Association of renalase with clinical outcomes in hospitalized patients with COVID-19

Abstract

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March—June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91–0·98) and increased survival alone by 6% (HR 0·95; CI 0·90–0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.

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

“…Renalase was, however, suggested to be a factor in the survival of COVID-19, whose plasma levels most probably rise in order to counteract inflammatory marker levels, supporting the evidence of renalase's anti-inflammatory traits. The additional study [91] further supports the hypothesis that sufficient renalase plasma levels are important for biological integrity and injury responses. Patients presented with increased renalase/decreased IL-6 (established marker of mortality in COVID-19) plasma levels had the best survival compared to other evaluated groups, while decreased renalase concentration ("blunted response") experienced worse outcomes, as defined by higher mortality, greater hypoxia, a longer length of stay, higher intensive care unit admission, use of vasopressors, and cardiopulmonary resuscitation rate [91].…”

“…The additional study [91] further supports the hypothesis that sufficient renalase plasma levels are important for biological integrity and injury responses. Patients presented with increased renalase/decreased IL-6 (established marker of mortality in COVID-19) plasma levels had the best survival compared to other evaluated groups, while decreased renalase concentration ("blunted response") experienced worse outcomes, as defined by higher mortality, greater hypoxia, a longer length of stay, higher intensive care unit admission, use of vasopressors, and cardiopulmonary resuscitation rate [91]. Moreover, every 1000 ng/ml increase in renalase levels decreased the risk of death or intubation by 5% (HR=0.95) and increased survival alone by 6% (HR=0.95), after adjustments for socio-demographics, initial disease severity, comorbidities, and inflammation.…”

“…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][91][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-1β, IL-6, and TNF-α [90].…”

The Multi-Faceted Nature of Renalase for Mitochondrial Dysfunction Improvement in Cardiac Disease

“…Finally, renalase can hinder inflammasome activation and the release of IL-1β [ 32 , 44 , 62 ]. Taken together, renalase favors significant cytoprotection related to inflammation, oxidative stress, and apoptosis [ 28 , 29 , 30 , 31 , 32 , 37 , 38 , 39 , 50 , 59 , 62 ], whereby recent research also discloses its potential in diverse cardiac [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] and kidney pathologies [ 75 , 76 , 77 , 78 ] and in the pathophysiology of COVID-19 [ 79 , 80 ]. It will be captivating to conduct future scrutiny toward an excellent comprehension of renalase pleiotropy.…”