BACKGROUND AND AIMS One of the complications described in critically ill patients in intensive care units with severe COVID-19 was acute kidney injury (AKI). The pathophysiology of AKI in patients with COVID-19 is multifactorial. In addition to the direct virulence of SARS-CoV-2 in renal cells, the tissue inflammation and local immune cell infiltration, cytokine storm, secondary infections and nephrotoxicity associated drugs may contribute to AKI [1]. Mounting evidence throughout the pandemic suggests that patients with severe COVID-19 may have a cytokine storm syndrome, one of the possible causes of AKI in these patients [2]. The present prospective cohort study analysed the correlation between circulating cytokine profile and estimated glomerular filtration rate (eGFR) in patients with COVID-19. METHOD After signing the informed consent, patients positive for SARS-CoV-2 infection (n = 74) had blood samples (n = 139) collected at hospital admission until the day of the outcome. ELISA measured the cytokines IL-10, IL-4, L-6, TNF-α and IFN-γ, and the eGFR was calculated by the CKD-EPI Cystatin C equation. Statistics description: Continuous variables were checked for normality and presented as mean ± standard deviation or median and interquartile range. The association between continuous variables is shown in scatterplots, and a predicted response with 95% confidence interval (95% CI) is plotted using fractional polynomials. For linear correlations, we obtained P-values using Pearson's correlation coefficient. RESULTS There is a more significant distribution of eGFR below 90 mL/min in the population studied, associated with older patients. Glomerular filtration rates were negatively correlated with age as expected (–0.60; P < 0.0001). Lower eGFR was correlated with levels of proinflammatory cytokines such as IL-6 (–0.33; P < .0007) and TNF- α (–0.21; P < .03); but without positive correlation with IL-10 (0.04; P < 0.68) or IFN-γ (–0.14; P < .16), even though higher IFN-γ levels have been linked to a worse prognosis in patients with severe COVID-19 [3]. Curiously, a positive correlation was observed between lower eGFR and IL-4 levels. CONCLUSION These results demonstrate that a shift in the immune response profile, cytokines with a Th2 profile such as IL-4, and cytokines with systemic functions such as IL-6 and TNF-α can be related to renal failure. The elucidation of the potential pathophysiological mechanisms of AKI associated with COVID-19 as well as monitoring of cytokine levels can (a) help to identify patients with severe COVID-19 at risk of loss of renal function, (b) provide information on specific therapeutic strategies.
Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, shares structural similarities with the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). We explored the hypothesis that CMPF at a concentration seen in uremia activates Piezo1 located on red blood cells (RBC). We incubated RBC from five healthy individuals with either Jedi1 or CMPF (both 87 μM), with or without the Piezo1 inhibitor GsMTx-4 (2 μM), and quantified the cells osmotic fragility. Our results indicate that compared to controls (i.e., RBC incubated with buffer), both Jedi1 and CMPF increase the osmotic fragility of RBC (i.e., reduce their resistance to osmotic stress). Effects of Jedi1 and CMPF were reversed to the control level by GsMTx-4. These results indicate a role of Piezo1 in augmenting RBC osmotic fragility and modulation of this effect by Jedi1 and CMPF. Our findings open the possibility that CMPF may act as an endogenous chemical activator of Piezo1.
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