key: cord-0962351-4ewhkjkr authors: Kerget, Buğra; Kerget, Ferhan; Aksakal, Alperen; Aşkın, Seda; Uçar, Elif Yılmazel; Sağlam, Leyla title: Evaluation of the relationship between KIM‐1 and suPAR levels and clinical severity in COVID‐19 patients: A different perspective on suPAR date: 2021-05-28 journal: J Med Virol DOI: 10.1002/jmv.27099 sha: d08a244c7588f834f568e61426822fe4f598e2d3 doc_id: 962351 cord_uid: 4ewhkjkr Coronavirus disease 2019 (COVID‐19) is one of the most pressing health problems of this century, but our knowledge of the disease is still limited. In this study, we aimed to examine serum‐soluble urokinase plasminogen activator receptor (suPAR) and kidney injury molecule 1 (KIM‐1) levels based on the clinical course of COVID‐19. Our study included 102 patients over the age of 18 who were diagnosed as having COVID‐19 between September 2020 and December 2020 and a control group of 50 health workers over the age of 18 whose severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) PCR results were negative. KIM‐1 was measured by ELISA and suPAR by suPARnostic™ assay. Analysis of previously identified variables of prognostic significance in COVID‐19 revealed high neutrophil to lymphocyte ratio, lactose dehydrogenase, prothrombin time, C‐reactive protein, PaO(2)/FiO(2), D‐dimer, ferritin, and fibrinogen levels in patients with severe disease (p < 0.05 for all). KIM‐1 and suPAR levels were significantly higher in COVID‐19 patients compared to the control group (p = 0.001 for all). KIM‐1 level was higher in severe patients compared to moderate patients (p = 0.001), while suPAR level was lower (p = 0.001). KIM‐1, which is believed to play an important role in the endocytosis of SARS‐CoV‐2, was elevated in patients with severe COVID‐19 and may be a therapeutic target in the future. SuPAR may have a role in defense mechanism and fibrinolysis, and low levels in severe patients may be associated with poor prognosis in the early period. group of 50 health workers over the age of 18 whose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR results were negative. KIM-1 was measured by ELISA and suPAR by suPARnostic™ assay. Analysis of previously identified variables of prognostic significance in COVID-19 revealed high neutrophil to lymphocyte ratio, lactose dehydrogenase, prothrombin time, C-reactive protein, PaO 2 /FiO 2 , D-dimer, ferritin, and fibrinogen levels in patients with severe disease (p < 0.05 for all). KIM-1 and suPAR levels were significantly higher in COVID-19 patients compared to the control group (p = 0.001 for all). KIM-1 level was higher in severe patients compared to moderate patients (p = 0.001), while suPAR level was lower (p = 0.001). KIM-1, which is believed to play an important role in the endocytosis of SARS-CoV-2, was elevated in patients with severe COVID-19 and may be a therapeutic target in the future. SuPAR may have a role in defense mechanism and fibrinolysis, and low levels in severe patients may be associated with poor prognosis in the early period. Most people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes COVID-19, experience mild symptoms, such as headache, sore throat, joint pain, and loss of taste and smell. However, the infection can also cause severe morbidity and mortality, especially in individuals over 65 and those with comorbidity. 1 The main conditions associated with severe course from the onset of COVID-19 are acute respiratory distress syndrome (ARDS), macrophage activation syndrome (MAS), and thrombotic events secondary to endothelial dysfunction. In addition to proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), IL-6, and, IL-18, the expression of urokinase plasminogen activator (uPAR) is also markedly increased during the development and progression of ARDS and MAS. Kallikrein, which is released from lung endothelial cells, plays an important role in the conversion of uPAR into its circulating soluble form (soluble urokinase plasminogen activator receptor [suPAR]). Studies have demonstrated suPAR elevation in diabetes, coronary artery disease, cancer, kidney disease, and infections, and it has been suggested that suPAR may be a proinflammatory biomarker that can be used as an early mortality indicator in these diseases. In studies of COVID-19 patients, it has been emphasized that suPAR elevation was correlated with clinical severity and played an important role in the development of pulmonary, renal, and cardiac complications. However, another study showed that although suPAR level increased with disease severity like in the previous study, it was even higher in asymptomatic carriers compared to symptomatic patient groups. This increased the need for more extensive studies to better understand the role of suPAR in COVID-19. One of the first discoveries about SARS-CoV-2 was that it binds to the cell surface and enters cells using the angiotensin-converting enzyme 2 receptor. However, as we gained more information about the disease, it was found that kidney injury molecule 1 (KIM-1) may have a greater role than ACE receptors in the severe kidney damage caused by COVID-19. In particular, the IgV domain of the KIM-1 molecule has been highlighted as a potential SARS-CoV-2 binding receptor. The discovery of the KIM-1 receptor in the lungs has also led to speculation that it may offer a new therapeutic target that can minimize pulmonary complications due to SARS-CoV-2. There have been no studies on KIM-1 in relation to the clinical course at the pulmonary level in COVID-19 patients. The aim of this study was to investigate the relationship between the clinical severity of COVID-19 and patients' serum levels of suPAR, for which there are conflicting data on this disease, and serum levels of KIM-1, which is thought to be a new viral entry pathway in the lungs. As standard procedure, high-resolution computed tomography (HRCT) was performed for high-risk patients with COVID-19. Patients with typical HRCT findings (bilateral ground-glass opacity with primarily peripheral distribution, subsegmental consolidation or linear opacities, cobblestone pattern, and inverse halo sign) and patients with atypical radiological findings but consistent clinical presentation were hospitalized. Hematological parameters; biochemical parameters, including liver and kidney function tests; coagulation parameters, such as ferritin, D-dimer, troponin-I, C-reactive protein (CRP); and arterial blood gas parameters were analyzed at admission and daily thereafter. The 152 people included in our study were divided into 3 groups: Group 1, asymptomatic health workers whose PCR results were negative for SARS-CoV-2 (n = 50); Group 2, moderately ill patients with nonsevere pneumonia (severe pneumonia was defined as meeting any of the following criteria: respiratory rate ≥30 breaths/min, SpO 2 ≤92%, and >50% lung infiltration) (n = 62); and Group 3, severely ill patients who were admitted with severe pneumonia and developed MAS during follow-up (n = 40). Patients with chronic or clinically significant infectious or inflammatory conditions in the last month, asthma, chronic obstructive pulmonary disease (COPD), malignancy, invasive surgical intervention in the last month, uncontrolled hypertension, high fasting blood glucose, diabetes, cerebrovascular disease, kidney disease, and coronary artery disease were excluded. History and laboratory parameters obtained at admission were used to evaluate patients in terms of the exclusion criteria. The presence of coronary artery disease, asthma, COPD, and diabetes was determined based on consultation with the cardiology, chest diseases, and internal medicine departments. Axillary body temperature higher than 37.3°C was defined as fever. The mean age of the 102 patients (59 men, 43 women) included in the study was 56.1 ± 14.9 years. The mean age of the control group was 53.1 ± 18.1 years. There was no statistically significant difference in age between the patient and control groups (p = 0.34). The mean age of the male patients was 56.3 ± 15.8 years and that of the female patients was 55.9 ± 13.8 years (p = 0.9). Comparisons of suPAR and KIM-1 levels between the patient groups and with the control group are shown in Table 2 . KIM-1 and suPAR levels were significantly higher in the patient groups than in the control group (p = 0.001 for all). When compared between patients with moderate and severe COVID-19, the KIM-1 level was higher in the severe group (p = 0.001), while the suPAR level was higher in the moderate group (p = 0.034). A very weak negative correlation was observed between suPAR and age (r = −0.197; p = 0.05), while a weak positive correlation was observed between suPAR and PaO 2 /FiO 2 (r = 0.336; p = 0.01) ( Figure 1 ). There was no significant relationship between suPAR level The results of multivariate analysis between moderate and severe COVID-19 patients are shown in Table 3 . The results demonstrated significant differences in both suPAR and KIM-1 levels T A B L E 2 Comparison of admitting suPAR and KIM-1 levels between COVID-19 patients with moderate and severe disease and between patients and controls COVID-19 severity Control (mean ± SD) (n = 50) *p/**p Moderate (mean ± SD) (n = 62) Severe (mean ± SD) (n = 40) By enabling a number of proteolytic activities to occur in the extracellular matrix, suPAR facilitates the migration of cells involved in the immune response. 11 Studies investigating the relationship between suPAR level and inflammatory diseases found that levels were high in diabetes mellitus, coronary artery disease, communityacquired and ventilator-associated pneumonia, smoking, acute exacerbations of COPD, and sepsis when compared with healthy controls. [12] [13] [14] [15] [16] [17] [18] [19] [20] Studies in patients with sepsis also showed that suPAR may have an important place in the prediction of early mortality and surveillance, and in a study of COVID-19 patients, high suPAR level was evaluated as a potential early biomarker indicating the need for intensive care admission. 21 In another study, it was observed that although suPAR level increased in correlation with disease severity, asymptomatic COVID-19 patients had higher suPAR levels than symptomatic patient groups. This was interpreted as possibly being due to increased production or increased shedding from the cell surface. In this study, it was observed that laboratory parameters ex- The most important limitation of this study was that the number of patients with severe disease was small compared to those with moderate disease. The small number of patients was a result of our exclusion of patients with comorbidities due to concern about their effect on the study parameters. In conclusion, KIM-1 has been identified as a new entry pathway for SARS-CoV-2 and its increase in correlation with disease severity as shown in our study indicates that it may be used as a therapeutic target in the future. Although suPAR has been evaluated as an early marker of poor prognosis in many diseases, more extensive studies are needed to determine if the same is true in COVID-19. COVID-19 pathophysiology: a review Interobserver reliability of the Berlin ARDS definition and strategies to improve the reliability of ARDS diagnosis The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? 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Conceptualization, methodology, software, validation, formal analysis: Visualization, supervision, project administration: Leyla Sağlam. The data that support the findings of this study are available from the corresponding author upon reasonable request.