The Good Treatment, the Bad Virus, and the Ugly Inflammation: Pathophysiology of Kidney Involvement During COVID-19

Abstract

Kidney involvement is a common complication during SARS-CoV-2 infection. Its association with poor outcomes, especially in critically ill patients, raises issues whether kidney involvement reflects multi-organ damage or if it is a specific feature of the infection. Based on observational studies, autopsy series, and on current understanding of the route of entry of the virus, this review will highlight the different types of kidney involvement during COVID-19 and put them in the perspective of the different pathophysiological hypotheses. Virus entry route through ACE2 ligation and TMPRSS2 coligation allows identifying potential viral targets in the kidney, including tubules, endothelial cells, and glomerulus. While reports have described damages of all these structures and virus kidney tropism has been identified in renal extracts in autopsy series, no direct viral infection has been found in the latter structures thus far on kidney biopsies. Notwithstanding the technical challenge of disclosing viral invasion within tissues and cells, viral direct cytopathogenic effect generally does not appear as the cause of the observed renal damage. Inflammation and altered hemodynamics, described as "viral sepsis," might rather be responsible for organ dysfunction, including kidneys. We shall place these various mechanisms into an integrated vision where the synergy between direct viral pathogenicity and systemic inflammation enhances renal damage. As SARS-CoV-2 inexorably continues its rampant spread, understanding the sequence of events in the kidneys might thus help inform improved therapeutic strategies, including antiviral drugs and immunomodulators.

Keywords: AKI (acute kidney injury); COVID; COVID–19; SARS – CoV – 2; inflammation; kidney; viral sepsis.

FIGURE 1

Summary of the potential pathophysiological mechanisms of SARS-CoV-2–associated AKI. SARS-CoV-2 infection induces direct pulmonary injury that might lead to systemic inflammation. Hemodynamic changes are also frequent in patients admitted in ICU, due to the infection and its complication, as well as to medical interventions. These modifications result in GFR decrease and thus prerenal azotemia, potentially leading to acute ischemic tubular injury. Other factors including inflammation itself and tubular toxicity due to nephrotoxic agents (antibiotics, antiviral drugs, etc.) contribute to acute tubular injury in these patients. Few cases of TMA and renal vascular thrombosis have also been reported, raising the hypothesis of endothelial dysfunction and systemic hypercoagulability in the most severe patients. Collapsing glomerulopathy is a specific feature of SARS-CoV-2–related AKI, also called COVAN (COVID-associated nephropathy) in reference to HIVAN (HIV-associated nephropathy), as they probably share common mechanisms, including the strong association with APOL1 genetic variants. Finally, following the report of the autopsy series from Puelles et al. (2020), a direct tubular or glomerular viral invasion has not yet been confirmed in other reports. Consequently, this mechanism remains controversial. Arrows in bold represent the proposed major mechanisms. PEEP, positive end-expiratory pressure; GFR, glomerular filtration rate; TMA, thrombotic microangiopathy; TLR, Toll-like receptors; DAMP, damage-associated molecular patterns; ROS, reactive oxygen species.