on the renal parenchyma mediated by activating the angiotensin-converting enzyme 2 (ACE2), which functions as a SARS-CoV-2 receptor. ACE-2 and transmembrane protease, serine 2 (TMPRSS2) genes are expressed in kidney cells as much as in lung, small intestine and oesophagus; supporting their role as profound targets of SARS-CoV-2. 8 Moreover, recent studies suggest podocytes and proximal convoluted tubules, which express the ACE2 gene, as important host cells of the SARS-CoV-2, implying that the renal tissue is a possible target of SARS-CoV-2. 9 Beyond functioning as a viral receptor, ACE2 may act as a linker between Covid-19, the renin-angiotensin system (RAS), and the kallikrein-kinin system (KKS), 10, 11 Figures 1 and 2 . The second mechanism through which Covid-19 can affect the kidney includes the immune system, which can in turn result in kidney damage. Another mechanism is the occurrence of a cytokine storm after a viral infection that can both influence the kidney directly and indirectly by inducing sepsis, shock, hypoxia, and rhabdomyolysis. 12 Organ interactions between lung, heart, and kidney would be other possible causes of the Covid-19-induced kidney injury. Finally, the generation of microthrombi in Covid-19 patients which can lead to acute ischaemia and AKI is the last proposed mechanism ( Figure 3 ). There is no information regarding the impact of hyperinflammation, proteinuria and/or tubular damage on SARS-CoV-2 viral entry and ACE2 expression in proximal tubules. Theoretically, the replication of the virus in podocytes and further injuries could result in proteinuria. 3 Furthermore, the Covid-19related microangiopathy and hemophagocytic macrophage activation could result in AKI. However, a result showed that AKI is uncommon in Covid-19 and the viral infection does not either cause AKI or worsen the chronic kidney disease (CKD) in these patients. 13 In this review, we explore the potential pathways of kidney damage during Covid-19 in more details. Although Covid-19 mainly targets the respiratory and immune systems, AKI is also found in Covid-19 patients. Kidney injury and the subsequent clinical events such as haematuria and proteinuria have been observed in approximately 40% of the Covid-19 patients. 14 This has been speculated to be in close connection with the expression of the ACE2 receptors in the brush border of proximal tubular cells. The exact impact of SARS-CoV-2 on kidney and the possible induction of acute renal failure have to be investigated. 15 Besides, 27% of affected and two-thirds of deceased patients have shown elevated blood urea nitrogen. From the pathological point of view, inflammation, oedema and a reduced density have been reported in kidney tissues of the suffers. 16 In a recent study conducted by Cheng et al., 44% of the 710 hospitalized Covid-19 patients showed haematuria and proteinuria, while 27% of them had haematuria on admission. 9,17 Accordingly, kidney involvement appears to be a common event in SARS-CoV-2 infection and AKI is an independent prognostic factor. 18 Despite the amelioration of proteinuria and AKI, kidney complications were linked with exacerbated rates of mortality in Covid-19 patients, three weeks after the commencement of symptoms. The AKI and/or abnormal urine dipstick findings have been observed in approximately 75% of the 333 patients. 19 Urine analysis and postmortem samplings from the kidney tissues of the infected patients show SARS-CoV-2, confirming the kidney to be a novel target of 21 Moreover, SARS-CoV-2 nucleocapsid protein antigen accumulates in the renal tubules as observed by an immunohistochemistry examination. Virus-like particles are visible when an electronic microscope is used. 9 Interestingly, collapsing glomerulopathy has been also reported in Covid-19 patients. 22 Altogether, these reports clarify that kidney cells are targeted by SARS-CoV-2 and new strategies are needed to treat Covid-19 to prevent organ infection and dysfunction. ACE2 receptors are the major binding site for SARS-CoV-2. Alveolar Type II cells, oesophagus keratinocytes, liver cholangiocytes, stomach epithelial cells, colon colonocytes, ileum, rectum and kidney proximal tubules express ACE2 receptors. 23 Kidney expresses ACE2 more than the lung tissue 24 in the proximal tubules' brush border apical membrane and to a lower extent, podocytes express ACE2 in kidney tissues. 24 Thus, it could be hypothesized that the virus enters arteriole and glomerular capillaries and initially infects the glomerular endothelial cells. Then, podocytes are infected and the virus enters the tubular fluid and consequently binds to its receptors in proximal tubules. 25 As depicted in Figure 1 , SARS-CoV-2 can enter the host cells the by two possible mechanisms: endocytic and non-endocytic pathways ( Figure 1 ). The fusion of the virus envelope to the host cellular membrane is vital for virus entrance into the renal cells. A specific proteolytic cleavage of the S protein, called the priming step, generates fusionactivated SARS-CoV-2 peptides. The expressions of ACE2, as well as the activity of certain proteases result in cell infection. Except ACE2, other surface receptors including TMPRSS2 and CD147 (basigin or extracellular matrix metalloproteinase inducer) may be involved in the entry of SARS-CoV-2. 26 Single-cell RNA sequencing of 13 human tissues was used to identify other candidate co-receptors of the coronavirus. The results showed that among serine protease dipeptidyl peptidase 4 (DPP4), Alanyl aminopeptidase (ANPEP) and Glutamyl aminopeptidase (ENPEP) receptor, ENPEP can be another potential receptor for human CoVs. 23 On the other hand, the tropism of SARS-CoV-2 may be extended by the unique furin cleavage. 27 In Asian and Occidental groups, the number of renal cells expressing proteases of the TMPRSS family, the SARS-CoV-2 binding site and ACE2 were investigated. As a result, the Occidental showed higher rates of ACE2 and kidney-associated genes in comparison to Asian donors. However, the expression of TMPRSS genes did not show a noticeable difference between them proposing a higher susceptibility of the Occidental group to coronavirus-related renal damage. 8 It is assumed that the direct impact of the virus on the renal tubules reflects the kidney damage according to several findings. 28 First, the presence of viral fragments in urine either indicates a direct interaction of the coronavirus with renal tubules or indicates a possible exposure of the tubules to the virus. 29, 30 Second, the expression pattern of ACE2 is limited to proximal tubular cells. 29, 31, 32 Finally, between the second and third week of infection linked with the onset of AKI, SARS-CoV shedding was detected in the urine, 29,33 all implying the plausible role of SARS-CoV-2 in the induction of tubular damages. Since ACE2 receptors are highly expressed in the proximal tubular cell, the entry of SARS-CoV is supported by the activation of these receptors. Despite airway epithelial cells, proximal tubules express low levels of TMPRSS2 34, 35 ; hence, it is still vague whether other TMPRSS in the proximal tubule can regulate the priming process or not. Distal tubules in the kidney express TMPRSS2 rather than the proximal tubule which in turn primes the SARS-CoV-2 S protein. 27, 36, 37 This is a crucial step allowing the conformational rearrangement of remaining S2 unit leading to the fusion of cellular membrane. Subsequently, the virus enters the cell, liberates its constituents, replicates, and finally infects the other cells. 38 Recently, it is shown that SARS-CoV-2 attacks target cells through CD147, a transmembrane glycoprotein. CD147 is F I G U R E 1 SARS-CoV-2 and ACE2. SARS-CoV-2 enters into the ACE2-expressing cells through two possible pathways. (a) It binds to the host cell membrane-bound ACE2 via its viral spike protein. Moreover, SARS-CoV-2 requires the TMPRSS2 (cellular serine protease) for cleavage of it's spike protein and supporting its cell entry. (b) Internalization of the virus can also occur through endocytosis and the cleavage activation of the viral spike protein by cathepsin in endosomes. Virus-induced ACE2 down regulation may reduce its anti-inflammatory function and activate the harmful Ang II-AT1R axis and bradykinin-BKB1R axis. These events worsen the viral pathogenicity and lead to organ damage. Viral infection and AT1R activation lead to shedding of ACE2 into a soluble form by ADAM17 and its release into the body fluids. ACE2, angiotensin converting enzyme 2; Ang II, angiotensin II; AT1R, angiotensin II receptor type 1; BKB1R, DABK/bradykinin receptor B1; DABK, bradykinin [des-Arg973]; RAS, renin-angiotensin system; KKS, kallikrein-kinin system AHMADIAN ET AL. Although little is known about the involvement of the kidneys in Covid-19, AKI is an observed clinical event. 45 AKI has been reported to be an important non-respiratory clinical manifestation in Covid-19 regardless of any preceding kidney damage in different clinical studies. [46] [47] [48] Wang et al. reported that about 4% of the Covid-19 patients had AKI. 48 In another study, 10% of the 41 Covid-19 patients revealed an increased level of creatinine on admission and 7% were diagnosed with AKI. 47 The worsened Covid-19 symptoms, the more progressed kidney damages were reported. In addition, Covid-19 patients have shown similar patterns to SARS cases in the prevalence rate of AKI; a retroperspective study reported 6% of SARS patients to suffer also from F I G U R E 2 Direct effects of SARS-CoV-2 on kidney injury. Acute renal failure is observed in Covid-19 patients through the direct effect of the virus in kidney tubules and podocytes. The direct impact of SARS-CoV-2 on kidney is mediated by an ACE2 pathway that leads to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy, and mitochondrial impairment. ACE2, angiotensin converting enzyme 2 AKI. 49 Acute renal dysfunction was developed in about 7% of the SARS patients in an analysis of 536 cases, and this has been linked to a great extent of morality (91.7%). 50 Also, Covid-19 patients who were admitted to ICU were more prone to the incidence of AKI in comparison with patients who did not receive any care in the ICU. 48 Rarely has the effect of SARS-CoV-2 in patients suffering from CKD been investigated. However, this condition is accompanied by an elevated risk of severe Covid-19 infection according to a reported meta-analysis. 51 Different factors could result in AKI during SARS-CoV-2 infection. Direct viral damage and/or disturbed haemodynamics of the kidney might account for AKI in Covid-19. Besides the direct impact of SARS-CoV-2 on kidney cells, other secondary insults, including cytokine storms, hypoxia, drug-associated nephrotoxicity, and secondary infection with other viruses, bacteria, and fungi can be contributed to AKI. Furthermore, sepsis-associated pathways are the probable mechanism for the kidney injury. Since septic conditions can induce kidney damage as a consequence of altered haemodynamics, it is assumed that some cases of kidney injury are sepsis-unrelated events. The virus influences kidney cells including podocytes and tubules in the latter group. 28 Postmortem studies show lymphocyte infiltration and an extensive acute tubular necrosis in kidney tissues. Angiotensin II (AngII) overactivity, the coagulation system, and innate/adaptive immune and complement pathways, systemic effects, and organ crosstalk determine the severity of AKI and its consequences. We will highlight these factors in the following sections. The majority of ACE2 is in the insoluble form bound to cell membranes. ACE2 in both soluble and insoluble form converts angiotensin II to angiotensin (1-7) which is crucial in controlling different hazardous effects on the body such as inflammation, vasoconstriction F I G U R E 3 Indirect effects of SARS-CoV-2 on kidney injury. SARS-CoV-2 infects alveolar macrophages and lung epithelial cells to amplify viruses and release cytokines and chemokines. Infected dendritic cells and the activated macrophages activate immune response extensively and initiate cytokine storm in the lung. Chemokines release can attract extra inflammatory cells to migrate into the inflammation site that intensify cytokine storm and may have indirect impacts on multi-organ failure, specially kidney, and death. Organ interaction between the damaged lung, the heart and the kidney can deteriorate the viral pathology. Numerous mechanisms including unmasked cardiovascular diseases (CAD), cytokine-induced myocardial damage, microangiopathy and viral myocarditis may clarify the main driver of myocardial damage and/or increased levels of troponin in Covid-19 cases. Endothelial dysfunction, microangiopathy, coagulation dysfunction are also involved in the kidney pathology in Covid-19 AHMADIAN ET AL. and thrombosis. An enhanced production of angiotensin (1-7) stimulates these counter-regulatory protective impacts through the activation of Mas receptors. However, SARS-CoV-2 entry significantly down-regulates the expression of ACE2 and thus inhibits its protective roles, decreases anti-inflammatory effects, and increases the effects of angiotensin II in infected patients. 10, 52 These detrimental effects occur as a result of the binding of angiotensin II to type 1 angiotensin receptors (AT1) that lead to pulmonary inflammation and coagulation ( Figure 1 ). This might result in the activation of AT1 and decreased generation of angiotensin (1-7) and subsequent AKI triggering. ACE2 deficiency has been reported clinically in SARS-CoV-2 patients with different features such as hypertension, cardiovascular diseases, diabetes, and older age. Thus, the virus-related downregulation of ACE2 might be particularly harmful to individuals with baseline ACE2 deficit accompanied with the above mentioned status. A further deficiency of ACE2 after SARS-CoV-2 infection may increase the dysregulation between the protective (angiotensin (1-7)) and adverse (AT1) roles of RAS. The dysregulation of these axes in the lungs will lead to thrombotic and inflammatory conditions by the local function of angiotensin II in contrast to angiotensin (1-7) . 52 It is plausible that an increased kaliuresis, as a marker of RAS activation, may be connected with a high level of angiotensin II in patients with Apart from the RAS, ACE2 is connected with the kallikrein-kinin Covid - injuries) leading to multi-organ failure in kidney. 68 Haemophagocytosis occurs as a result of this cytokine storm and induces disturbances in kidney. Infiltration of CD68 þ macrophages into tubulointerstitium is induced by a viral infection. 9 Moreover, viral infection leads to infiltration of CD56 þ natural killer cells and CD4 þ T cells into the tubular interstitium and secretion of their proinflammatory cytokines that damage tubules. 9 Over-activity of these immune cells might stimulate fibrosis, apoptosis, and micro-vascular alteration after their infiltration into the infected kidney. 69 Lymphopenia is clinically observed in severe Covid-19 patients. 74 The smears. Elevated D-dimer levels in hospitalization time or during illness correlate with high mortality rate in patients. 88 The antiphospholipid antibodies leading to thrombotic events are enhanced in Covid-19 patients with thrombocytopaenia. Therefore, regarding the effect of Covid-19 in thrombosis, prophylaxis with heparin has been suggested for hospitalized Covid-19 patients. Covid-19 infection has been accompanied by surged clotting, disseminated intravascular coagulation, pulmonary infarction, and thrombosis. 89 Moreover, poor outcomes have been detected in cases with lower platelet level and enhanced D-dimer. 89 The evidence of microangiopathy in other organs has also been reported such as spleen and kidney resulting in infarction in these vital tissues. In Covid-19 patients who undergo dialysis, an increased level of circuit clotting has been widely reported. 90 In addition, elevated myocardial damage similar to myocardial infarction is a plausible outcome of microangiopathy and myocarditis in heart tissue of Covid-19 patients. 90 Therefore, hypercoagulation might spread acute tubular necrosis to cortical necrosis and thus, induce irreversible kidney damage in severe Covid-19. Also, microthrombi and microangiopathy states can elevate the risk of micro-infarctions in different organs such as heart, liver and kidney, further leading to impairments in multiple tissues. Several factors can induce rabdomyolysis, a serious damage of skeletal muscle. Skeletal muscle injury and subsequent release of breakdown products into the blood could be followed by AKI. 91, 92 Rhabdomyolysis can be a clinical manifestation of Covid-19. 93, 94 Autopsy results from Covid-19 patients demonstrate acute proximal tubular damage, glomerular fibrin thrombi with ischaemic collapse, and peritubular erythrocyte aggregation. 95 Rhabdomyolysis as determined by the presence of pigment casts as well as inflammation has also been reported. Particularly, a number of patients have not shown the signs of AKI, proposing the probability of extensive subclinical renal damage. 95 Different assumptions have been proposed regarding the molecular mechanism of viral-induced rhabdomyolysis. (1) A direct virus invasion can result in rhabdomyolysis, (2) The occurrence of cytokine storm and following injuries happen in muscle tissue and (3) the direct destruction of muscle cell membrane occurs by circulating viral toxins. 93, 96 However, the exact Covid-19 rhabdomyolysis mechanism has not yet been investigated but cytokine overproduction might be the contributing factor. The crosstalk between the lung and kidney has been observed in ARDS. 97 The disease severity, the presence of diabetes, and older age are risk factors for AKI in ARDS patients. Additionally, the severity of AKI is connected with a history of heart failure (cardio-renal syn- 97 The lung-kidney axis and the subsequent damages are linked with cytokine storm. IL-6 is up-regulated in response to renal tubular damage, and IL-6 overexpression is accompanied by lung injury during the progress of AKI. 100 However, the role of IL-6 in the induction of pulmonary haemorrhage and increased alveolar-capillary permeability need to be elucidated on. Renal medullary hypoxia could also be induced by ARDS. 100 Beyond preferentially targeting patient's lungs, dysfunction in cardiovascular system is frequently seen in early stage of Covid-19, leading to acute myocardial infarction, myocarditis, and heart failure. These effects are established by increased levels of troponin and natriuretic peptides that can be mediated by RAS imbalance. This mechanism may complicate the clinical course mediated by the hyperinflammation, microvascular damage and endothelial dysfunction. 101 Diffuse microangiopathy along with thrombosis can occur due to inflammation in the vascular system. Also, the inflammatory process in myocardium can lead to myocarditis, arrhythmias, heart failure, rapid deterioration, acute coronary syndrome and even sudden death. 102 CRS contains a total of circumstances involving both the kidneys and heart, in which any dysfunction in one organ can manually promote an impairment in the other. The function of these two organs can be impaired by a chronic or acute systemic condition. 103 The crosstalk between the cardiovascular system and kidney may be also 106 controlling immune responses may be important strategies to target the virus and decrease multi-organ dysfunction. We wish to express our appreciation to Fatemeh Zununi Vahed for her kind assistance in English editing of the manuscript. No conflict of interest is declared. SZV and MA designed the study and prepared the outline. SZV performed literature review research and prepared the first draft. EA and SMHK cooperated in drafting and revising the sentences. All authors contributed in revising the manuscript. All authors read and signed the paper manuscript. This is a review article; data openly available in a public repository that issues datasets with DOIs. 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