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Severe Acute Respiratory Syndrome Coronavirus-2-Associated Acute Kidney Injury: A Narrative Review Focused Upon Pathophysiology

Redant, Sébastien MD; De Bels, David MD; Honoré, Patrick M. PhD

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doi: 10.1097/CCM.0000000000004889
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  • COVID-19


In 2019, an epidemic emerged in Wuhan, China. The organism was identified as a novel coronavirus and was called “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) (1), with the resultant disease named “ coronavirus disease 2019 (COVID-19).” SARS-CoV and Middle East respiratory syndrome (MERS)-CoV have infected more than 10,000 people in the last 20 years (2). SARS-CoV-2 is more contagious than the previous coronaviruses and has become pandemic (2). SARS-CoV-2 has been shown to affect multiple organ systems, including the kidney (3).

In a prospective cohort study of 701 COVID patients, serum creatinine (SC) and blood urea nitrogen (BUN) were increased at admission in 14.4% and 13.1% of patients respectively (4). Multivariate analysis revealed that proteinuria of any degree, hematuria of any degree, elevated baseline BUN, peak SC, and acute kidney injury (AKI) over stage 2 were all associated with inhospital death (4). SARS-CoV-2 has been found in the urine of infected patients (2,5).

AKI prevalence in intensive care (IC) is generally between 20% and 50% with a mortality of up to 50% (6). Several meta-analysis showed an AKI prevalence of 8.9% (4.6–14.5) (7). A second meta-analysis reported a prevalence of 36.4% in COVID-19 patients in IC (8). Some studies reported a prevalence of 85% (8). The problem is not only in the higher prevalence but even more so in the associated mortality rate, which has been reported to be up to 93% (9). The COVID-19 AKI is not clearly defined in the literature and appears to be multifactorial.


Direct Viral Toxicity

SARS-CoV-2 spike (S) protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor, employing cellular transmembrane serine proteases (TMPRSSs) for priming (10,11). When the virus binds to the ACE2 receptor, protein S is activated and cleaved by the TMPRSSs, allowing endocytosis of the SARS-CoV-2 (11,12). A study of 15 normal kidney samples analyzed the proportions of renal cells expressing both the ACE2 receptor and the protease TMPRSSs (11,12). The ACE2 and TMPRSSs genes were found to be coexpressed by the podocyte and the proximal tubules (11).

Between 20% and 70% of patients admitted to IC for MERS-CoV infection needed renal replacement therapy (13). MERS-CoV infection of kidney has been demonstrated via detection of viral protein in renal tubular cells and podocytes (14). Recent experimental studies have identified the podocyte as the predominant injury cell in glomerular diseases typified by heavy proteinuria, which is one of the main features of SARS-CoV-2 (4,15).

Postmortem examination has demonstrated the SARS-CoV-2 infection also induces infiltration of the tubulointerstitium by macrophages and enhances complement deposition on tubules (14). The kidney therefore seems to be directly attacked by COVID-19. Although these data cannot confirm that these findings are present in all cases, it demonstrates potential mechanisms contributing to AKI.

Cytokine Storm

Cytokine profiles showed interferon-gamma (IFN-γ) and interleukin (IL)-1, IL-6, and IL-12 elevation for 2 weeks after disease onset, without elevation of antiinflammatory cytokines IL-10, IL-2, and IL-4 (16). In vitro studies have shown increased sensitivity of lung cells to IFN-γ (17). Similarly, IFN-γ is known to cause renal cell apoptosis (18,19). The cytokine storm phenomenon is also implicated in the AKI etiology in other contexts such as postcardiac surgery AKI following cardiopulmonary bypass (20). Th2-type reaction is expressed with the secretion of IL-4 and IL-10 (21,22). It has yet to be determined whether the “cytokine storm”-induced systemic inflammatory response or a virus-induced cytotoxic effect, or perhaps a combination of the two, may be the cause of AKI (11). IL-6 levels in patients are 10–40 times lower than those previously reported in acute respiratory distress syndrome (ARDS) (23). Given that the mortality rate from COVID-19 ARDS is up to 50% (24,25), lower cytokine level compared with ARDS does not equate to lower pathogenicity. The inflammatory response is probably not the main cause of AKI but may contribute to it. A score combining admission levels of three cytokines has been reported to predict accurately COVID-19 severity and the need for IC (21).

Lung-Kidney Interaction

An interaction exists between AKI and ventilatory support given to ARDS patients. In the cases of SARS-CoV-2, multiple organ failure (MOF) is more likely to be responsible for AKI than the virus itself (26). In a randomized study comparing 37 patients with non-COVID ARDS assigned to receive either a “lung-protective” or conventional ventilation, the control group had significantly higher mediator concentrations in plasma and in bronchoalveolar lavage (27). The right ventricle badly tolerates high-positive end-expiratory pressure (PEEP) for ARDS. In severe ARDS, prone positioning is an efficient means of controlling right ventricular pressure (28). The interaction between mechanical ventilation and AKI, while not specific to COVID-19, plays an role in AKI pathogenesis.

Heart-Kidney Interaction

A recent study has analyzed RNA sequencing and constructed a risk map indicating the vulnerability of different organs to SARS-CoV-2, based on ACE2 receptors (3). The proportion of lung cells expressing the ACE2 receptor is about 2%. This proportion increases to 4% for the proximal tubule and up to 7.5% for myocardial cells. This could explain that in the case of viremia, that kidneys and heart could be affected in a significant way (3). A cohort study of 416 COVID-19 patients showed that SC was significantly higher in cardiac injury patients (29). This is consistent with type 5 cardiorenal syndrome, which is characterized by the combined presence of acute heart and AKI due to a systemic disorder (30). In the case of right heart decompensation, the engorgement of the venous system induces renal congestion leading to AKI (31). Heart-kidney interactions are not specific to severe COVID-19 and can also be seen in sepsis.

Autopsy show nonspecific cardiac lesions, indicating preexisting pathology, myocardial infarction, and sudden death (32,33). Patients with chronic heart failure may become unstable in the presence of viral infection because of the imbalance between the patient’s low myocardial reserve and the increased metabolic demand due to infection (34). This imbalance increases the risk of acute coronary syndrome, cardiac decompensation, and sudden death (34).

Acute myocarditis has been reported in the literature. In a case series of 14 autopsies, one patient was found to have lymphocyte infiltration surrounding myocyte necrosis but with negative SARS-CoV-2 S protein (32). The same type of lesion has been reported in another case report, again with the absence of the viral genome (35). In another case of a COVID-19 cardiogenic shock, endomyocardial biopsy demonstrated interstitial and myocardial inflammation (36). A third case report described a case of myocarditis with diffuse ST-segment elevation, increased cardiac enzyme, severe left ventricular dysfunction, and a pericardial effusion without prior respiratory symptoms but who tested positive for SARS-CoV-2 (37). These cases confirm that acute myocarditis is a mechanism of myocardial injury in some COVID-19 and demonstrate that SARS-CoV-2 may be present in the heart but without evidence for cardiotropic viral cell entry (38).


A case series of 63 influenza patients reported a prevalence of 9.5% (39). Influenza and HIV are the most common viruses associated with rhabdomyolysis (40). The supposed mechanisms are a direct muscle invasion proven by biopsies (41,42). A rhabdomyolysis case report with elevation of creatine kinase (CK) beyond 10,000 international units (IU)/L has been reported in association with SARS-CoV-2 (43). Myoglobin released can cause intrarenal vasoconstriction, direct and ischemic tubular injury, and tubular obstruction (44). A CK peak greater than 12,750 IU/L is associated with AKI with an odds ratio of 4.9 in non-COVID patients (45). One-third of the patients hospitalized in Wuhan had myalgia (46). On a larger scale, 15% of patients in China had myalgia (47).

Thrombotic Microangiopathy and Endothelialitis

COVID-19 patients have a coagulation disorder leading to a procoagulant state (48). A study compared 94 COVID-19 patients with a control group of 40 patients. They found values of antithrombin and prothrombin time (PT) activity lower in COVID-19, whereas the values of d-dimer, fibrinogen, and fibrin/fibrinogen-degradation products (FDPs) were higher in COVID-19 patients. No differences could be observed regarding activated partial thromboplastin time (aPTT), PT, international normalized ratio, and thrombin time between the two groups (49). A retrospective study of 183 COVID-19 patients showed differences in terms of coagulation between survivors and nonsurvivors (50). The overall mortality was 11.5%. The nonsurvivors had significantly higher d-dimer and FDP levels, longer PT, and aPTT. In addition, 71.4% of nonsurvivors met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Increasing d-dimer values and PT support the idea that DIC may be common in COVID-19 (51).

DIC and endothelial dysfunction are conditions that can lead to thrombotic microangiopathy. Cases of thrombotic microangiopathy have been reported in association with a wide range of infections and one of the sequelae is AKI (52).

Viral elements have been found within endothelial cells. These lesions were visible in the lungs but also in the small intestine and the kidney (53). The hypoxic state results in an increase in inflammation, such as hypoxia-inducible factor and nuclear factor-κB (54,55). The actions of those factors can lead to endothelial cell apoptosis (56,57).

The lesions of endothelialitis, thrombosis, and angiogenesis exist in infections other than COVID-19 (e.g., influenza). Pulmonary autopsies from seven patients who died from COVID-19 have been compared with seven patients who died from influenza A ARDS (58). Alveolar capillary microthrombi were nine times as prevalent in patients with COVID-19 than in patients with influenza. An autopsy of 80 COVID-19 patients found severe lesions of kidney arteriolosclerosis (33). Thrombotic microangiopathy and endothelialitis may be AKI-triggering factors that are more specific to SARS-CoV-2.

Antiinfectious Agents

Commonly used antibiotics in COVID-19 including beta lactams are nephrotoxic (59). Beta-lactams can produce structural damage and proximal tubular necrosis in rabbits within 24 hours (59). Several mechanisms are responsible for tubular injury, including the ability of beta-lactams to accumulate in proximal tubules (59). A combination of the tubular toxicity of SARS-CoV-2 and beta-lactams could induce AKI. After IV administration of cidofovir and adefovir, a renal excretion of 35% and 60%, respectively, is seen, and these drugs have been shown to accumulate in proximal tubules (59). Dose-limiting nephrotoxicity can be observed in nearly 15% of cases (60). Renal-related side effects reported in patients with antiviral agents induce AKI, diabetes insipidus, and tubular dysfunction (59,60). Nephrotoxicity tends to occur in patients with prescribed concomitant nephrotoxic agents (60). An AKI high rate (38.8% of ICU patients) was observed in a small prospective study of compassionate use of remdesivir (61). AKI was the most frequent reason leading to treatment discontinuation (61). Subsequently, a large multicenter, randomized, controlled study did not show a greater AKI prevalence associated with the use of remdesivir (62). A similar study of lopinavir-ritonavir showed no more AKI in the treatment group (63). So far, the antivirals prescribed in COVID-19 have no proven renal toxicity to date.


Is AKI Secondary to COVID-19 or Hypoxia?

Controversy exists regarding whether COVID-19 is specifically associated with AKI. A study on 138 patients showed an SC of 0.8 mg/dL (46). Another retrospective study from 1,099 COVID patients showed a prevalence of SC higher than 1.5 mg/dL of 1.6% (47). This study did not report the patients’ number in whom basal creatinine level increased by 1.5 times or 0.3 mg/dL, which in itself already constitutes AKI KDIGO class 1 (64). Nevertheless, these two studies led some authors to say that coronavirus infection does not cause AKI (65). These authors, in their own series of 116 patients, reported an elevation in creatinine in 12 of the patients (10.8%). This study has the merit of calling into question the hypothesis that AKI is a common consequence of SARS-CoV-2 infection, but does not exclude the possibility of other mechanisms such as lesions secondary to hypoxemia (64).

Direct Virus Nephrotoxicity or Indirect via MOF?

Unlike AKI seen in association with SARS-CoV, which was believed to be related to MOF, in SARS-CoV-2, the viral capsid nucleus was examined postmortem in the kidney and SARS-CoV-2 antigens accumulated in the renal tubules, suggesting that SARS-CoV-2 directly infects the kidney (66). It was found mainly in the proximal tubules and podocytes and in an amount 100 times greater than that in the lungs (66). An autopsy study in 26 COVID patients showed evidence of acute tubular injury and virus-like particles in six of 26 autopsies, and SARS-CoV nucleoproteins by immunofluorescence in 3/26 autopsies (67). The authors concluded that these findings were evidence for direct viral infection of tubular epithelial cells and podocytes (68). However, transmission electron microscopy can only suggest the presence of SARS-CoV-2, and Immuno-Electron Microscopy using specific SARS-CoV-2 antigen should be used to confirm SARS-CoV-2 infection (68). In another report, a kidney biopsy in a COVID-19 patient who developed nephrotic syndrome showed focal segmental glomerulosclerosis and acute tubular necrosis and the electron microscopy showed vacuoles containing numerous spherical particles that authors claim may correspond to viral inclusion bodies, even though the polymerase chain reaction for SARS-CoV-2 was negative (69,70). Miller and Brealey (71) and Calomeni et al (72) questioned these findings and expressed concerns, suggesting that these purported virus-like particles were not viral particles, but rather normal cell organelles (73).

COVID-19-Associated Coagulopathy: Direct Effect or Not?

COVID-19-associated coagulopathy has been widely reported to induce hypoxia, and DIC resulting from severe inflammation is a potential mechanism (74). Siguret et al (74) reported antiphospholipid antibodies in 12% of COVID patients. Researchers have suggested a high prevalence of thrombotic events in the inferior vena cava, which was noted in mice treated with the IgG of COVID patients (74, 75). Therefore, it looks more like an indirect effect of coagulopathy, which is more specific to COVID (74). Other studies have shown that COVID-19 ARDS patients have high rates of severe thromboembolic complications and endothelialitis despite anticoagulation (74–76). Indeed, fibrin thrombi in the glomerular capillary loops with associated endothelial damage have been observed. Present data show that endothelial dysfunction is a risk factor for COVID-19 coagulopathy, characterized by high d-dimer levels and microvascular damage.

AKI Due to Heart Failure or Not?

SARS-CoV-2 AKI is consistent with type 5 cardiorenal syndrome, which is characterized by the combined presence of acute heart and AKI due to a systemic disorder (30). However, in a recent case-control study, it was demonstrated that both renal macro- and microvascular flows are significantly reduced in AKI COVID-19 patients and are independent of the changes in cardiac output or right ventricular function (58). A renal microvascular pathogenesis for COVID-19 AKI is a plausible hypothesis (58).


AKI management in COVID-19 patients is supportive (75). There are few specific therapies, and no evidence to suggest that AKI in COVID-19 patients should be managed differently to AKI of other etiologies (75). As such, management should follow current consensus recommendations for AKI. In all patients, the aim should be to achieve and maintain euvolemia and, where there is volume depletion, this may be corrected through IV fluid therapy. In IC, this may be better managed with dynamic hemodynamic assessment, which reduces the risk of AKI and respiratory failure (76–78). When respiratory support is needed in patients with severe COVID-19 ARDS, a lung-protective mechanical ventilation should be used (75). PEEP levels should be individualized, minimizing excessive pressures, as this may result in high systemic venous pressure and a reduction in kidney perfusion and subsequently glomerular filtration (79). The use of proning techniques does not seem to affect AKI risk (76). Overall, there are no specific strategies in the treatment of COVID-19 AKI.


Although the temporality of injury is not specific to SARS-CoV-2 AKI, it is an important factor to note. A large cohort study of patients with sepsis due to community-acquired pneumonia has previously demonstrated that the cytokine storm may be present prior to admission to the hospital (80). Cytokine levels seen in patients with COVID-19 have been consistent with this finding and the proinflammatory state is present early in the course (20).The procoagulant state also appears only later (81). Direct toxicity on the heart is not evident at admission and may present later (28). Renal toxicity is found on autopsy, biopsy, and experimental models, and therefore not exclusively with immediate presentation (4,14,15,20,46), as illustrated in Figure 1.

Figure 1.
Figure 1.:
Model of timeline of appearance of different mechanisms of renal injury.


COVID-19 AKI is likely to be of multifactorial origin. In addition, the temporality of injury is an important consideration: different factors hit the kidney at different moments. Some insults occur prior to presentation, whereas others can take place at various stages during the course of hospital admission. Accordingly, identifying the timing and severity of disease is fundamental to ensuring the delivery of the appropriate, personalized treatment to each patient. Temporality of injury in COVID-19 AKI remains a hypothesis and is not specific to the disease. At this time, there is also no clear evidence that the pathophysiology or management is specific for COVID-19 AKI. More studies are needed to explore further the different mechanisms of AKI occurring as a result of SARS-CoV-2.


We thank Dr. Melissa Jackson for her critical review of the article.


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acute kidney injury; coronavirus disease 2019; critically ill patients; pathophysiology

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