Covid-19 and kidney injury: Pathophysiology and molecular mechanisms

Abstract

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.

Keywords: SARS-CoV-2; acute kidney injury; angiotensin; bardikinin; coronovirus; proteinuria; renal injury.

FIGURE 1

SARS‐CoV‐2 and ACE2. SARS‐CoV‐2 enters into the ACE2‐expressing cells through two possible pathways. (a) It binds to the host cell membrane‐bound ACE2 via its viral spike protein. Moreover, SARS‐CoV‐2 requires the TMPRSS2 (cellular serine protease) for cleavage of it's spike protein and supporting its cell entry. (b) Internalization of the virus can also occur through endocytosis and the cleavage activation of the viral spike protein by cathepsin in endosomes. Virus‐induced ACE2 down regulation may reduce its anti‐inflammatory function and activate the harmful Ang II–AT1R axis and bradykinin‐BKB1R axis. These events worsen the viral pathogenicity and lead to organ damage. Viral infection and AT1R activation lead to shedding of ACE2 into a soluble form by ADAM17 and its release into the body fluids. ACE2, angiotensin converting enzyme 2; Ang II, angiotensin II; AT1R, angiotensin II receptor type 1; BKB1R, DABK/bradykinin receptor B1; DABK, bradykinin [des‐Arg973]; RAS, renin–angiotensin system; KKS, kallikrein–kinin system

FIGURE 2

Direct effects of SARS‐CoV‐2 on kidney injury. Acute renal failure is observed in Covid‐19 patients through the direct effect of the virus in kidney tubules and podocytes. The direct impact of SARS‐CoV‐2 on kidney is mediated by an ACE2 pathway that leads to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy, and mitochondrial impairment. ACE2, angiotensin converting enzyme 2

FIGURE 3

Indirect effects of SARS‐CoV‐2 on kidney injury. SARS‐CoV‐2 infects alveolar macrophages and lung epithelial cells to amplify viruses and release cytokines and chemokines. Infected dendritic cells and the activated macrophages activate immune response extensively and initiate cytokine storm in the lung. Chemokines release can attract extra inflammatory cells to migrate into the inflammation site that intensify cytokine storm and may have indirect impacts on multi‐organ failure, specially kidney, and death. Organ interaction between the damaged lung, the heart and the kidney can deteriorate the viral pathology. Numerous mechanisms including unmasked cardiovascular diseases (CAD), cytokine‐induced myocardial damage, microangiopathy and viral myocarditis may clarify the main driver of myocardial damage and/or increased levels of troponin in Covid‐19 cases. Endothelial dysfunction, microangiopathy, coagulation dysfunction are also involved in the kidney pathology in Covid‐19