Advertisement

Relationship Between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Etiology of Acute Kidney Injury (AKI)

Published:October 27, 2020DOI:https://doi.org/10.1016/j.amjms.2020.10.025

      Abstract

      Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since it was first recognized in December 2019, it has resulted in the ongoing worldwide pandemic. Although acute hypoxic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are the main features of the disease, the involvement of other organs needs to be explored. There has been a growing concern regarding the association between acute kidney injury (AKI) and poor outcomes in SARS-CoV-2 patients. Based on current observational data, AKI is the 2nd most common cause of morbidity and mortality behind ARDS in SARS-CoV-2 patients. Angiotensin-converting enzyme 2 (ACE2) receptor has been shown to be the cornerstone of SARS-CoV-2 infection and possibly plays a significant role in the occurrence of renal injury. The pathogenesis of AKI is likely multifactorial that involves not only direct viral invasion but also dysregulated immune response in the form of cytokine storm, ischemia to kidneys, hypercoagulable state, and rhabdomyolysis, among others. We performed a literature search of the Pubmed and Google Scholar database from 1996 to 2020 using the following keywords: severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, angiotensin-converting enzyme 2 receptor, and acute kidney injury to find the most pertinent and highest-quality of evidence. Any cited references were reviewed to identify relevant literature. The purpose of this review is to discuss, explore, and summarize the relationship between AKI in SARS-CoV-2 patients, with a focus on its epidemiology, association with ACE2 receptors, and pathophysiology of AKI.

      Key Indexing Terms

      Introduction

      Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since it was first identified in December 2019, it has spread globally, resulting in the ongoing worldwide pandemic.
      • Zhu N
      • Zhang D
      • Wang W
      • et al.
      A novel coronavirus from patients with pneumonia in China, 2019.
      SARS-CoV-2 belongs to the same coronavirus family responsible for respiratory illnesses such as the severe acute respiratory syndrome (SARS-CoV), and Middle East respiratory syndrome (MERS-CoV) that were responsible for the 2003 and 2012 epidemic, respectively.
      • Lu R
      • Zhao X
      • Li J
      • et al.
      Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
      SARS-CoV-2 has 80% similarity in genetic sequence to SARS-CoV but only 50% similarity when compared to MERS-CoV. The clinical presentation of SARS-CoV-2 can range from asymptomatic infection or self-limited flu-like illness to life-threatening illness in the form of sepsis, acute hypoxic respiratory failure (AHRF), acute respiratory distress syndrome (ARDS), coagulopathy, and multi-organ failure.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      Pulmonary involvement with AHRF and ARDS has been the primary focus of the disease in patients with SARS-CoV-2 due to its high prevalence between 40 to 85%.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      However, similar observational reports have highlighted that AKI is also relatively common in SARS-CoV-2, with prevalence between 3 to 29% in SARS-CoV-2 infections.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      There is a growing interest in identifying whether there is an association between the pathophysiology of SARS-CoV-2 and the emergence of AKI in an attempt to alter the disease course and overall prognosis .
      This review aimed to describe how the novel SARS-CoV-2 cause AKI based on the current evidence in the literature (Fig. 1). An electronic search was performed through Pubmed and Google Scholar database from 1996 to 2020 using the following keywords: severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, angiotensin-converting enzyme 2 receptor, and acute kidney injury. All relevant English language articles were included in this review.
      Fig 1:
      Figure 1Etiologies of Acute Kidney Injury in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

      Epidemiology

      AKI results from an abrupt loss of kidney function and is strongly associated with an increase in morbidity and mortality. During the SARS-CoV epidemic in 2003, the incidence of AKI was reported to be 6.7% in 536 patients. However, the mortality rate for those with renal impairment was 91.7%, as opposed to 8.8% in those without renal impairment.
      • Chu KH
      • Tsang WK
      • Tang CS
      • et al.
      Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.
      According to retrospective studies in China, the prevalence of AKI was around 3% in hospitalized SARS-CoV-2 patients that increased to 29% in those who are critically ill.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      Cheng and colleagues assessed 701 SARS-CoV-2 hospitalized patients in China, and they observed that the incidence of AKI was 5% but significantly doubled to 12% in those with a history of chronic kidney disease (CKD).
      • Cheng Y
      • Luo R
      • Wang K
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      Among those with CKD, their in-hospital mortality increased by up to 34% from 13% in those without a history of renal impairment. A study of 28-day mortality after ICU admission among 52 SARS-CoV-2 patients by Yang and colleagues showed that the prevalence of AKI was 38% among non-survivors compared to 15% among survivors.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      A multi-centered study by Li and colleagues demonstrated that SARS-CoV-2 patients who developed AKI had a 5.3-fold increase in mortality compared to those without AKI.

      Li Z, Wu M, Yao J, et al. Caution on Kidney Dysfunctions of COVID-19 Patients.:25.

      Studies by Yang and Li further demonstrated that AKI was the 2nd most common cause of death behind ARDS in critically ill SARS-CoV-2 patients.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      ,

      Li Z, Wu M, Yao J, et al. Caution on Kidney Dysfunctions of COVID-19 Patients.:25.

      The findings of these studies supports our suspicion that AKI is an emerging cause of morbidity and mortality in SARS-CoV-2 in a similar fashion as ARDS.

      The Association Between Severe Acute Respiratory Syndrome Coronavirus 2 and Angiotensin-Converting Enzyme 2 Receptors

      The renin-angiotensin-aldosterone system (RAAS) is an elegant cascade of vasoactive peptides that mastermind key processes in human physiology. SARS-CoV-2 interface with RAAS and cause infections similar to other coronaviruses such as SARS-CoV by exploiting the same membrane-bound protein of angiotensin-converting enzyme 2 (ACE2) receptor.
      • Hamming I
      • Timens W
      • Bulthuis M
      • Lely A
      • Navis G
      • van Goor H
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ,
      • Li W
      • Moore MJ
      • Vasilieva N
      • et al.
      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
      The transmission of SARS-CoV-2 is commonly in the form of aerosolized droplets and direct contact with respiratory secretions.
      • Jia HP
      • Look DC
      • Shi L
      • et al.
      ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia.
      ,
      • Zhou P
      • Yang X-L
      • Wang X-G
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      The respiratory system is the primary point of entry for SARS-CoV-2 into the body as ACE2 receptors are expressed by the epithelial cells along with the nasopharyngeal, oropharyngeal, and bronchial mucosa before the virus finally settle in the lung alveoli.
      • Hamming I
      • Timens W
      • Bulthuis M
      • Lely A
      • Navis G
      • van Goor H
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ,
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      ACE2 receptor is expressed in abundance not only in the upper and lower respiratory tract but also in the heart, intestines, and epithelial apical brush borders of the proximal renal tubules, as well as podocytes but less intensity.
      • Zou X
      • Chen K
      • Zou J
      • Han P
      • Hao J
      • Han Z
      Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
      The primary function of ACE2 (membrane-bound aminopeptidase) is to convert angiotensin II (AGII) to form angiotensin 1-7 (AG1-7), which has a vasodilatory, anti-inflammatory, and natriuretic properties (Fig. 2).
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      ,
      • Santos RAS
      • Sampaio WO
      • Alzamora AC
      • et al.
      The ACE2/Angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7).
      AGII, which is a potent vasoconstricting hormone, is synthesized from angiotensin I (AGI) by angiotensin-converting enzyme (ACE). Other than its vasoconstrictive properties, AGII plays a vital role in RAAS, where it displays proinflammatory, prothrombotic, and anti-diuresis effects. AGII will also stimulate the secretion of other hormones such as aldosterone and vasopressin.
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      ,
      • Cordazzo C
      • Neri T
      • Petrini S
      • et al.
      Angiotensin II induces the generation of procoagulant microparticles by human mononuclear cells via an angiotensin type 2 receptor-mediated pathway.
      ,
      • Leisman DE
      • Deutschman CS
      • Legrand M
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      AGI is a product of angiotensinogen (amino-acid protein), that is secreted by the liver and metabolized by enzyme renin.
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      SARS-CoV-2 can binds with angiotensin-converting enzyme 2 (ACE2) receptor via spike glycoprotein on its cell membrane that allows the virus to gain access in the targeted human cells where it will intracellularly replicate and display its cytotoxic properties.
      • Lu R
      • Zhao X
      • Li J
      • et al.
      Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
      ,
      • Zhou P
      • Yang X-L
      • Wang X-G
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ,
      • Diao B
      • Wang C
      • Wang R
      • et al.
      Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
      ,
      • Fan C
      • Li K
      • Ding Y
      • Lu WL
      • Wang J
      ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-NCoV infection.
      Moreover, SARS-CoV-2 not only utilizes ACE2 to gain entry into a cell, but it will also downregulate ACE2 expression. Therefore, the level of AGII will increase due to the lack of a negative feedback mechanism involving ACE2 to degrade it into AG1-7. The elevated levels of AGII, which itself is a pro-inflammatory marker, will promote an increase in neutrophil infiltration of organs, production of cytokines, and vascular permeability, causing end-organ injuries.
      • Sodhi CP
      • Wohlford-Lenane C
      • Yamaguchi Y
      • et al.
      Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
      ,
      • Xu Z
      • Li W
      • Han J
      • et al.
      Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).
      Fig 2:
      Figure 2Flowchart of Renin-Angiotensin-Aldosterone System (RAAS) with Site of Action of ACE Inhibitors and ARBs, and SARS-CoV-2 Displayed.

      Etiology of AKI in SARS-CoV-2 Patients

      Viral Tropism

      SARS-CoV-2 was initially suspected to involve the kidneys based on reverse transcriptase-polymerase chain reaction (RT-PCR) testing of the urine that showed the presence of SARS-CoV-2 in a cohort of infected patients.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Moreover, computed tomography (CT) scan of the kidneys in SARS-CoV-2 patients has even demonstrated reduced Hounsfield density that suggests underlying inflammation with edema in patients with AKI.

      Li Z, Wu M, Yao J, et al. Caution on Kidney Dysfunctions of COVID-19 Patients.:25.

      Autopsy findings of 26 kidneys in SARS-CoV-2 patients by Su and colleagues showed diffuse proximal tubule injury with loss of brush border and frank necrosis together with vacuolar degeneration were frequently noted on light microscopy.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      Under electron microscopy, SARS-CoV-2 was seen in the tubular epithelium predominantly in the proximal tubule and podocyte. These were confirmed on immunostaining testing that showed the presence of SARS-CoV-2 nucleoprotein antibody. We know from previous studies that ACE2 is present in abundance, especially in the proximal tubule but, to a lesser extent, in the distal tubule and podocyte.
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      ,
      • Santos RAS
      • Sampaio WO
      • Alzamora AC
      • et al.
      The ACE2/Angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7).
      The preference of SARS-CoV-2 towards the kidneys is likely due to a low pH environment created by urine and pH-dependent enzyme of cysteine cathepsins (protease responsible for endosomal transport) that thrives in an acidic environment. This will facilitate the entry into the cells by endocytosis after binding occurs between ACE2 receptor and SARS-CoV-2 during periods of viremia.
      • Zumla A
      • Chan JFW
      • Azhar EI
      • Hui DSC
      • Yuen K-Y
      Coronaviruses — drug discovery and therapeutic options.
      In one observational study, around 15% of SARS-CoV-2 were found to have viremia.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Similar pathological findings were noted in the kidneys of patients infected with SARS-CoV that suggest ACE2 receptors play a crucial role in viral infiltration of cells.
      • Gu J
      • Gong E
      • Zhang B
      • et al.
      Multiple organ infection and the pathogenesis of SARS.
      Observational studies have reported that 40 to 60% of SARS-CoV-2 patients had an elevated amount of proteins in their urine.
      • Cheng Y
      • Luo R
      • Wang K
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,

      Li Z, Wu M, Yao J, et al. Caution on Kidney Dysfunctions of COVID-19 Patients.:25.

      Podocytes are involved in filtration and synthesizing aspects of the glomerular filtration barrier that prevents proteins from passing through.
      • Menzel S
      • Moeller MJ
      Role of the podocyte in proteinuria.
      The presence of SARS-CoV-2 has been seen using light and electron microscopy at the level of the podocytes where effacement of foot process and detachment from the glomerular basement membrane is observed signifying viral-related cell destruction.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      These findings explain the etiology of proteinuria found in SARS-CoV-2 patients. Other than SARS-CoV-2 causing renal impairment due to its direct cytotoxic effects on cells, SARS-CoV-2 can also trigger the innate immune system to cause indirect cell destruction to the kidneys. Diao and colleagues observed that macrophage, specifically CD68+, together with complement levels of C5b-9, were responsible for innate immune cell-related damage of the kidneys based on their autopsy findings in six SARS-CoV-2 patients.
      • Diao B
      • Wang C
      • Wang R
      • et al.
      Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
      Their report also suggested that the level of destruction was not limited to the proximal renal tubules where the virus was most commonly located at but also affected the surrounding distal tubules and podocytes. As mentioned above, SARS-CoV-2 will also downregulate the expression of ACE2 after binding to it. The level of AGII will increase due to the lack of ACE2 to degrade it. The elevated levels of AGII will promote neutrophil infiltration of the kidneys, increase vascular permeability, and release of inflammatory mediators causing AKI.
      • Sodhi CP
      • Wohlford-Lenane C
      • Yamaguchi Y
      • et al.
      Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
      ,
      • Xu Z
      • Li W
      • Han J
      • et al.
      Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).
      Collapsing glomerulopathy, also known as collapsing focal segmental glomerulosclerosis, is an aggressive and distinct variant of focal segmental glomerulosclerosis often associated with human immunodeficiency virus (HIV) infection.
      • Nasr SH
      • Kopp JB
      COVID-19–associated collapsing glomerulopathy: an emerging entity.
      However, collapsing glomerulopathy is increasingly recognized in non-HIV patients where it has been described in several case reports of SARS-CoV-2 patients of African descent as a cause of AKI.
      • Larsen CP
      • Bourne TD
      • Wilson JD
      • Saqqa O
      • Sharshir MA
      Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19).
      • Kissling S
      • Rotman S
      • Gerber C
      • et al.
      Collapsing glomerulopathy in a COVID-19 patient.
      • Peleg Y
      • Kudose S
      • D'Agati V
      • et al.
      Acute kidney injury due to collapsing glomerulopathy following COVID-19 infection.
      The hallmark of the disease is patients typically present with nephrotic syndrome range of proteinuria define as more than 3 g of proteins daily in the urine and variable degree of renal impairment. Collapsing glomerulopathy can be precipitated by direct SARS-CoV-2 insult and/or alteration to the activity of the immune system by SARS-CoV-2 similar to HIV infection resulting in damage to the glomerular epithelial cells and loss of podocytes integrity.
      • Nasr SH
      • Kopp JB
      COVID-19–associated collapsing glomerulopathy: an emerging entity.
      ,
      • Lu T-C
      • He JC
      • Wang Z-H
      • et al.
      HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein.
      ,
      • Rosenberg AZ
      • Naicker S
      • Winkler CA
      • Kopp JB
      HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.
      This will occur in patients with dysfunctional APOL1 protein. APOL1 gene of G1 and G2, which is rampant in individuals of African ancestry, has been identified as a precipitating factor for collapsing glomerulopathy.
      • Rosenberg AZ
      • Naicker S
      • Winkler CA
      • Kopp JB
      HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.
      Segmental or globally collapsed and sclerotic glomerular capillaries, with hyperplasia and hypertrophy of glomerular epithelial cells will be seen on kidney biopsy.
      • Nasr SH
      • Kopp JB
      COVID-19–associated collapsing glomerulopathy: an emerging entity.
      Therefore, SARS-CoV-2 causes AKI and proteinuria by direct viral invasion of the renal tubules through ACE2 receptors, triggers indirect cytotoxic damage of renal tubules and podocytes by the innate immune system, increases levels of AGII and by collapsing glomerulopathy (Fig. 3).
      Fig 3:
      Figure 3Pathogenesis of SARS-CoV-2 Causing AKI in The Kidneys.

      Cytokine Storm

      Many observational studies in SARS-CoV-2 patients demonstrated the presence of elevated inflammatory markers such as white blood cell (WBC) count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, lactate dehydrogenase (LDH), ferritin, and D-dimer.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      In those studies, patients with elevated inflammatory markers had a higher likelihood of developing AKI and poor outcomes. These same cohorts of patients had a higher requirement for ICU admission, vasopressor use, and mechanical ventilation. A study by Zhou and colleagues showed that elevated inflammatory markers were independently associated with poor survival and increasing incidence of AKI up to 50-fold.
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      The elevated inflammatory markers are likely representative of cytokine immune response during SARS-CoV-2 infections, where similar findings were noted during in vitro cell experiments done on other forms of coronavirus infections such as SARS and MERS during their respective outbreaks.
      • Cheung CY
      • Poon LLM
      • Ng IHY
      • et al.
      Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis.
      ,
      • Lau SKP
      • Lau CCY
      • Chan K-H
      • et al.
      Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
      High levels of proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1A (MIP-1A) have been demonstrated to play a significant role in the pathogenesis of ARDS in SARS-CoV patients.
      • Jiang Y
      • Xu J
      • Zhou C
      • et al.
      Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.
      ,
      • Cameron MJ
      • Bermejo-Martin JF
      • Danesh A
      • Muller MP
      • Kelvin DJ
      Human immunopathogenesis of severe acute respiratory syndrome (SARS).
      Cytokine storm is a form of severe systemic inflammatory response syndrome (SIRS) that can be triggered by any external stimuli such as infections from SARS-CoV-2, which causes massive recruitment of immune cells to an organ resulting in the production of a large amount of cytokines.
      • Ye Q
      • Wang B
      • Mao J
      The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
      Cytokine storm is suspected of playing a significant role in the pathogenesis of organ dysfunction and poor outcomes in SARS-CoV-2 patients. In a normal inflammatory phase, cells infected by SARS-CoV-2 will secrete inflammatory mediators (cytokines) and recruit immune cells to destroy it. Once the infected cells have contained the offending pathogens (SARS-CoV-2), the healing phase of inflammation ensues, involving tissue repair and restoration of homeostasis in the body with a reduction in the formation of inflammatory mediators and cessation of recruitment of immune cells. However, in certain circumstances, excessive, delayed, and persistent cytokine response may occur, leading to immune-related damage of not only lung tissues that the SARS-CoV-2 predominantly infects but also surrounding healthy uninfected organs such as the kidneys, heart, and liver.
      • Ye Q
      • Wang B
      • Mao J
      The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
      ,
      • Tisoncik JR
      • Korth MJ
      • Simmons CP
      • Farrar J
      • Martin TR
      • Katze MG
      Into the eye of the cytokine storm.
      Post-mortem findings by Diao and colleagues supported the notion that innate immune cells, specifically CD68+ macrophages and C5b-9 complement level, were responsible for indirect cytotoxic damage to renal tubules that had been infected by SARS-CoV-2.
      • Diao B
      • Wang C
      • Wang R
      • et al.
      Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
      Similar findings of cytokine storm-mediated AKI has been appreciated in several clinical conditions such as treatment with chimeric antigen receptor (CAR) T cell therapy in patients with hematological malignancies and thymoglobulin treatment in renal transplant patients.
      • Perazella MA
      • Shirali AC
      Nephrotoxicity of cancer immunotherapies: past, present and future.
      ,
      • Moicean AD
      • Popp AM
      • Sinescu I
      Cytokine storm has even been suggested to cause collapsing glomerulopathy due to elevated proinflammatory cytokines detected in SARS-CoV-2 patients that result in immune-directed injury to the glomeruli.
      • Nasr SH
      • Kopp JB
      COVID-19–associated collapsing glomerulopathy: an emerging entity.
      ,
      • Peleg Y
      • Kudose S
      • D'Agati V
      • et al.
      Acute kidney injury due to collapsing glomerulopathy following COVID-19 infection.

      Ischemia secondary to hypoperfusion

      AKI secondary to impaired perfusion to kidneys can be due to multiple etiologies in SARS-CoV-2. SARS-CoV-2 induced septic shock can also cause hypoxia and ischemia to the kidneys due to a decrease in blood perfusion. Septic shock is the 3rd most common cause of death in SARS-CoV-2 patients behind AHRF from ARDS and AKI, where it is the primary cause of multi-organ dysfunction.
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Zhou and colleagues also demonstrated that septic shock is commonly seen in up to 70% of non-survivors in SARS-CoV-2.
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Post-mortem findings by Su and colleagues on SARS-CoV-2 patients, where up to 62% of them developed septic shock revealed diffuse proximal tubule injury with loss of brush border, vacuolar degeneration, and frank necrosis on light microscopy.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      Acute tubular injury can be seen in either SARS-CoV-2 infiltration of cell or ischemic injury due to hypoperfusion. However, there was also diffuse erythrocyte stagnation in the peritubular and glomerular capillary loops without distinct fragmentation of erythrocytes or platelet noted on autopsy findings. In some cases, there was predominant glomerular loop occlusion by erythrocyte over peritubular capillaries. These findings favored ischemic and hypoxic injury to the kidneys from hypoperfusion over SARS-CoV-2 infiltration of the cell.
      • Basile DP
      • Anderson MD
      • Sutton TA
      Pathophysiology of acute kidney injury.
      Other than septic shock, these ischemic events can also be due to high levels of AGII in circulation. SARS-CoV-2 has been shown to downregulate ACE2 upon binding, making more AGII available. AGII has proinflammatory and potent vasoconstricting properties that will cause vasoconstriction of renal vessels that further reduce renal blood flow, causing ischemia.
      • Basile DP
      • Anderson MD
      • Sutton TA
      Pathophysiology of acute kidney injury.
      ,
      • Long DA
      • Price KL
      • Herrera-Acosta J
      • Johnson RJ
      How does angiotensin II cause renal injury?.
      In a subpopulation of patients who has CKD, especially those with diabetic and hypertensive kidney disease, the expression of ACE is upregulated, but ACE2 is downregulated in the kidney at baseline. This combination will prime a proinflammatory state in the kidneys due to an excess amount of circulating AGII produce by ACE and lack of AGII metabolize by ACE2.
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      ,
      • Batlle D
      • Soler MJ
      • Sparks MA
      • et al.
      Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology.
      Therefore, the risk of AKI increases by 1.5-fold in patients with baseline CKD in the setting of SARS-CoV-2.
      • Cheng Y
      • Luo R
      • Wang K
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.

      Lung-Kidney Cross-Talk

      Lung-kidney cross-talk is based on the similarities that both of these organs share and why a different disease that affects one organ can have repercussions on the other organ. This interaction is becoming a topic of interest due to the frequency of involvement of both organs by SARS-CoV-2. Respiratory failure can trigger AKI due to multiple etiologies such as 1) systemic hypoxia, 2) hypercapnia, 3) acute lung injury leading to SIRS, and 4) even mechanical ventilation.
      • Husain-Syed F
      • Slutsky AS
      • Ronco C
      Lung–kidney cross-talk in the critically ill patient.
      Systemic hypoxia secondary to AHRF, especially in the setting of ARDS, are potential etiologies for AKI due to ischemic injury, especially to the renal tubules in the kidneys and is associated with a poor prognosis. Yang and colleagues revealed that not only was the prevalence of ARDS (81%) higher in non-survivors compared to survivors (45%) for SARS-CoV-2, but the prevalence of AKI was increased by 2.5-fold (38%) in non-survivors compared to survivors.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      Similar results were noted in another retrospective study where parallel findings of a high prevalence of respiratory failure and AKI were observed in non-survivors compared to survivors suggesting a close correlation between the two organs.
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      The kidneys have a high rate of oxygen consumption per gram of tissue, second to that of the heart, making them susceptible to hypoxic injury.
      • Ricksten S-E
      • Bragadottir G
      • Redfors B
      Renal oxygenation in clinical acute kidney injury.
      Neurohormonal regulators such as AGII and nitric oxide are essential to maintain the balance between oxygen supply/demand and renal blood flow in the kidneys. This is lost during the state of septic shock, where renal oxygen demand increases, but oxygen supply and blood flow decrease. In acute lung injury, hypercapnia, which is common, will cause reduce perfusion to the kidney due to vasoconstriction of intrarenal vessels from activation of the sympathetic nervous system.
      • Husain-Syed F
      • Slutsky AS
      • Ronco C
      Lung–kidney cross-talk in the critically ill patient.
      Pulmonary vascular resistance will also increase that leads to right ventricular dysfunction from pulmonary hypertension and congestion of renal vessels due to decrease venous return.
      • Mekontso Dessap A
      • Charron C
      • Devaquet J
      • et al.
      Impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome.
      Acute lung injury that occurs in SARS-CoV-2 can indirectly affect other organs such as the kidney as part of lung-kidney cross-talk. As discussed previously, the levels of AGII will be increased during the early phase of the disease as ACE2 is downregulated by SARS-CoV-2 infection. AGII will induce an inflammatory SIRS response with the recruitment of immune cells and increase vascular permeability, vasoconstriction, cytokine release, activation of platelet, and endothelium, leading to injury not only to the lung but other organs as well.
      • Liu Y
      • Yang Y
      • Zhang C
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      The inflammation that occurs at the level of pulmonary vasculature will cause the release of surface-bound ACE into the interstitium (ACE shedding).
      • Atochina EN
      • Muzykantov VR
      • Al-Mehdi AB
      • Danilov SM
      • Fisher AB
      Normoxic lung ischemia/reperfusion accelerates shedding of angiotensin converting enzyme from the pulmonary endothelium.
      This will further increase the amount of circulating AGII level synthesized from AGI. ACE is known to be present in the pulmonary capillaries but also in the kidneys.
      • Mizuiri S
      ACE and ACE2 in kidney disease.
      As inflammation progresses, the levels of ACE will eventually dissipate due to more ACE consumed to form AGII but the insufficient amount produced by the pulmonary vasculature endothelium and negative feedback mechanism induced by AGII. Therefore, the upregulation of ACE2 will occur due to less AGII that is synthesized by ACE. The infection caused by SARS-CoV-2 will be augmented due to an increase in the presence of ACE2, allowing greater viral infiltration and replication to occur (Fig. 4).
      • Leisman DE
      • Deutschman CS
      • Legrand M
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      ,
      • Liu Y
      • Yang Y
      • Zhang C
      • et al.
      Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
      Multi-organ failure will follow, especially involving organs that contain abundant ACE2 such as lungs, heart, kidneys, and intestine.
      Fig 4:
      Figure 4Interaction Between SARS-CoV-2, AGII, ACE2, and ACE in Lung-Kidney-Cross-Talk.
      Furthermore, acute lung injury does not have to be precipitated by SARS-CoV-2 infection of the lung. Mechanical ventilation has been shown to alter the systemic hemodynamics and also the neurohormonal system. The use of mechanical ventilation is widespread in SARS-CoV-2 patients who are critically ill. Paradoxically, these interventions may have undesirable effects on the kidneys where mechanical ventilation is associated with a three-fold increase in the risk of developing AKI in critically ill patients.
      • van den Akker JPC
      • Egal M
      • Groeneveld ABJ
      Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis.
      Moreover, AKI is associated with mortality around 58% in those requiring mechanical ventilation.
      • Lombardi R
      • Nin N
      • Lorente JA
      • et al.
      An assessment of the acute kidney injury network creatinine-based criteria in patients submitted to mechanical ventilation.
      Ventilator-induced lung injury due to pulmonary overdistension from barotrauma and volutrauma, and atelectrauma from repetitive alveolar collapse will trigger the release of a variety of inflammatory mediators (biotrauma). These inflammatory mediators such as IL-6, IL-8, TNF-a, MCP-1, and MIP-1A will translocate into the systemic circulation due to an increase in alveolar-capillary permeability during acute lung injury. AKI will occur after exposure to these inflammatory mediators through mechanisms of leukocyte infiltration, apoptosis of mesangial, tubular and glomerular cells, endothelial dysfunction, and vasodilatation.
      • Kuiper J
      • Vaschetto R
      • Corte F
      • Plötz FB
      • Groeneveld AJ
      Bench-to-bedside review: ventilation-induced renal injury through systemic mediator release - just theory or a causal relationship?.
      Mechanical ventilation will also increase the intrathoracic pressure, pulmonary vascular resistance, and central venous pressure. This will lead to a decrease in venous return and impede right ventricular function causing renal congestion. Dilated right ventricular due to high pulmonary vascular pressure will limit left ventricular filling due to bowing of interventricular septum from right to left (ventricular interdependence) that reduce stroke volume and cardiac output.
      • Anand IS
      Cardiorenal syndrome: a cardiologist's perspective of pathophysiology.
      The rise in intrathoracic pressure and flattening of the diaphragm during mechanical ventilation will create an increase in intra-abdominal pressure and further impede venous drainage causing renal edema.
      • Verbrugge FH
      • Dupont M
      • Steels P
      • et al.
      Abdominal contributions to cardiorenal dysfunction in congestive heart failure.
      These constellations of physiologic changes will impair perfusion to the kidneys causing AKI (Fig. 5).
      Fig 5:
      Figure 5Physiologic Changes by Mechanical Ventilation Leading to Acute Renal Failure.

      Hypercoagulable/Prothrombotic State

      Several observational studies have shown a marked elevation in D-dimer levels in patients suffering from SARS-CoV-2, and up to 25% was found to have venous thromboembolism events (VTE).
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Cheng Y
      • Luo R
      • Wang K
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ,
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Cui S
      • Chen S
      • Li X
      • Liu S
      • Wang F
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      In these studies, the incidence of multi-organ dysfunction, including renal failure, was noted to be higher in those with elevated D-dimer. Autopsy findings by Su and colleagues noted that in 73% of SARS-CoV-2 patients, D-dimer was markedly elevated.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      Tang and colleagues revealed that elevated D-dimers were associated with a higher mortality rate (72% in non-survivors versus 0.6% in survivors) in SARS-CoV-2 patients.
      • Tang N
      • Li D
      • Wang X
      • Sun Z
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      D-dimer represents the end-products of fibrin clot (generated in any thrombotic state) that has been metabolized by plasmin (antithrombotic) enzyme. The high levels of D-dimer represent not only a prothrombotic state in SARS-CoV-2 but possibly disseminated intravascular coagulation (DIC) process occurring, especially in those with elevated prothrombin time and partial thromboplastin time. Therefore, suspicion exists that micro-thrombosis could potentially play a significant role in the pathogenesis of organ dysfunction in SARS-CoV-2 infections (Fig. 6).
      Fig 6:
      Figure 6Hypercoagulable/Prothrombotic State in SARS-CoV-2.
      Micro-thrombosis has been demonstrated to occur at the level of small arteries in the lungs of SARS-CoV-2 patients who died of hypoxic respiratory failure.
      • Barton LM
      • Duval EJ
      • Stroberg E
      • Ghosh S
      • Mukhopadhyay S
      COVID-19 autopsies, Oklahoma, USA.
      ,
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      The appearance of diffuse and focal segmental fibrin thrombus in the glomerular capillary loops associated with endothelial injury has been observed in autopsy reports of kidneys in SARS-CoV-2 patients.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      These findings are typically seen in thrombotic microangiopathy-related kidney disease due to complement level dysregulation.
      • Lusco MA
      • Fogo AB
      • Najafian B
      • Alpers CE
      AJKD atlas of renal pathology: thrombotic microangiopathy.
      ,
      • Joseph C
      • Gattineni J
      Complement disorders and hemolytic uremic syndrome.
      Magro and Diao have both described the presence of complements C3d, C4d, and C5b-9 together with enzymes of mannose-binding lectin (MBL) and mannose-associated serine protease (MASP2) deposition in the lungs, skin, and kidneys during post-mortem report on SARS-CoV-2 patients.
      • Diao B
      • Wang C
      • Wang R
      • et al.
      Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
      ,
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      C3d is found in the alternative complement pathway, and C4d are core components of the classical complement pathways, whereas MBL and MASP2 are essential enzymes of lectin complement pathway.
      • Merle NS
      • Church SE
      • Fremeaux-Bacchi V
      • Roumenina LT
      Complement system part I – molecular mechanisms of activation and regulation.
      ,
      • Dunkelberger JR
      • Song W-C
      Complement and its role in innate and adaptive immune responses.
      These three distinct pathways are crucial for complement pathway activation to form membrane attack complex (MAC) of C5Bb-9 complements that are likely to cause disruption of cells and micro-thrombosis seen in organs of SARS-CoV-2 patients. Both the kidneys and lungs have been shown to contain an abundance of ACE2 receptors, which SARS-CoV-2 requires to replicate and thrive. The levels of AGII will be increased in SARS-CoV-2 infection that gives rise to the release of more inflammatory mediators and the recruitment of more immune cells.
      • Leisman DE
      • Deutschman CS
      • Legrand M
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      Many of these inflammatory mediators are prothrombotic that predispose to the development of macro and micro-thrombosis. The elevated levels of circulating AGII and inflammatory mediators will activate the platelets and endothelial cells of the blood vessels to release tissue and clotting factors causing thrombosis.
      • Cordazzo C
      • Neri T
      • Petrini S
      • et al.
      Angiotensin II induces the generation of procoagulant microparticles by human mononuclear cells via an angiotensin type 2 receptor-mediated pathway.
      ,
      • Senchenkova EY
      • Russell J
      • Esmon CT
      • Granger DN
      Roles of coagulation and fibrinolysis in angiotensin II-enhanced microvascular thrombosis.
      Sepsis can create a prothrombotic state by directly and indirectly affecting coagulation factors and enzymes in our body through three possible mechanisms. 1) Sepsis-related overproduction of plasminogen activator inhibitor-1 enzyme that disrupts the function of circulating tissue plasminogen activator (antithrombotic) enzyme, which is essential to prevent thrombosis. 2) Sepsis-related downregulation of endothelial thrombomodulin proteins, which is required for activation of protein C (anticoagulation) enzyme. 3) The decrease in levels of antithrombin (anticoagulant) enzyme in sepsis due to extravasation in the setting of an increase in vascular permeability and consumption by inflammatory mediators.
      • Tang N
      • Li D
      • Wang X
      • Sun Z
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      ,
      • Iba T
      • Levy JH
      • Warkentin TE
      • et al.
      Diagnosis and management of sepsis‐induced coagulopathy and disseminated intravascular coagulation.
      The hypercoagulable state in SARS-CoV-2 can also be triggered by hypoxia that stimulates thrombosis through an increase in blood viscosity and activation of hypoxia-inducible transcription factor pathway.
      • Evans CE
      Hypoxia and HIF activation as a possible link between sepsis and thrombosis.
      This pathway will stimulate the production of integrin by platelet that allows it to combine with clotting factors and other platelets to form a thrombus. For these reasons using data from observational clinical studies, some medical institutions will recommend considering empirically anticoagulating patients with D-dimer levels of 1.5–3 mg/L and more, as it is a useful marker in predicting VTE in those with confirmed SARS-CoV-2 infections if no contraindications exist.
      • Cui S
      • Chen S
      • Li X
      • Liu S
      • Wang F
      Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
      ,
      • Thachil J
      • Tang N
      • Gando S
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID‐19.
      ,
      • Tang N
      • Bai H
      • Chen X
      • Gong J
      • Li D
      • Sun Z
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.

      Paradoxical Effect of Anti-Hypertensive of ACE inhibitors and ARBs

      Based on current epidemiological data, about 50% of SARS-CoV-2 patients suffer from comorbidities of cardiovascular disease or its related risk factors of diabetes, hypertension, and hyperlipidemia.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      The mortality rate was also significantly higher in those with cardiovascular disease-related comorbidities.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      • Yang X
      • Yu Y
      • Xu J
      • et al.
      Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
      Many patients with diabetes or cardiovascular disease are either on ACE inhibitors or ARBs due to their reno-protective properties in diabetic nephropathy, and also congestive heart failure.
      • Navis G
      • Faber HJ
      • de Zeeuw D
      • de Jong PE
      ACE inhibitors and the kidney. A risk-benefit assessment.
      ACE inhibitors and ARBs have major effects on the RAAS, which are essential components of the sympathetic nervous system. These drugs have been shown to disrupt the synthesis and action of angiotensin II (potent vasoconstrictor), decrease the production of aldosterone (anti-natriuresis), and constrict the afferent arteriolar flow in the kidneys causing hypotension, hyperkalemia, worsening renal failure and shock.
      • Schoolwerth AC
      • Sica DA
      • Ballermann BJ
      • Wilcox CS
      Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the council on the kidney in cardiovascular disease and the council for high blood pressure research of the American heart association.
      Therefore in hospitalized patients with sepsis, these medications are typically held due to the increased risk of adverse drug events.
      As ACE2 receptor protein plays a vital role in SARS-CoV-2 infection, the use of anti-hypertensive drugs such as ACE inhibitors and angiotensin-receptor 2 blockers (ARBs) have been evaluated in multiple studies. A study by Reynolds and colleagues revealed that in patients with SARS-CoV-2, there was no association that the use of ACE inhibitors and ARBs would lead to a greater risk of SARS-CoV-2 infections or developing severe illness-related to SARS-CoV-2.
      • Reynolds HR
      • Adhikari S
      • Pulgarin C
      • et al.
      Renin–Angiotensin–aldosterone system inhibitors and risk of COVID-19.
      An autopsy finding in SARS-CoV-2 patients showed that there was no evidence of alteration in ACE2 receptor expression in kidneys despite the use of ACE inhibitors.
      • Lely A
      • Hamming I
      • van Goor H
      • Navis G
      Renal ACE2 expression in human kidney disease.
      Mancia and colleagues found that the use of ACE inhibitors and ARBs was more common among those infected with SARS-CoV-2 than those who were not.
      • Mancia G
      • Rea F
      • Ludergnani M
      • Apolone G
      • Corrao G
      Renin–angiotensin–aldosterone system blockers and the risk of COVID-19.
      However, these findings were inconclusive as their observational study did not have sufficient statistical power to prove an independent association.
      Animal models of mice have revealed that ACE inhibitors and ARBs upregulate the expression of ACE2 proteins in the heart and kidneys by three to five-fold.
      • Ferrario CM
      • Jessup J
      • Chappell MC
      • et al.
      Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
      ACE inhibitors will bind with ACE and decrease the conversion of AGI to AGII, resulting in more AGII available to link with the SARS-CoV-2 instead (Fig. 1).
      • Santos RAS
      • Sampaio WO
      • Alzamora AC
      • et al.
      The ACE2/Angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7).
      ARBs will upregulate the expression of more ACE2 for SARS-CoV-2 to bind with by increasing the synthesis of ACE2 messenger ribonucleic acid (mRNA) by the cell nucleus for the ribosomes to produce ACE2 proteins.
      • Ishiyama Y
      • Gallagher PE
      • Averill DB
      • Tallant EA
      • Brosnihan KB
      • Ferrario CM
      Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors.
      ,
      • Soler MJ
      • Ye M
      • Wysocki J
      • William J
      • Lloveras J
      • Batlle D
      Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan.
      For these reasons, concerns exist that the use of these drugs will predispose to more severe SARS-CoV-2 infections in the form of septic shock and multi-organ failure, including renal failure.
      • Mehra MR
      • Desai SS
      • Kuy S
      • Henry TD
      • Patel AN
      Cardiovascular disease, drug therapy, and mortality in COVID-19.
      As the quality of evidence, has remained constricted to observational studies, the current consensus remains divided on the decision to stop the use of ACE inhibitors and ARBs in SARS-CoV-2 patients versus continuing them in light of their underlying comorbidities.

      Rhabdomyolysis

      Rhabdomyolysis is a clinical and laboratory syndrome defined as an injury to the skeletal muscle that results in the leakage of muscle contents, specifically creatine kinase (CK) and myoglobin into the blood and urine.
      • de Meijer AR
      • Fikkers BG
      • de Keijzer MH
      • van Engelen BGM
      • Drenth JPH
      Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.
      ,
      • Bosch X
      • Poch E
      • Grau JM
      Rhabdomyolysis and acute kidney injury.
      AKI is the most common end-organ damage related to rhabdomyolysis, with an incidence of up to 46% reported where electrolyte dysfunction is the most detrimental complications.
      • de Meijer AR
      • Fikkers BG
      • de Keijzer MH
      • van Engelen BGM
      • Drenth JPH
      Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.
      • Bosch X
      • Poch E
      • Grau JM
      Rhabdomyolysis and acute kidney injury.
      • Hojs R
      • Ekart R
      • Sinkovic A
      • Hojs-Fabjan T
      Rhabdomyolysis and acute renal failure in intensive care unit.
      Viral-related cause of rhabdomyolysis has been increasingly reported in the literature where influenza is the most frequent virus associated with rhabdomyolysis.
      • Singh U
      • Scheld WM
      Infectious etiologies of rhabdomyolysis: three case reports and review.
      Autopsy findings of kidneys samples of SARS-CoV-2 patients revealed the presence of hemosiderin granules in the tubular epithelium and pigmented casts on light microscopy.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      ,
      • Bosch X
      • Poch E
      • Grau JM
      Rhabdomyolysis and acute kidney injury.
      These suggest rhabdomyolysis as a potential etiology of acute renal failure. Minimum CK levels of 5,000 to 10,000 IU/L has been suggested for the development of acute renal failure.
      • de Meijer AR
      • Fikkers BG
      • de Keijzer MH
      • van Engelen BGM
      • Drenth JPH
      Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.
      ,
      • Bosch X
      • Poch E
      • Grau JM
      Rhabdomyolysis and acute kidney injury.
      ,
      • Beetham R
      Biochemical investigation of suspected rhabdomyolysis.
      The first incidence of coronavirus-related rhabdomyolysis was reported in a case series of SARS-CoV patients where they all developed AKI with peak CK levels ranging from 7,000 to 330,000 IU/L.
      • Wang J-L
      • Wang J-T
      • Yu C-J
      • et al.
      Rhabdomyolysis associated with probable SARS.
      Jin and colleagues were the first to describe a 60-year-old man admitted with SARS-CoV-2 pneumonia and subsequently developed rhabdomyolysis on day 9th of hospital admission.
      • Jin M
      • Tong Q
      Rhabdomyolysis as potential late complication associated with COVID-19.
      His peak laboratory values of CK, LDH, and CRP were markedly elevated at 12,000 IU/L, 2,347 IU/L, and 206 mg/L, respectively. Guan and colleagues reported that the prevalence of rhabdomyolysis among hospitalized SARS-CoV-2 patients in China was around 0.2%.
      • Guan W
      • Ni Z
      • Hu Y
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      The peak levels of CK documented in these patients range from 300 to 2500 IU/L. Hence, peak CK has been shown to have a weak correlation with the development of AKI in the setting of viral-associated rhabdomyolysis.
      It is currently unclear if rhabdomyolysis in SARS-CoV-2 patients is related to direct viral invasion as skeletal muscles lack the ACE2 receptors, which are crucial for SARS-CoV-2 invasion of cells. In patients infected with SARS-CoV-2, high values of CK and myoglobin were found in their serum together with marked elevation in their inflammatory markers.
      • Chen N
      • Zhou M
      • Dong X
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      ,
      • Zhang J
      • Dong X
      • Cao Y
      • et al.
      Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China.
      Chong and colleagues described a 37-year-old man diagnosed with AHRF secondary to COVID-19 pneumonia, AKI, and rhabdomyolysis. His CK on admission was 17,000 and peaked at 35,000 IU/L. His inflammatory markers of LDH (1300 IU/L), CRP (60 mg/L), D-dimer (54 mg/L), and ferritin (1100 ng/mL) were markedly elevated on admission and continued to rise during hospitalization in concordant with his declining renal function, before his demise.
      • Chong W
      • Saha B
      Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Associated with Rhabdomyolysis and Acute Kidney Injury (AKI).
      These findings suggest that the overactive immune system in SARS-CoV-2 patients is responsible for not only the development of rhabdomyolysis but also AKI as part of multi-organ dysfunction secondary to cytokine storm.
      • Chong W
      • Saha B
      Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Associated with Rhabdomyolysis and Acute Kidney Injury (AKI).
      There is still a lack of clear clinical evidence that thrombosis can occur in the skeletal muscles due to the scarcity of autopsies being performed during the SARS-CoV-2 pandemic. However, one can only presume that micro-thrombosis is likely to occur at the level of skeletal muscles causing ischemia and rhabdomyolysis from tissue hypoperfusion in a similar fashion to the lungs and kidneys.
      • Su H
      • Yang M
      • Wan C
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      ,
      • Barton LM
      • Duval EJ
      • Stroberg E
      • Ghosh S
      • Mukhopadhyay S
      COVID-19 autopsies, Oklahoma, USA.
      ,
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ,
      • Thachil J
      • Tang N
      • Gando S
      • et al.
      ISTH interim guidance on recognition and management of coagulopathy in COVID‐19.

      Conclusions

      SARS-CoV-2 is capable of causing multi-organ dysfunction through different processes. While the incidence and prevalence of AKI in SARS-CoV-2 remain underappreciated when compared to AHRF and ARDS, the significant value of recognizing and understanding the pathophysiology of AKI is extremely important to improve the outcome in SARS-CoV-2 patients. Patients with SARS-CoV-2 infections share many similarities where the precipitating factors that cause acute lung injury will also cause AKI. A good understanding of the etiology of AKI will allow more prompt diagnosis and improvement in the management of SARS-CoV-2 patients.

      References

        • Zhu N
        • Zhang D
        • Wang W
        • et al.
        A novel coronavirus from patients with pneumonia in China, 2019.
        N Engl J Med. 2020; 382: 727-733
        • Lu R
        • Zhao X
        • Li J
        • et al.
        Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
        The Lancet. 2020; 395: 565-574
        • Huang C
        • Wang Y
        • Li X
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        The Lancet. 2020; 395: 497-506
        • Guan W
        • Ni Z
        • Hu Y
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720
        • Yang X
        • Yu Y
        • Xu J
        • et al.
        Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
        Lancet Respir Med. 2020; 8: 475-481
        • Chen N
        • Zhou M
        • Dong X
        • et al.
        Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
        The Lancet. 2020; 395: 507-513
        • Chu KH
        • Tsang WK
        • Tang CS
        • et al.
        Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.
        Kidney Int. 2005; 67: 698-705
        • Cheng Y
        • Luo R
        • Wang K
        • et al.
        Kidney disease is associated with in-hospital death of patients with COVID-19.
        Kidney Int. 2020; 97: 829-838
      1. Li Z, Wu M, Yao J, et al. Caution on Kidney Dysfunctions of COVID-19 Patients.:25.

        • Hamming I
        • Timens W
        • Bulthuis M
        • Lely A
        • Navis G
        • van Goor H
        Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
        J Pathol. 2004; 203: 631-637
        • Li W
        • Moore MJ
        • Vasilieva N
        • et al.
        Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
        Nature. 2003; 426: 450-454
        • Jia HP
        • Look DC
        • Shi L
        • et al.
        ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia.
        J Virol. 2005; 79: 14614-14621
        • Zhou P
        • Yang X-L
        • Wang X-G
        • et al.
        A pneumonia outbreak associated with a new coronavirus of probable bat origin.
        Nature. 2020; 579: 270-273
        • Mizuiri S
        ACE and ACE2 in kidney disease.
        World J Nephrol. 2015; 4: 74
        • Zou X
        • Chen K
        • Zou J
        • Han P
        • Hao J
        • Han Z
        Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
        Front Med. 2020; 14: 185-192
        • Santos RAS
        • Sampaio WO
        • Alzamora AC
        • et al.
        The ACE2/Angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7).
        Physiol Rev. 2018; 98: 505-553
        • Cordazzo C
        • Neri T
        • Petrini S
        • et al.
        Angiotensin II induces the generation of procoagulant microparticles by human mononuclear cells via an angiotensin type 2 receptor-mediated pathway.
        Thromb Res. 2013; 131: e168-e174
        • Leisman DE
        • Deutschman CS
        • Legrand M
        Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
        Intensive Care Med. 2020; (Published online April 28)https://doi.org/10.1007/s00134-020-06059-6
        • Diao B
        • Wang C
        • Wang R
        • et al.
        Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
        Infectious Diseases (except HIV/AIDS), 2020https://doi.org/10.1101/2020.03.04.20031120
        • Fan C
        • Li K
        • Ding Y
        • Lu WL
        • Wang J
        ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-NCoV infection.
        Urology, 2020https://doi.org/10.1101/2020.02.12.20022418
        • Sodhi CP
        • Wohlford-Lenane C
        • Yamaguchi Y
        • et al.
        Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
        Am J Physiol Lung Cell Mol Physiol. 2018; 314: L17-L31
        • Xu Z
        • Li W
        • Han J
        • et al.
        Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).
        Sci Rep. 2017; 7: 44911
        • Su H
        • Yang M
        • Wan C
        • et al.
        Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
        Kidney Int. 2020; (Published online AprilS0085253820303690)https://doi.org/10.1016/j.kint.2020.04.003
        • Zumla A
        • Chan JFW
        • Azhar EI
        • Hui DSC
        • Yuen K-Y
        Coronaviruses — drug discovery and therapeutic options.
        Nat Rev Drug Discov. 2016; 15: 327-347
        • Gu J
        • Gong E
        • Zhang B
        • et al.
        Multiple organ infection and the pathogenesis of SARS.
        J Exp Med. 2005; 202: 415-424
        • Menzel S
        • Moeller MJ
        Role of the podocyte in proteinuria.
        Pediatr Nephrol. 2011; 26: 1775-1780
        • Nasr SH
        • Kopp JB
        COVID-19–associated collapsing glomerulopathy: an emerging entity.
        Kidney Int Rep. 2020; (Published online MayS246802492031233X)https://doi.org/10.1016/j.ekir.2020.04.030
        • Larsen CP
        • Bourne TD
        • Wilson JD
        • Saqqa O
        • Sharshir MA
        Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19).
        Kidney Int Rep. 2020; (Published online AprilS2468024920311724)https://doi.org/10.1016/j.ekir.2020.04.002
        • Kissling S
        • Rotman S
        • Gerber C
        • et al.
        Collapsing glomerulopathy in a COVID-19 patient.
        Kidney Int. 2020; (Published online AprilS0085253820303951)https://doi.org/10.1016/j.kint.2020.04.006
        • Peleg Y
        • Kudose S
        • D'Agati V
        • et al.
        Acute kidney injury due to collapsing glomerulopathy following COVID-19 infection.
        Kidney Int Rep. 2020; (Published online AprilS2468024920312195)https://doi.org/10.1016/j.ekir.2020.04.017
        • Lu T-C
        • He JC
        • Wang Z-H
        • et al.
        HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein.
        J Biol Chem. 2008; 283: 8173-8182
        • Rosenberg AZ
        • Naicker S
        • Winkler CA
        • Kopp JB
        HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatment.
        Nat Rev Nephrol. 2015; 11: 150-160
        • Zhou F
        • Yu T
        • Du R
        • et al.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        The Lancet. 2020; 395: 1054-1062
        • Cheung CY
        • Poon LLM
        • Ng IHY
        • et al.
        Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis.
        J Virol. 2005; 79: 7819-7826
        • Lau SKP
        • Lau CCY
        • Chan K-H
        • et al.
        Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
        J Gen Virol. 2013; 94: 2679-2690
        • Jiang Y
        • Xu J
        • Zhou C
        • et al.
        Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.
        Am J Respir Crit Care Med. 2005; 171: 850-857
        • Cameron MJ
        • Bermejo-Martin JF
        • Danesh A
        • Muller MP
        • Kelvin DJ
        Human immunopathogenesis of severe acute respiratory syndrome (SARS).
        Virus Res. 2008; 133: 13-19
        • Ye Q
        • Wang B
        • Mao J
        The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
        J Infect. 2020; (Published online AprilS0163445320301651)https://doi.org/10.1016/j.jinf.2020.03.037
        • Tisoncik JR
        • Korth MJ
        • Simmons CP
        • Farrar J
        • Martin TR
        • Katze MG
        Into the eye of the cytokine storm.
        Microbiol Mol Biol Rev. 2012; 76: 16-32
        • Perazella MA
        • Shirali AC
        Nephrotoxicity of cancer immunotherapies: past, present and future.
        J Am Soc Nephrol. 2018; 29: 2039-2052
        • Moicean AD
        • Popp AM
        • Sinescu I
        Thymoglobulin – new approaches to optimal outcomes. 2. 2009: 6
        • Basile DP
        • Anderson MD
        • Sutton TA
        Pathophysiology of acute kidney injury.
        in: Terjung R Comprehensive physiology. John Wiley & Sons, Inc., 2012
        • Long DA
        • Price KL
        • Herrera-Acosta J
        • Johnson RJ
        How does angiotensin II cause renal injury?.
        Hypertension. 2004; 43: 722-723
        • Batlle D
        • Soler MJ
        • Sparks MA
        • et al.
        Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology.
        J Am Soc Nephrol. 2020; 31: 1380-1383
        • Cheng Y
        • Luo R
        • Wang K
        • et al.
        Kidney disease is associated with in-hospital death of patients with COVID-19.
        Kidney Int. 2020; 97: 829-838
        • Husain-Syed F
        • Slutsky AS
        • Ronco C
        Lung–kidney cross-talk in the critically ill patient.
        Am J Respir Crit Care Med. 2016; 194: 402-414
        • Ricksten S-E
        • Bragadottir G
        • Redfors B
        Renal oxygenation in clinical acute kidney injury.
        Crit Care. 2013; 17: 21
        • Mekontso Dessap A
        • Charron C
        • Devaquet J
        • et al.
        Impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome.
        Intensive Care Med. 2009; 35: 1850-1858
        • Liu Y
        • Yang Y
        • Zhang C
        • et al.
        Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.
        Sci China Life Sci. 2020; 63: 364-374
        • Atochina EN
        • Muzykantov VR
        • Al-Mehdi AB
        • Danilov SM
        • Fisher AB
        Normoxic lung ischemia/reperfusion accelerates shedding of angiotensin converting enzyme from the pulmonary endothelium.
        Am J Respir Crit Care Med. 1997; 156: 1114-1119
        • van den Akker JPC
        • Egal M
        • Groeneveld ABJ
        Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis.
        Crit Care Lond Engl. 2013; 17: R98
        • Lombardi R
        • Nin N
        • Lorente JA
        • et al.
        An assessment of the acute kidney injury network creatinine-based criteria in patients submitted to mechanical ventilation.
        Clin J Am Soc Nephrol CJASN. 2011; 6: 1547-1555
        • Kuiper J
        • Vaschetto R
        • Corte F
        • Plötz FB
        • Groeneveld AJ
        Bench-to-bedside review: ventilation-induced renal injury through systemic mediator release - just theory or a causal relationship?.
        Crit Care. 2011; 15: 228
        • Anand IS
        Cardiorenal syndrome: a cardiologist's perspective of pathophysiology.
        Clin J Am Soc Nephrol CJASN. 2013; 8: 1800-1807
        • Verbrugge FH
        • Dupont M
        • Steels P
        • et al.
        Abdominal contributions to cardiorenal dysfunction in congestive heart failure.
        J Am Coll Cardiol. 2013; 62: 485-495
        • Cui S
        • Chen S
        • Li X
        • Liu S
        • Wang F
        Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
        J Thromb Haemost. 2020; 18: 1421-1424
        • Tang N
        • Li D
        • Wang X
        • Sun Z
        Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
        J Thromb Haemost. 2020; 18: 844-847
        • Barton LM
        • Duval EJ
        • Stroberg E
        • Ghosh S
        • Mukhopadhyay S
        COVID-19 autopsies, Oklahoma, USA.
        Am J Clin Pathol. 2020; 153: 725-733
        • Magro C
        • Mulvey JJ
        • Berlin D
        • et al.
        Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
        Transl Res. 2020; 220: 1-13
        • Lusco MA
        • Fogo AB
        • Najafian B
        • Alpers CE
        AJKD atlas of renal pathology: thrombotic microangiopathy.
        Am J Kidney Dis. 2016; 68: e33-e34
        • Joseph C
        • Gattineni J
        Complement disorders and hemolytic uremic syndrome.
        Curr Opin Pediatr. 2013; 25: 209-215
        • Merle NS
        • Church SE
        • Fremeaux-Bacchi V
        • Roumenina LT
        Complement system part I – molecular mechanisms of activation and regulation.
        Front Immunol. 2015; 6https://doi.org/10.3389/fimmu.2015.00262
        • Dunkelberger JR
        • Song W-C
        Complement and its role in innate and adaptive immune responses.
        Cell Res. 2010; 20: 34-50
        • Senchenkova EY
        • Russell J
        • Esmon CT
        • Granger DN
        Roles of coagulation and fibrinolysis in angiotensin II-enhanced microvascular thrombosis.
        Microcirculation. 2014; 21: 401-407
        • Iba T
        • Levy JH
        • Warkentin TE
        • et al.
        Diagnosis and management of sepsis‐induced coagulopathy and disseminated intravascular coagulation.
        J Thromb Haemost. 2019; 17: 1989-1994
        • Evans CE
        Hypoxia and HIF activation as a possible link between sepsis and thrombosis.
        Thromb J. 2019; 17: 16
        • Thachil J
        • Tang N
        • Gando S
        • et al.
        ISTH interim guidance on recognition and management of coagulopathy in COVID‐19.
        J Thromb Haemost. 2020; 18: 1023-1026
        • Tang N
        • Bai H
        • Chen X
        • Gong J
        • Li D
        • Sun Z
        Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
        J Thromb Haemost. 2020; 18: 1094-1099
        • Navis G
        • Faber HJ
        • de Zeeuw D
        • de Jong PE
        ACE inhibitors and the kidney. A risk-benefit assessment.
        Drug Saf. 1996; 15: 200-211
        • Schoolwerth AC
        • Sica DA
        • Ballermann BJ
        • Wilcox CS
        Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the council on the kidney in cardiovascular disease and the council for high blood pressure research of the American heart association.
        Circulation. 2001; 104: 1985-1991
        • Reynolds HR
        • Adhikari S
        • Pulgarin C
        • et al.
        Renin–Angiotensin–aldosterone system inhibitors and risk of COVID-19.
        N Engl J Med. 2020; 382: 2441-2448
        • Lely A
        • Hamming I
        • van Goor H
        • Navis G
        Renal ACE2 expression in human kidney disease.
        J Pathol. 2004; 204: 587-593
        • Mancia G
        • Rea F
        • Ludergnani M
        • Apolone G
        • Corrao G
        Renin–angiotensin–aldosterone system blockers and the risk of COVID-19.
        N Engl J Med. 2020; 382: 2431-2440
        • Ferrario CM
        • Jessup J
        • Chappell MC
        • et al.
        Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
        Circulation. 2005; 111: 2605-2610
        • Ishiyama Y
        • Gallagher PE
        • Averill DB
        • Tallant EA
        • Brosnihan KB
        • Ferrario CM
        Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors.
        Hypertension. 2004; 43: 970-976
        • Soler MJ
        • Ye M
        • Wysocki J
        • William J
        • Lloveras J
        • Batlle D
        Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan.
        Am J Physiol Renal Physiol. 2009; 296: F398-F405
        • Mehra MR
        • Desai SS
        • Kuy S
        • Henry TD
        • Patel AN
        Cardiovascular disease, drug therapy, and mortality in COVID-19.
        N Engl J Med. 2020; (Published online May 1NEJMoa2007621)https://doi.org/10.1056/NEJMoa2007621
        • de Meijer AR
        • Fikkers BG
        • de Keijzer MH
        • van Engelen BGM
        • Drenth JPH
        Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.
        Intensive Care Med. 2003; 29: 1121-1125
        • Bosch X
        • Poch E
        • Grau JM
        Rhabdomyolysis and acute kidney injury.
        N Engl J Med. 2009; 361: 62-72
        • Hojs R
        • Ekart R
        • Sinkovic A
        • Hojs-Fabjan T
        Rhabdomyolysis and acute renal failure in intensive care unit.
        Ren Fail. 1999; 21: 675-684
        • Singh U
        • Scheld WM
        Infectious etiologies of rhabdomyolysis: three case reports and review.
        Clin Infect Dis. 1996; 22: 642-649
        • Beetham R
        Biochemical investigation of suspected rhabdomyolysis.
        Ann Clin Biochem. 2000; 37: 581-587
        • Wang J-L
        • Wang J-T
        • Yu C-J
        • et al.
        Rhabdomyolysis associated with probable SARS.
        Am J Med. 2003; 115: 421-422
        • Jin M
        • Tong Q
        Rhabdomyolysis as potential late complication associated with COVID-19.
        Emerg Infect Dis J. 2020; 26https://doi.org/10.3201/eid2607.200445
        • Zhang J
        • Dong X
        • Cao Y
        • et al.
        Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China.
        Allergy. 2020; 75: 1730-1741
        • Chong W
        • Saha B
        Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Associated with Rhabdomyolysis and Acute Kidney Injury (AKI).
        Am J Med Sci. 2020; 360: 738-739