ABSTRACT
BACKGROUND AND AIMS: A cytokine storm drives the pathogenesis of severe coronavirus disease (COVID-19) and several biomarkers with different mechanisms of action have been linked to mortality. Chronic kidney disease (CKD) emerged as a very common risk factor for severe COVID-19. Indeed, CKD patients are at increased risk of premature death from many causes, including, but not limited to, cardiovascular disease (CVD) and infections. In this study, we aimed to investigate the associations between the growth differentiation factor 15 (GDF-15), an established cardiovascular and inflammatory biomarker and outcomes in CKD patients hospitalized for COVID-19. METHOD: A retrospective study on COVID-19 hospitalized subjects in the acute phase of the disease. A broad range of cytokines (CD25, IL-18, TNF-α, TNF RI, TNF RII, GDF-15, IL-7, LIF, IL-6, CHITINASE3-LIKE1, RAGE and Pentraxin-3) were assessed in plasma (Luminex, ELISA) collected upon hospitalization. A total of 77 subjects were divided into two groups according to their estimated glomerular filtration rate (eGFR, by CKD-EPI formula), ≥45 mL/min (n = 44), or <45 mL/min (n = 33). RESULTS: We found no statistical differences between the two groups in terms of demographic features. Among comorbidities, we found a higher percentage of patients with diabetes in the eGFR < 45 group. Likewise, the serum tests upon admission showed in the eGFR < 45 group a higher value of neutrophilic count. Upon hospital admission, the patient groups were comparable in terms of symptoms, time from symptom onset to admission and death or discharge, radiological evidence of pneumonia and respiratory parameters and time of hospitalization. Furthermore, there were no statistical differences between medical therapy during hospitalization, need for respiratory support with Continuous Positive Airways Pressure or Non-Invasive Mechanical Ventilation, or death rather than discharge as the clinical outcome. Serum levels of 20 different compounds were measured in COVID-19 patients admitted to the hospital 4-5 days after the onset of symptoms. Interestingly, we found that patients with lower renal function (eGFR < 45 mL/min) had a significant increase of GDF-15, CD-25 and RAGE and, furthermore, higher serum levels of these molecules were detected in non-survivor patients and in those who needed ventilation. Also, TNFα, TNFR I, TNFR II, IL-7 and LIF had a significant increase in patients with eGFR < 45 mL/min with more elevated levels in non-survivor patients. In univariate analysis low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk (Figure 1). Independent association between GDF-15 quartiles and mortality risk was confirmed in Cox model adjusted for eGFR, age, fever, dyspnoea and P/F [hazard ratio (HR) 2.28, 95% confidence interval (CI) 1.53-3.39, P < 0.0001) The strength of association between GDF-15 quartiles and mortality risk was increased in patients with eGFR < 45 mL/min/1.73 m2 (HR 2.53, CI 1.34-4.79) compared with the other eGFR group (HR 1.99, CI 1.17-3.39) (Table 1). CONCLUSION: Our results demonstrate that GDF-15 is an independent predictor of COVID-19 mortality in CKD patients. Given the reported increase of this cytokine with age and its possible mechanistic role in various pathological conditions, our findings suggest that GDF-15 signalling pathway inhibitors may be included as possible therapeutic candidates for COVID-19 in CKD. (Table Presented).
ABSTRACT
Background: A cytokine storm drives the pathogenesis of severe COVID-19 and has therefore prompted the use of cytokine/transduction pathway inhibitors in the treatment of disease. However, numerous markers with different mechanisms of action have been linked to mortality, complicating the understanding of disease pathogenesis and the elaboration of therapeutic strategies. Methods: Retrospective study on COVID-19 hospitalized subjects in the acute phase of disease. A broad range of cytokines (CD25, IL-18, TNF-α, TNF RI, TNF RII, GDF-15, IL-7, LIF, IL-6, CHITINASE3-LIKE1, RAGE and Pentraxin-3) was assessed on plasma samples (Luminex, ELISA) collected upon hospitalization. Subjects were divided into two groups according to their clinical in-hospital death (Survivors: S;Non-Survivors: NS). Comparisons between groups were performed by Fisher's exact test or Mann-Whitney U test as appropriate. The association between each variable and mortality was analysed through univariate and multiple logistic regression models. Subsequently, survival analysis was conducted with Cox proportional hazard models. Results: 77 hospitalised Covid-19 patients were enrolled: 42 S and 35 NS (Figure 1A). As expected, in the NS group we found a higher proportion of subjects with fever and dyspnoea upon admission, development of ARDS and need of PEEP respiratory support (Figure 1A). NS also displayed significantly higher blood neutrophils/lymphocytes, C-reactive protein, LDH and procalcitonin as well as lower PaO2/FiO2 and peripheral O2 saturation values at admission (Figure 1A). In keeping with these findings, CD25, IL-18, IL-6, TNF-α, TNFRI, TNFRII, GDF-15, IL-7, LIF and Chitinase3-Like1, Pentraxin-3 and RAGE were significantly higher in NS than S (Figure 1B) and were associated to mortality in univariate regression models. In the multivariate regression model GDF-15 and fever were the two more relevant features associated with mortality (Figure 1C). In the survival analysis GDF-15 was the strongest predictor of mortality (HR 2,26, 1,55-3,31;p<0,01 reference group bottom quartile Figure 1D, E). Conclusion: Our in-depth characterization of the cytokine storm demonstrates that GDF-15 is an independent predictor of Covid-19 mortality. Given the reported increase of this cytokine with age and its possible mechanistic role in various pathological conditions, our findings suggest that GDF-15 signalling pathway inhibitors may be included as possible therapeutic candidates for Covid-19.