Decreased plasma levels of the survival factor renalase are associated with worse outcomes in COVID-19

Abstract

Introduction: Renalase (RNLS), a novel secreted plasma flavoprotein, has anti-inflammatory effects in a variety of disease processes. Severe COVID-19 disease is associated with disordered inflammatory responses. We hypothesized that reduced plasma RNLS levels could be a marker of COVID-19 disease severity. Methods: Plasma was collected from 51 hospitalized COVID-19 patients and 15 uninfected non-hospitalized controls. Plasma RNLS and cytokine levels were measured and sociodemographic and clinical data were collected from chart review. Data were analyzed using nonparametric analyses and Kaplan Meir curve log rank analysis. Results: Plasma RNLs levels were negatively correlated with inflammatory markers, including IL-1b, IL-6, and TNFa (p = 0.04, p = 0.03, p = 0.01, respectively). Patients with COVID-19 disease had lower levels of RNLS than controls. Lower levels of RNLS were associated with more severe disease among COVID-19 patients. Low RNLS was also associated with worse survival among COVID-19 patients (HR = 4.54; 95% CI: 1.06-19.43; p = 0.005). Conclusion: Low plasma RNLS levels are associated with severe COVID-19 disease and may be a useful additional biomarker when identifying patients with severe COVID-19 disease. Given RNLS anti-inflammatory properties and negative correlation with inflammatory markers, these findings also suggest evidence of a potential pathophysiological mechanism for severe COVID-19 disease.

Renal and Inflammation Markers—Renalase, Cystatin C, and NGAL Levels in Asymptomatic and Symptomatic SARS-CoV-2 Infection in a One-Month Follow-Up Study

“…A comparative discussion of renalase in COVID-19 patients is difficult because there is only one basic study on changes in renalase concentration in COVID-19 patients at the moment, which was released as a preprint. The study indicates that decreased plasma levels of renalase are associated with worse outcomes in COVID-19 [ 39 ]. The work is based on the assumption that renalase is a “survival factor”; hence, its deficiency results in worse prognosis and course of the disease.…”

Renalase Challenges the Oxidative Stress and Fibroproliferative Response in COVID-19

“…These understandings may be finally underlined with the most recent results of the pioneer studies of renalase's role in the SARS-CoV-2-related pandemic and interpreted through the context of the aforementioned postulations [ 90 – 92 ]. It was, however, evidenced that renalase plasma levels measured in COVID-19 patients were significantly decreased compared to that of the control group, and demonstrated a negative correlation with inflammatory cytokines plasma levels, namely, IL-1 β , IL-6, and TNF- α [ 90 ].…”

“…These understandings may be finally underlined with the most recent results of the pioneer studies of renalase's role in the SARS-CoV-2-related pandemic and interpreted through the context of the aforementioned postulations [ 90 – 92 ]. It was, however, evidenced that renalase plasma levels measured in COVID-19 patients were significantly decreased compared to that of the control group, and demonstrated a negative correlation with inflammatory cytokines plasma levels, namely, IL-1 β , IL-6, and TNF- α [ 90 ]. At the same time, decreased plasma renalase was associated with more severe clinical manifestations of COVID-19, and worse survival rates (HR=4.54), strongly supporting a theory of renalase being a useful biomarker additive for the identification of the most severe COVID-19 patients [ 90 ].…”

Renalase—A new understanding of its enzymatic and non‐enzymatic activity and its implications for future research

“…These papers were screened and divided into three areas: renalase enzymatic activity (16 records), 1,2,4,5,6,7,8,9,10,11,12,13,14,15,16,17 renalase polymorphisms (16 records) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and renalase non-enzymatic activity (11 records). [34][35][36][37][38][39][40][41][42][43][44]…”

“…37 Among others, renalase cytoprotective properties were described in terms of ischemic acute kidney injury (AKI), 17,38 cisplatin-induced toxic injury, 39 acute pancreatitis, 40 renal fibrosis, 41 cardiac remodelling, 38 as well as fatty liver ischemia/reperfusion injury. 42 For example, renalase knock-out (KO) mice were found to have significantly increased renal injury indicated by higher plasma creatinine levels compared with renalase wild-type (WT) mice after both moderate and severe renal ischaemia reperfusion (IR) injury. Moreover, administration of human recombinant renalase ameliorated ischemic AKI by targeting all three pathways (necrosis, apoptosis and inflammation) of renal cell injury.…”