suPAR: An Inflammatory Mediator for Kidneys

Sudhini, Yashwanth Reddy; Wei, Changli; Reiser, Jochen

doi:10.1159/000524965

Cited by 25 publications

(15 citation statements)

References 117 publications

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“…29 More subtle alterations of immune and coagulation laboratory parameters have also been recently observed among individuals with sickle cell trait. 15,30,31 Our results in WHI confirm and extend these observations to include several additional sickle cell trait-associated inflammatory or kidney tubule injury biomarkers (MCP-1, PLAUR, HAVCR1/KIM-1, UMOD, and A1M), [32][33][34][35] some of which may play important roles in sickle nephropathy. 9,36,37 PLAUR, MCP-1, and fractalkine are key mediators of inflammation and mediate monocyte release of innate immune cells and migration from the bone marrow to tissue sites of injury, such as the kidney.…”

Section: Discussionsupporting

confidence: 82%

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Cai

Franceschini

Surapaneni

et al. 2023

CJASN

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Background: Sickle cell trait affects ∼ 8% of African American individuals, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including end-stage kidney disease. The mechanisms underlying these associations remain poorly understood. We utilized proteomic profiling to gain insight into the pathobiology of sickle cell trait. Methods: We measured proteomics (N=1,285 proteins assayed by Olink Explore) using baseline plasma samples from 592 African American participants with sickle cell trait and 1:1 age-matched African American participants without sickle cell trait from the prospective Women’s Health Initiative (WHI) cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. Results: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in two independent cohorts of African American individuals (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are either known biomarkers of kidney function or injury (e.g., KIM-1, UMOD, ephrins), related to red cell physiology or hemolysis (EPO, HMOX1, AHSP), and/or inflammation (fractalkine, MCP-1, UPAR). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during WHI follow-up (odds ratio 1.32; 95%CI 1.10 - 1.58). Conclusions: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

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Section: Discussionsupporting

confidence: 82%

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Cai

Franceschini

Surapaneni

et al. 2023

CJASN

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“…In the current trial the higher suPAR plasma levels and the higher incidence of AKI in sevoflurane-exposed patients align with the Azam data [ 38 ]. It is unclear if suPAR is a biomarker or a causative factor [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Early sevoflurane sedation in severe COVID-19-related lung injury patients. A pilot randomized controlled trial

Beck-Schimmer,

Schadde,

Pietsch

et al. 2024

Ann. Intensive Care

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Background This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. Methods This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. Results 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. Conclusions No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. Trial registration The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21.

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“…The ability to perform it effectively and efficiently can have significant implications in the drug discovery process [ 27 ]. An in silico virtual screening and molecular docking studies were performed to screen the activity of some uPAR derivatives to be used as a clinical target for uPAR [ 28 ]. Thus, we speculated that designing molecules with a similar geometry and affinity to uPAR might ameliorate the worsening of kidney function in the case of COVID-19 infection or future similar epidemics.…”

Section: Discussionmentioning

confidence: 99%

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis

Abdellatif

Sultan

Nassar

et al. 2023

IJMS

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Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan–Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand–protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

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suPAR: An Inflammatory Mediator for Kidneys

Cited by 25 publications

References 117 publications

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait

Early sevoflurane sedation in severe COVID-19-related lung injury patients. A pilot randomized controlled trial

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis

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