Acute kidney injury in critically ill patients with COVID-19

Abstract

Acute kidney injury (AKI) has been reported in up to 25% of critically-ill patients with SARS-CoV-2 infection, especially in those with underlying comorbidities. AKI is associated with high mortality rates in this setting, especially when renal replacement therapy is required. Several studies have highlighted changes in urinary sediment, including proteinuria and hematuria, and evidence of urinary SARS-CoV-2 excretion, suggesting the presence of a renal reservoir for the virus. The pathophysiology of COVID-19 associated AKI could be related to unspecific mechanisms but also to COVID-specific mechanisms such as direct cellular injury resulting from viral entry through the receptor (ACE2) which is highly expressed in the kidney, an imbalanced renin-angotensin-aldosteron system, pro-inflammatory cytokines elicited by the viral infection and thrombotic events. Non-specific mechanisms include haemodynamic alterations, right heart failure, high levels of PEEP in patients requiring mechanical ventilation, hypovolemia, administration of nephrotoxic drugs and nosocomial sepsis. To date, there is no specific treatment for COVID-19 induced AKI. A number of investigational agents are being explored for antiviral/immunomodulatory treatment of COVID-19 and their impact on AKI is still unknown. Indications, timing and modalities of renal replacement therapy currently rely on non-specific data focusing on patients with sepsis. Further studies focusing on AKI in COVID-19 patients are urgently warranted in order to predict the risk of AKI, to identify the exact mechanisms of renal injury and to suggest targeted interventions.

Keywords: Acute kidney injury; COVID-19; Intensive care unit; Renin–angiotensin–aldosterone system.

Fig. 1

AKI incidence in hospitalized patients with COVID-19 infection. Forestplot showing incidence of AKI in patients with COVID-19 infection. The square indicates the proportion of patients in each study. The vertical dashed line indicates the population mean (all datasets combined) and the blue diamond the 95% CI around that mean

Fig. 2

AKI incidence in ICU in patients with COVID-19 infection. Forestplot showing incidence of AKI in critically ill patients with COVID 19 infection. The square indicates the proportion of patients in each study. The vertical dashed line indicates the population mean (all datasets combined) and the blue diamond the 95% CI around that mean

Fig. 3

Mechanisms of acute kidney injury (AKI) during severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection. SARS-CoV-2 can penetrate proximal tubule cells by linking with ACE2 and CD147, as well as in the podocytes, by linking with ACE2. Virus entry may be responsible for podocyte dysfunction, leading to glomerular diseases such as focal segmental glomerulosclerosis (FSGS), and acute proximal tubular injury leading to tubular necrosis. SARS-CoV-2 is responsible for an imbalanced RAAS activation that promotes glomerular dysfunction, fibrosis, vasoconstriction and inflammation. SARS-CoV-2 infection also triggers coagulation activation, leading to kidney vascular injury such as ischemic glomeruli and fibrinoid necrosis. Glomerular capillaries obstruction by red blood cells has also been reported during SARS-CoV-2 infection. The elevation of cytokines induced by severe SARS-CoV-2 infection may also participate to the genesis of AKI. Finally, unspecific factors relative to intensive care unit (ICU) management may aggravate kidney injury. TNF-α, tumor necrosis factor alpha; IL-6, interleukine 6; IL-1β, interleukin 1; MCP1, monocyte chemoattractant protein 1; ACE2, angiotensin-converting enzyme 2; FSGS, focal segmental glomerulosclerosis; RAAS, renin–angiotensin–aldosterone system; PEEP, positive end-expiratory pressure; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ICU, intensive care unit

Fig. 4

Role of ACE2 and renin–angiotensin–aldosterone system (RAAS) during SARS-CoV-2 infection. Angiotensinogen is converted into angiotensin I by renin and then into angiotensin II (also known as angiotensin (1–8)) by ACE. Angiotensin II, through its binding to AT1R, is responsible for the deleterious effects of RAAS activation (i.e., fibrosis, inflammation, vasoconstriction). ACE2 counteracts deleterious effects of RAAS activation by converting angiotensin I into angiotensin (1–9) and angiotensin II into angiotensin 1–7 that binds to Mas receptor and exerts anti-inflammatory and vasodilatory effects. SARS-CoV-2 binds to membrane-bound ACE2 and invades the cell membrane by endocytosis thus reducing levels of membrane-bound ACE2. Cell invasion depends on ACE2 expression and also on the presence of the protease TMPRSS2, that is able to cleave the viral spike. Diminution of ACE2 results in an accumulation of angiotensin II that is responsible for overactivation of RAAS, leading to increased inflammation, fibrosis, vasoconstriction. Circulating ACE2 could act as a decoy and bind to SARS-CoV-2, thereby preventing internalization of membrane-bound ACE2 by SARS-CoV-2. Under physiological conditions, ACE2 is linked to AT1R, forming a complex that prevents degradation of membrane-bound ACE2 through lysozome internalization. Angiotensin II links to AT1R and decreases the interaction between ACE2 and AT1R, inducing ubiquitination and internalization of ACE2. ARB may increase membrane-bound ACE2 availability by preventing its internalization. However, as the virus requires membrane-bound ACE2 internalization to penetrate the cell, ARB may also decrease the susceptibility to the virus by preventing from virus-ACE2 internalization. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RAAS, renin–angiotensin–aldosterone system; ACE, angiotensin-converting enzyme; ATII, angiotensin II; AT1R, angiotensin receptor type I; ACE2, angiotensin-converting enzyme 2; Mas-R, Mas receptor; ARB, angiotensin receptor blocker; TMPRSS2, transmembrane protease, serine 2