Clinical trial NCT06498336: miRNA in Septic Acute Kidney Injury
Official title: Specific miRNA Associated With Endothelial Dysfunction and Mitochondrial Damage in Patients With Septic Acute Kidney Injury
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sepsis
Acute Kidney Injury
Acute Kidney Injury Due to Sepsis
Keywords: acute kidney injury
endothelial dysfunction
mitochondrial damage
Pentraxin 3
miRNA
sepsis
uromodulin
Lead sponsor: University Hospital Ostrava
Sponsor class: OTHER
Collaborators: name: University Hospital Olomouc
First posted: 2024-07-12
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Critically ill adult patients suffering from sepsis defined according to SEPSIS 3 definition, with or without acute kidney injury defined by KDIGO 2012 (2) and healthy volunteers

Brief summary: Acute kidney injury is a common and serious complication of sepsis and septic shock, which may be associated with a worse outcome of the patient's condition. The exact pathophysiological mechanism of septic acute kidney injury remains a challenge. One of the possible causes appears to be endothelial dysfunction and mitochondrial damage of renal tubular cells. The aim of this study is to identify specific microRNAs associated with these pathophysiological events in sepsis and septic acute kidney injury. And to establish a new potential diagnostic or therapeutic target for the prevention or treatment of septic acute kidney injury.

Detailed description: Sepsis is generally characterized as a life-threatening organ dysfunction and dysregulating host reaction to the infection (e.g., bacterial, viral, mycotic (1). Typical pathophysiological processes of sepsis include systemic inflammation, immune suppression, activation of the clotting cascade, and increase of endothelial vascular permeability with subsequent leak of fluids into the interstitial space. One of the most important organ damage due to ongoing sepsis is acute kidney injury (AKI), which is also a predictor of mortality in critically ill patients. The exact pathophysiology of septic AKI remains a challenging and poorly understood mechanism. A decrease of oxygen delivery to the tissues during the septic shock and usually high oxygen consumption of renal tubular cells make them prone to ischemia injury with consequences in tubular cell death. Among potential immune inflammatory response biomarkers in sepsis and septic shock might be promising pentraxin 3 (PTX3), which plays an important role in endothelial dysfunction with several pathogenic pathways' activation. Recently has been shown the positive effect of PTX3 on the inhibition of reactive oxygen species, mitochondrial injury, and apoptosis pathway in AKI (3,4). Another promising urinary or serum biomarker of AKI seems to be uromodulin, which is dynamically regulated in response to sepsis. Serum uromodulin concentrations decrease during septic human AKI development and are associated with increased renal and systemic oxidative damage (5,6,7). MicroRNAs are small non-coding RNAs, that have been reported to be useful biomarkers for AKI development or potential target for AKI treatment. Determination of serum PTX3 and uromodulin concomitantly with specific circulating miRNAs associated with PTX3 and uromodulin-specific signaling pathways in critically ill septic patients could bring new insights to septic AKI pathophysiology and contribute to future development of new preventive or therapeutic options in septic patients.

Eligibility criteria: Inclusion Criteria:

The study group of patients with sepsis with or without acute kidney injury

* age \> 18 years
* newly diagnosed sepsis or septic shock with or without acute kidney injury

Healthy volunteers

* no evidence of infection on clinical or laboratory examination
* age \> 18 years
* signed informed consent

Exclusion Criteria:

The study group of patients with sepsis with or without acute kidney injury

* age \< 18 years
* chronic kidney disease at stage 4 or 5 according to KDIGO recommendations (KDIGO) for chronic kidney disease 2024
* patients on chronic dialysis treatment, or after renal transplantation

Healthy volunteers

* acute or chronic infection
* renal disease

Primary outcomes:
measure: Determination of serum expression of pentraxin 3 (PTX3) and uromodulin
timeFrame: 4 days
measure: Determination of expression and 4 days course investigation of miRNAs
timeFrame: 4 days
measure: Target genes of miRNAs and their association with endothelial dysfunction and mitochondrial injury in sepsis
timeFrame: 4 days
Secondary outcomes:
Other outcomes:
Locations:
city: Ostrava
country: Czechia
facility: University Hospital Ostrava
state: Moravian-Silesian Region
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
state: Olomouc Region
Study officials:
affiliation: University Hospital Ostrava
name: Naděžda Petejová, Assoc.Prof.,MD,PhD,MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
citation: Chen J, Matzuk MM, Zhou XJ, Lu CY. Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury. Kidney Int. 2012 Dec;82(11):1195-207. doi: 10.1038/ki.2012.268. Epub 2012 Aug 15.
citation: Lee HH, Kim SY, Na JC, Yoon YE, Han WK. Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury. PLoS One. 2018 Apr 19;13(4):e0195758. doi: 10.1371/journal.pone.0195758. eCollection 2018.
citation: El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44. doi: 10.1152/ajprenal.00083.2008. Epub 2008 May 21.
citation: LaFavers KA, Hage CA, Gaur V, Micanovic R, Hato T, Khan S, Winfree S, Doshi S, Moorthi RN, Twigg H, Wu XR, Dagher PC, Srour EF, El-Achkar TM. The kidney protects against sepsis by producing systemic uromodulin. Am J Physiol Renal Physiol. 2022 Aug 1;323(2):F212-F226. doi: 10.1152/ajprenal.00146.2022. Epub 2022 Jun 27.
citation: LaFavers KA, Macedo E, Garimella PS, Lima C, Khan S, Myslinski J, McClintick J, Witzmann FA, Winfree S, Phillips CL, Hato T, Dagher PC, Wu XR, El-Achkar TM, Micanovic R. Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel. Sci Transl Med. 2019 Oct 2;11(512):eaaw3639. doi: 10.1126/scitranslmed.aaw3639.
citation: Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024 Apr;105(4S):S117-S314. doi: 10.1016/j.kint.2023.10.018. No abstract available.