The Effectiveness of Urine mtDNA and Beta 2-MG to Predict Acute Kidney Injury for Critically Ill Surgical Patients

The Effectiveness of the Urine Mitochondrial Deoxyribonucleic Acid and, Serum Beta 2 Microglobulin as a Biomarker of Renal Function Impairment in Critically Ill Surgical Patients

1. Research background

1. Research hypothesis The development of acute kidney injury (AKI) can be predicted using urine mitochondrial deoxyribonucleic acid (UmtDNA), serum and urine beta-2 microglobulin (β2-MG) in critically ill surgical patients

2. Basis of research hypothesis

   i. Correlation between mitochondria and renal function (Results of previous studies)

   • Mitochondria are involved in development and recovery of diabetic nephropathy.

   • UmtDNA can be used as early marker to detect the development of AKI

     ※ Mitochondria

   • As an organelle located within the cell, it is an organ that produces energy through adenosine triphosphate (ATP) through cellular oxidative phosphorylation.

   • The kidney has the second most mitochondria after the heart.

   II. Correlation between elevation of β2-MG and renal function

   • Circulating β2-MG infiltrates the glomerulus and is reabsorbed and metabolized in the proximal tubule of the kidney. Therefore, it increases in the blood due to a decrease in metabolism when renal function is abnormal.

     ※ Beta 2-microglobulin

   • As the light chain of the class I major histocompatibility antigen, it is a protein distributed in nucleated cells (especially lymphocytes and monocytes) in the body.

   III. Mechanism of acute kidney injury in critically ill surgical patients

   • Blood flow to the kidneys is reduced due to decreased cardiac output, vasoconstriction due to systemic inflammatory response, hemodynamic changes, and decreased body fluid. This leads to renal tubular injury along with ischemic reperfusion injury.
   • Renal tubular injury increases the permeability of the transition pore that connects the outer and inner mitochondrial membranes, resulting in mitochondrial structural damage and oxidative injury. It causes a decrease of ATP in kidney cells and induces apoptosis of kidney cells.
   • Urine mtDNA, a product of this kidney injury, could be used as a biomarker to predict impairment of renal function in critically ill surgical patients.
   • Serum β2-MG maybe increase due to a decrease of metabolism of β2-MG in AKI.

1. Research objective

1. Demonstrate of the association between urine mitochondrial deoxyribonucleic acid copy number (UmtDNAcn), beta 2-microglobulin (β2-MG) and acute kidney injury in critically ill surgical patients
2. Demonstrate of the effectiveness of UmtDNAcn and β2-MG as a biomarker to predict AKI development and recovery

2. Contents of the research project.

1. Analysis of correlation between UmtDNAcn, β2-MG and development of AKI

   • Verifying the correlation between UmtDNAcn and blood β2-MG measured at the initial presentation and patients diagnosed AKI according to the Acute Kidney Injury Network (AKIN) criteria.

2. Analysis of correlation between UmtDNAcn, β2-MG and recovery of AKI

   • Verifying the correlation between UmtDNAcn and blood β2-MG measured at the initial presentation and AKI recovery
   • AKI recovery was defined as the case when the AKI stage according to the AKIN criteria on the 7th day of AKI onset was reduced from AKI stage measured at the beginning of the AKI onset.

3. Comparison with other biomarkers (delta neutrophil index, creatinine, cystatin C) - Comparison of sensitivity and specificity of UmtDNAcn, β2-MG, and other biomarkers previously used such as creatinine, cystatin C, and delta neutrophil index.

3. Strategies and methods for the research project

1. subject: all surgical patients who planned to admit surgical and trauma intensive care unit in emergency room

2. Study period and patient recruitment i. 1st and 2nd year

   • 120 patients

3. Measurement of UmtDNAcn, β2-MG i. urine and blood sampling: at the initial presentation and again on hospital say #1 and #3

4. Analysis of correlation between UmtDNAcn, β2-MG and AKI development, recovery

   i. Statistical analysis of UmtDNAcn, β2-MG measured at the initial presentation, on hospital day #1, and #3 between patients with no AKI and AKI

   ii. Statistical analysis of UmtDNAcn, β2-MG measured at the initial presentation, on hospital day #1, and #3 between patients with no AKI recovery and AKI recovery

   ※ AKI recovery was defined as the case when the AKI stage according to the AKIN criteria on the 7th day of AKI onset was reduced from AKI stage measured at the beginning of the AKI onset.

   iii. Comparison with other biomarkers (delta neutrophil index, creatinine, cystatin C)

   • Comparison of sensitivity and specificity to predict AKI of UmtDNAcn, β2-MG, and other biomarkers previously used such as creatinine, cystatin C, and delta neutrophil index measure at the initial presentation, on hospital day #1 and #3. .

Inclusion Criteria:

• All surgical patients who planned to admit to surgical and trauma intensive care unit in emergency room

Exclusion Criteria:

• Age ≤18 years
• Pregnancy in women
• Chronic kidney disease history
• Death at initial presentation of the case