Pathophysiology of COVID-19-associated acute kidney injury

Abstract

Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.

Fig. 1. Shared pathophysiology between lung and kidney injury in COVID-19.

Coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome involves regional inflammation with the recruitment of immune cells, including macrophages, effector T cells and polymorphonuclear neutrophils. Cytokines are released locally within the lung in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) and contribute to the further recruitment of inflammatory cells and tissue damage. Secretion of interferon (IFN) from immune cells contributes to viral clearance. Neutrophil extracellular traps (NETs), released by activated neutrophils, may also contribute to the local inflammatory response, pathogen clearance and thrombosis. Acute respiratory distress syndrome likely contributes to the development of acute kidney injury through systemic processes (for example, venous congestion and decreased cardiac output as a consequence of right-sided heart failure, high levels of intrathoracic pressure and hypoxia). Increased renal interstitial pressure due to tissue oedema is also likely to contribute to tubular injury. Release of DAMPs and PAMPs into the circulation contributes to regional inflammation within the kidney, the immune response and immune-mediated thrombosis. Direct infection of kidney cells has been observed in some patients and may also contribute to local inflammation and kidney damage. Conversely, acute kidney injury in other settings has been shown to contribute to promoting lung injury by stimulating regional inflammation, lung capillary permeability and fluid overload. DC, dendritic cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 2. Different stages of COVID-19-associated acute kidney injury.

Proteinuria and/or haematuria is indicative of kidney injury, even in the absence of a rise in serum creatinine (SCr) level or a drop in glomerular filtration rate (GFR). Further injury is associated with a drop in GFR and rise in SCr. Underlying chronic kidney disease or factors such as ageing limits the baseline functional reserve and can precipitate the development of acute kidney injury (AKI). Kidney replacement therapy (KRT) is required for severe cases of AKI. COVID-19, coronavirus disease 2019.