Does citrinin cause nephrotoxicity, and do uranium and gadolinium increase kidney oxidative stress through renal handling?

The mycotoxin citrinin, the heavy metal uranium, and the contrast metal gadolinium represent distinct toxicological hazards that converge in the kidneys, driving cellular damage through shared pathways of renal clearance, mitochondrial dysfunction, and oxidative stress.

Citrinin-induced renal damage

• Targeted tubular necrosis: Citrinin preferentially accumulates in proximal tubule epithelial cells, causing severe tubular degeneration and acute tubular necrosis. This manifests physiologically as functional filtration failure, marked by reduced glomerular filtration rate (GFR) and elevated serum creatinine and urea.
• Intracellular mechanisms: Citrinin impairs mitochondrial bioenergetics by uncoupling respiration, inhibiting electron transport chain complexes I and II, and depleting ATP.
• Oxidative stress and cell death: This mitochondrial disruption drives endoplasmic reticulum (ER) stress, lipid peroxidation, and the depletion of key antioxidants (glutathione, superoxide dismutase, and catalase). These pathways culminate in PANoptosis, a coordinated cell death process encompassing apoptosis, necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis.

Renal clearance and oxidative stress of uranium and gadolinium

• Uranium handling: Uranyl complexes undergo glomerular filtration and are actively reabsorbed by proximal tubular cells via NaPi-IIa cotransporters and receptor-mediated endocytosis. Within these cells, uranium targets mitochondrial complexes II and III, triggering a massive surge in reactive oxygen species (ROS), glutathione depletion, and lipid peroxidation.
• Gadolinium handling: Gadolinium-based contrast agents (GBCAs) are primarily cleared via glomerular filtration. Under conditions of delayed clearance or chelate instability, dissociated free Gd³⁺ directly exposes tubular epithelial cells, disrupting calcium homeostasis and mitochondrial respiration to induce oxidative cellular injury.

Bottom line

• Citrinin, uranium, and gadolinium directly target and damage renal tubular pathways; their filtration, reabsorption, and cellular accumulation disrupt mitochondrial bioenergetics, driving severe oxidative stress and tubular cell death.