Specific miRNAs in Sepsis and Nephrotoxic Antibiotic Treatment

Differentiation of Acute Kidney Injury in Sepsis and Due to Nephrotoxic Antibiotic Treatment With Vancomycin and Gentamicin Based on Measurements of Specific miRNAs

Critically ill patients are prone to develop acute kidney injury due to sepsis itself and by administration of potentially nephrotoxic antibiotic treatment (vancomycin or gentamicin). Blood-specific miRNA levels associated with renal tubular damage change in patients treated with vancomycin or gentamicin compared to septic patients treated with other antimicrobials.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Acute Kidney Injury
• Intervention / Treatment: Diagnostic test: Blood-specific miRNA levels

Detailed Description

Sepsis is generally defined as a life-threatening and dysregulated reaction to infection (bacterial, fungal, or viral) leading to systemic inflammation and organ dysfunction including acute kidney injury [1]. Acute kidney injury in critically ill patients is a common and usually serious condition associated with increased patient morbidity and mortality. Critically ill patients are prone to develop acute kidney injury due to sepsis itself and by administration of potentially nephrotoxic antibiotic treatment (vancomycin or aminoglycoside-gentamicin). To prevent nephrotoxicity and avoid subtherapeutic dosing, drug serum concentrations are usually monitored, with adjustment of dose or dosing interval according to the pharmacokinetic model. However, renal tubular injury can occur even if the treatment is optimally set. In the quest for new preventive or therapeutic targets (biomarkers) in septic/nephrotoxic acute renal damage, a current research focus in microRNAs. Based on data from previously published experimental and human studies we identified specific miRNAs associated with biochemical pathways involved in inflammation, organ ischemia, and nephrotoxicity with their exact determination and time-changing detection during the seven days in studied patients. Blood-specific miRNA levels associated with renal tubular damage change in patients treated with vancomycin or gentamicin compared to septic patients treated with other antimicrobials.

Sampling method:

Whole blood samples were taken on the first, fourth, and seventh days of antibiotic treatment. The first 24 samples (8 patients) were extracted in duplicate for screening of the selected miRNAs. Blood samples were collected into 2.5 mL tubes (Vacutainer® PAXgene, PreAnalytiX® GmbH, A Qiagen/BD Company, Switzerland). Concomitant-ly, the blood samples for NGAL determination were collected into 2.6 or 2 mL neutral tubes (S-Monovette® K3 EDTA, 2.6 mL, red, Sartstedt AG & Co. KG, Germany; or Vacuette® K3 EDTA 2 mL, violet, Greiner Bio-One GmbH, Germany). The blood samples for biochemical (renal and inflammatory) parameters (serum creatinine, interleukin-6, procalcitonin, C-reactive protein) were collected concomitantly with other dai-ly routine biochemical parameters (S-Monovette® serum-gel, 4.9 mL, brown, Sartstedt AG & Co. KG, Germany in University Hospital Ostrava; or Vacuette® serum-gel, 5.0 mL, red, Greiner Bio-One GmbH, Germany in University Hospital Olomouc). The serum antibiotic concentrations (vancomycin and gentamicin) were monitored according to standard care in both cooperating hospitals without needing more blood samples for study.

• Study Type: Observational
• Enrollment (Actual): 53

Contacts and Locations

Study Locations

• Czechia
  • Moravian-Silesian Region
    • Ostrava, Moravian-Silesian Region, Czechia, 70852
      • University Hospital Ostrava

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Critically ill patients suffering from sepsis and treated with vancomycin, gentamicin, or other antibiotic groups.

Description

Inclusion Criteria:

- Critically ill adult septic patients with or without acute kidney injury treated by antimicrobial therapy

Exclusion Criteria:

- Patients in the chronic dialysis program, with stage 4 and 5 chronic kidney disease, or concomitantly treated with another potentially severe nephrotoxic medication (cisplatin, colistin) or combination vancomycin/gentamicin.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Vancomycin; Critically ill patients who suffered from sepsis, treated with vancomycin.	Diagnostic test: Blood-specific miRNA levels; Blood-specific miRNA levels associated with renal tubular damage change in patients treated with vancomycin or gentamicin compared to septic patients treated with other antimicrobials.
Gentamicin; Critically ill patients who suffered from sepsis, treated with gentamicin.	Diagnostic test: Blood-specific miRNA levels; Blood-specific miRNA levels associated with renal tubular damage change in patients treated with vancomycin or gentamicin compared to septic patients treated with other antimicrobials.
Other antibiotic groups; Critically ill patients who suffered from sepsis, treated by other antibiotic groups except for vancomycin or aminoglycoside (gentamicin).	Diagnostic test: Blood-specific miRNA levels; Blood-specific miRNA levels associated with renal tubular damage change in patients treated with vancomycin or gentamicin compared to septic patients treated with other antimicrobials.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
miRNAs expression over 7 days of treatment	Determine and investigate specific circulating miRNAs linked to sepsis itself, septic, ischemic, or nephrotoxic acute kidney injury in patients suffered from sepsis. Tracking changes in miRNAs expression over 7 days of treatment with nephrotoxic (vancomycin or gentamicin) as compared with other, non-nephrotoxic antibiotic treatment.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between circulating miRNA expression and serum neutrophil gelatinase-associated lipocalin (NGAL) and other renal or inflammatory markers	Association between circulating miRNA expression and serum neutrophil gelatinase-associated lipocalin (NGAL) and other renal or inflammatory markers to assess the potential of these small RNAs as pathophysiological biomarkers of nephrotoxic acute kidney injury or preventive, or therapeutic targets in sepsis and/or acute kidney injury.	7 days

Collaborators and Investigators

• Sponsor: University Hospital Ostrava
• Collaborators: University Hospital Olomouc; University of Ostrava; Palacky University; Technical University of Ostrava
• Investigators: Principal Investigator: Naděžda Petejová, Assoc.Prof.,MD,PhD,MSc, University Hospital Ostrava

Publications and helpful links

General Publications

• 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.
• Eckardt KU, Kasiske BL. Kidney disease: improving global outcomes. Nat Rev Nephrol. 2009 Nov;5(11):650-7. doi: 10.1038/nrneph.2009.153. Epub 2009 Sep 29. Review.
• Petejova N, Martinek A, Zadrazil J, Kanova M, Klementa V, Sigutova R, Kacirova I, Hrabovsky V, Svagera Z, Stejskal D. Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents-Pathophysiology and Biomarkers-A Review. Int J Mol Sci. 2020 Sep 26;21(19). pii: E7115. doi: 10.3390/ijms21197115. Review.
• Petejova N, Martinek A, Zadrazil J, Klementa V, Pribylova L, Bris R, Kanova M, Sigutova R, Kacirova I, Svagera Z, Bace E, Stejskal D. Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents. BMC Nephrol. 2022 Mar 19;23(1):111. doi: 10.1186/s12882-022-02726-6.

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2019
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: July 27, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Estimate): December 6, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: septic shock; microRNA; acute kidney injury; sepsis; nephrotoxicity; vancomycin; gentamicin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Renal Insufficiency; Shock; Sepsis; Toxemia; Shock, Septic; Acute Kidney Injury
• Other Study ID Numbers: IK-01-miRNA; 01 - RVO - FNOs/2019 (Other Grant/Funding Number: University Hospital Ostrava)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to make individual participant data available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No