The COVID-19 pandemic has presented numerous challenges, and one of the emerging concerns is kidney damage associated with the SARS-CoV-2 virus. Recent research conducted by the American University of Beirut-Lebanon, University Paris Saclay, INSERM UMR_1180, France, Immeuble Les Gemeaux, France, and University of Mississippi Medical Center-USA has shed light on the involvement of toll-like receptor 4 (TLR-4), kidney injury molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1), and cluster of differentiation 147 (CD147) in the development of kidney damage caused by SARS-CoV-2.
Kidney damage in COVID-19 can occur even in patients without pre-existing kidney disease. Acute kidney injury (AKI) has been observed in both mild and severe cases of COVID-19, with a higher prevalence in critically ill patients. AKI has been identified as the most prominent extra-pulmonary complication in intensive care unit (ICU) patients, surpassing cardiac dysfunction and liver injury. Furthermore, AKI has been found to be a strong predictor of 30-day mortality among critically ill COVID-19 patients.
Histopathologic examinations have revealed acute tubular necrosis and podocytopathy as characteristic features of SARS-CoV-2-related AKI. The mechanisms underlying kidney damage include hemodynamic instability, disruption of the renin-angiotensin aldosterone system, direct invasion of kidney cells by the virus, and cytokine storms leading to inflammation and cell death. While angiotensin-converting enzyme 2 (ACE2) was initially thought to be the primary receptor, recent evidence suggests that TLR-4, KIM-1/TIM-1, and CD147 may also serve as alternative receptors, contributing to kidney injury.
Autopsy studies have shown the presence of SARS-CoV-2 antigens in renal epithelial tubules, podocytes, and proximal tubular epithelium. Microscopic examinations of ICU patients have revealed glomerular, acute tubular, and tubulointerstitial injuries. These findings highlight the complex nature of COVID-19-induced kidney abnormalities.
TLR-4, expressed in renal tubular epithelial cells, has been implicated in the pathogenesis of kidney disease. Activation of TLR-4 leads to inflammation, immune response activation, and disruption of ion transport, contributing to tubular dysfunction. Recent evidence suggests that TLR-4 binds to the spike protein of SARS-CoV-2, intensifying the hyperinflammatory response and potentially explaining the thrombotic events observed in COVID-19 patients. KIM-1/TIM-1, a receptor overexpressed in kidney injuries, plays a dual role in repairing tubular epithelial cells and promoting inflammation and fibrosis. Increased levels of KIM-1 have been observed in severe COVID-19 cases, suggesting its potential as a therapeutic target. CD147, a glycoprotein widely distributed in various organs, including the kidneys, is associated with inflammatory diseases and renal fibrosis. Recent research indicates that CD147 may serve as an entry route for SARS-CoV-2, contributing to renal damage.
While the involvement of TLR-4, KIM-1/TIM-1, and CD147 in SARS-CoV-2-associated kidney damage is supported by evidence, there are still debates regarding the direct infection of kidney cells by the virus. Other factors, such as host responses, genetic factors, physiological disturbances, or therapies, may also contribute to kidney damage. Further research is needed to fully understand the complex relationship between SARS-CoV-2 and kidney damage.
Recent studies have also highlighted a potential link between long-COVID and chronic kidney disease (CKD). Patients with pre-existing CKD are at increased risk of severe COVID-19 infections, which can lead to multi-organ damage and an exaggerated inflammatory response. The mechanisms connecting long-COVID to CKD involve direct renal damage, blood clot formation, and autonomic nervous system disruption. Postural orthostatic tachycardia syndrome (POTS), a common long-COVID complication, may also involve kidney-related factors.
In conclusion, the research on SARS-CoV-2 and kidney damage continues to evolve, revealing the intricate interplay between the virus and the kidneys. TLR-4, KIM-1/TIM-1, and CD147 hold promise as potential therapeutic targets for mitigating the inflammatory response and improving treatment efficacy. Ongoing research is crucial for developing effective therapeutic strategies and improving patient outcomes in the face of this global health crisis.