Dose-dependent alterations in the metabolome during radiation nephropathy: current insights and biomarker discovery prospects

Ionizing radiation has a pronounced nephrotoxic effect, initiating a cascade of pathophysiological processes leading to the development of radiation nephropathy (RN) and renal failure. This review is devoted to an analysis of the current state of research in the field of identifying metabolomic biomarkers that allow for early diagnosis and prediction of radiationinduced kidney damage under external irradiation. The paper systematizes literature data obtained using mass spectrometry (MS) and nuclear magnetic resonance (NMR) regarding changes in the profiles of lowmolecularweight metabolites in urine. The main focus is on profound disturbances in purine metabolism (primarily due to the accumulation of xanthine and hypoxanthine), critical shifts in the tricarboxylic acid cycle (TCA), reflecting mitochondrial dysfunction, as well as an imbalance in the lipid profile, including the accumulation of acylcarnitines. These metabolic alterations are key indicators of oxidative stress and proximal tubule dysfunction, and the degree of their severity directly correlates with clinical and dosimetric parameters. The review provides a detailed examination of critical dose thresholds: moderate functional changes manifest when the absorbed dose to the kidneys exceeds 4 Gy, while irreversible structural degradation and manifest RN develop when the threshold of 10 Gy is exceeded. The authors emphasize that the introduction of metabolomic profiling into clinical practice can radically improve the effectiveness of monitoring the condition of patients who have undergone radiation exposure. Unlike classical protein damage markers (NGAL, KIM1), which are sensitive only at late stages, dynamic patterns of acylcarnitines, TCA cycle intermediates, and purine metabolites make it possible to carry out early biodosimetry. This makes it possible not only to detect the fact of radiation damage but also to assess the received radiation dose in the very first hours after exposure, enabling timely nephroprotective therapy.