Kidney Injury in COVID-19: Epidemiology, Molecular Mechanisms and Potential Therapeutic Targets

Abstract

As of December 2021, SARS-CoV-2 had caused over 250 million infections and 5 million deaths worldwide. Furthermore, despite the development of highly effective vaccines, novel variants of SARS-CoV-2 continue to sustain the pandemic, and the search for effective therapies for COVID-19 remains as urgent as ever. Though the primary manifestation of COVID-19 is pneumonia, the disease can affect multiple organs, including the kidneys, with acute kidney injury (AKI) being among the most common extrapulmonary manifestations of severe COVID-19. In this article, we start by reflecting on the epidemiology of kidney disease in COVID-19, which overwhelmingly demonstrates that AKI is common in COVID-19 and is strongly associated with poor outcomes. We also present emerging data showing that COVID-19 may result in long-term renal impairment and delve into the ongoing debate about whether AKI in COVID-19 is mediated by direct viral injury. Next, we focus on the molecular pathogenesis of SARS-CoV-2 infection by both reviewing previously published data and presenting some novel data on the mechanisms of cellular viral entry. Finally, we relate these molecular mechanisms to a series of therapies currently under investigation and propose additional novel therapeutic targets for COVID-19.

Long-Term Sequelae of COVID-19 in Experimental Mice

“…While studies on various tissues from people who died of COVID-19 provide evidence of pathological changes in the acute phase, there is limited evidence available on the long-term effects of SARS-CoV-2 infection. Recent reports indicate that patients who survived after acute severe SARS-CoV-2 infection experience breathing difficulties [ 33 ], heart problems (inflammation of the heart muscle and increased heart rate, [ 34 ], and damage to the kidney [ 35 ], suggesting the possible lifelong defects in multiple organs post-SARS-CoV-2 infection. Therefore, we examined the long-term sequelae of COVID-19 using the MHV-1 mouse model of COVID-19, which we have established [ 1 , 8 – 10 ].…”

A Prospective Study on Risk Factors for Acute Kidney Injury and All-Cause Mortality in Hospitalized COVID-19 Patients From Tehran (Iran)

“…Furthermore, ACE-2 and TMPRSS2 are highly expressed in proximal tubules, where SARS-CoV-2 particles could be detected postmortem in the respective podocytes from COVID-19 patients ( 40 ), hinting that the novel coronavirus can directly target the kidneys ( 7 , 10 , 34 , 41 ). Experimental and epidemiological studies evidenced that SARS-CoV-2 can infect and damage target renal epithelial cells expressing ACE-2 and TMPRSS2, triggering a cytokine storm (sustained especially by IL-6 and interferon) and directly causing AKI by increasing vascular permeability, shock, and multiorgan failure or aggravating/perpetuating a kidney injury already initiated by non-viral processes ( 37 , 38 , 42 ). Less frequent autoptic findings include micro-angiopathy and collapsing glomerulopathy ( 40 ), a frequent cause of proteinuria rapidly progressing to kidney failure ( 43 – 45 ), which predominantly affect patients with homozygous apolipoprotein L1 (APOL-1) high-risk alleles ( 45 – 46 ).…”

“…AKI is reportedly a frequent pattern in patients dying from COVID-19 (15,(35)(36)(37)(38), with acute tubular injury being the most common morpho-pathologic finding in kidney autopsies (37)(38)(39). Furthermore, ACE-2 and TMPRSS2 are highly expressed in proximal tubules, where SARS-CoV-2 particles could be detected postmortem in the respective podocytes from COVID-19 patients (40), hinting that the novel coronavirus can directly target the kidneys (7,10,34,41).…”

Akute Nierenschädigung und COVID-19: pulmorenaler Crosstalk unter massiver Inflammation

“…Seit nunmehr 2 Jahren bestimmen das „severe acute respiratory syndrome coronavirus type 2“ (SARS-CoV-2) und die Coronaviruserkrankung 2019 (COVID-19) weltweit das Geschehen in Krankenhäusern und Intensivstationen. Neben der Lunge scheint auch die Niere vor allem bei schweren COVID-19-Verläufen besonders betroffen zu sein [ 57 ].…”

“…Dabei ist es zielführend, zwischen direkten und indirekten Faktoren zu unterscheiden. Während unter direkten Faktoren die Wirkung der SARS-CoV-2-Infektion auf die Niere selbst zu verstehen ist, beinhalten indirekte Faktoren alle Folgen der durch COVID-19 verursachten Erkrankung und – insbesondere auf der Intensivstation – auch deren Behandlung [ 57 ].…”