Can MOTS-C be a biomarker for the early detection of acute kidney injury?

Aim: Acute kidney injury (AKI) is a condition that is associated with a high mortality and morbidity rate that necessitates renal replacement therapy with significant financial costs and complications during treatment. Currently, parameters such as creatinine and cystatin C, which increase following the onset of renal dysfunction, are still employed as routine indicators of AKI. Investigations into the renal angina index, as well as biomarkers present in urine and serum, remain a valuable tool for determining the risk of AKI prior to its development and for detecting AKI in its subclinical stage before the onset of renal dysfunction. In recent years, the relationship between mitochondrial dysfunction and kidney damage has become a focus of research. In particular, in patients who have undergone neoplastic disease, trauma, and cardiac surgery in a hospital and intensive care unit, the production of reactive oxygen species (ROS) in mitochondria is increased following the development of oxidative stress as a consequence of the disruption of the oxidant and antioxidant balance. The kidney is a highly mitochondrial-rich organ, rendering it particularly susceptible to the detrimental effects of ROS that emerge following mitochondrial dysfunction. MOTS-C is a mitochondrial peptide that is encoded by mitochondrial DNA and that regulates cellular metabolic homeostasis. The only study to investigate the relationship between MOTS-C and kidney damage was conducted in patients with chronic kidney disease. The findings indicated that serum MOTS-C levels were significantly reduced in these patients. The objective of this study was to ascertain the level of MOTS-C in patients with AKI and to compare it with the levels of urine and serum NGAL, which are early biomarkers, in order to determine whether there are differences in levels according to the stage of AKI and its underlying etiology. Furthermore, the aim of the study was to investigate whether baseline serum MOTS-C levels with RAI could predict the development of AKI in children admitted to the pediatric intensive care unit (PICU). xv Method: The serum MOTS-C, serum NGAL, and urine NGAL levels of 46 patients diagnosed with AKI in our clinic and 32 healthy children were compared. The AKI patients were divided into subgroups according to KDIGO staging and etiology. The serum MOTS-C, serum NGAL, and urine NGAL parameters, which were measured by RAI scoring on the first day of hospitalization in 42 children admitted to the PICU, were evaluated for their ability to predict the development of AKI on the third day. The effect of the biomarkers and RAI on the prediction of AKI was assessed using ROC curves. Results: The serum level of MOTS-C was found to be significantly lower, whereas the urine level of NGAL was significantly higher in children with AKI compared to the control group. In accordance with the KDIGO staging system, serum MOTS-C and urine NGAL levels exhibited no significant differences between the E1, E2, and E3 groups. Conversely, cystatin C levels were found to be markedly elevated in E3 patients. Although serum and urine NGAL levels taken during admission to intensive care were found to be of limited value in predicting AKI alone, the AUC value (0.71) of serum MOTS-C levels in predicting AKI was found to be superior to the others. The AUC value of RAI ≥ 8 in predicting AKI development was 0.81, the AUC value of RAI ≥ 8+urine NGAL combination was 0.95, and the AUC value of RAI ≥ 8+MOTS C combination in predicting AKI was 0.86. Discussion: In the KDIGO staging system, serum MOTS-C and urine NGAL levels were found to be similar across all stages. However, cystatin C levels were significantly higher in patients classified as stage E3, indicating that serum MOTS-C and urine NGAL may serve as early-stage markers for AKI. Although serum and urine NGAL levels taken during admission to the intensive care unit alone had a low predictive value for AKI, we found that serum MOTS-C levels had a higher AUC value for predicting AKI. The combination of RAI ≥ 8+MOTS-C was found to predict AKI with a high degree of accuracy, whereasthe combination of RAI ≥ 8+urine NGAL demonstrated a perfect predictive capacity for AKI. The results demonstrate that mitochondrial dysfunction is initiated particularly during the initial stages of AKI, mitochondrial dysfunction contributes to the pathogenesis of AKI, and MOTS-C levels can be employed to predict AKI in high-risk patients. We think that our study is a xvi preliminary study for future experimental treatments of ABH with MOTS-C, which has beneficial effects on diabetes or metabolic homeostasis in experimental studies.