Targeting acute kidney injury in COVID-19

Abstract

As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid-base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia-reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

Keywords: AKI; COVID-19; mitochondria; mortality; sepsis.

FIGURE 1

Mechanisms of AKI in patients with COVID-19. Clockwise from the upper left corner: Lung injury releases DAMPs into circulation that are filtered at the glomerulus and bind with pattern recognition receptors on tubular epithelial cells. DAMPs also cause systemic inflammation which injures kidneys and other organs. Potentially nephrotoxic medications are commonly used in critically ill patients. Heart involvement is rare in COVID-19 but can have devastating effects on all organs including the kidney. High right heart pressures can occur from left heart failure but also from high positive end-expiratory pressures on mechanical ventilation. Direct viral infection of renal tubular epithelial cells has been reported. Genetic factors likely modify risk and disease presentation. Genetic variation in ACE receptor expression is one factor but also the APOL1 genotype is a known genetic risk factor for collapsing glomerulopathy that has been reported in some series. In a subset of patients with COVID-19, macrophage activation syndrome may occur resulting in uncontrolled inflammation and multiple organ failure. Mitochondrial damage and dysfunction can result from direct or indirect injury to the kidney. Rhabdomyolysis has been reported in some series resulting in AKI. Finally, endothelial damage and dysfunction appear commonly in COVID-19. Interestingly, disseminated intravascular coagulation is atypical and platelet counts remain normal in most patients suggesting that the kidney is not being damaged by thrombotic microagiopathy.