Gadolinium-Based Contrast Media Nephrotoxicity in Kidney Impairment: The Physio-Pathological Conditions for the Perfect Murder

Abstract

Gadolinium-based contrast media (GBCM) toxicity in patients with kidney disease is a concern for the possible development of systemic nephrogenic fibrosis and possible renal complications. This review focuses on the pathological mechanisms underlying the potential kidney toxicity of gadolinium. Gadolinium, as a free compound (Gd3+), is highly toxic in humans because it competes with divalent calcium (Ca2+) and magnesium (Mg2+) ions, interfering in some relevant biologic processes. Its toxicity is blunted by the complexing of Gd3+ with a carrier, allowing its use in magnetic resonance imaging. The binding reaction between gadolinium and a carrier is thermodynamically reversible. Consequently, under some conditions, gadolinium can be released in the interstitial space as a free Gd3+ compound with the possibility of toxicity. Other metals such as iron, copper, and calcium can interfere with the binding between gadolinium and its carrier because they compete for the same binding site. This process is known as transmetallation. In patients with kidney impairment, conditions such as low clearance of the Gd-carrier complex, acid-base derangements, and high serum phosphorous can increase the presence of free Gd3+, leading to a higher risk for toxicity.

Contrast-induced Acute Kidney Injury in Diabetic Patients and SGLT-2 Inhibitors: A Preventive Opportunity or Promoting Element?

“…Hence, in chronic kidney disease, the slower elimination of the gadolinium complexes and the increased presence of other competing cations such as copper, zinc, and iron, might displace gadolinium ions from the chelating complexes into the free gadolinium ions because of the transmetallation process. 95 Notably, the increased concentration of free gadolinium also promotes an inflammatory response, with enhanced release of cytokines and other proinflammatory mediators by inducing NOD-, LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. 96 Despite the previously reported molecular pathways, the incidence of CI-AKI after gadolinium-based CM remains uncommon.…”

Single-Atom Gadolinium Nano-Contrast Agents with High Stability for Tumor T1 Magnetic Resonance Imaging

“…Magnetic resonance imaging (MRI) is a powerful noninvasive diagnostic method for disease evaluations among diverse biomedical imaging modes, especially for early detection and accurate localization of tumors. − To overcome the low sensitivity of MRI, doctors have utilized contrast agents such as Gd-chelates to enhance the clinical imaging contrast by increasing the spin relaxation rates of water molecules in the body. − Nevertheless, because of the nonspecific distribution and rapid clearance of the small molecular Gd-chelates, they encounter the challenges of inadequate sensitivity and lack of selectivity for cancer diagnosis. , With the rapid development of nanotechnology, Gd-based nanomaterials are emerging as a promising substitute for Gd-chelates in cancer diagnosis because of better tumoral accumulation. − Gd-based nanomaterials also show improved relaxivity compared with Gd-chelates by increasing the rotational correlation time (τ r ) of the geometrically confined Gd elements. − However, most Gd atoms are inside the nanoparticles, and they are inaccessible to water molecules, resulting in the waste of Gd atoms. , Another significant problem that both the Gd-chelates and Gd-based nanomaterials face is the risk of nephrotoxicity caused by the release of toxic Gd 3+ ions . It is of great urgency to develop a kind of biocompatible, tumor-targeting, and stable Gd-based nano-contrast agents with high relaxivity for T 1 -weighted tumor MRI.…”

“…22,23 Another significant problem that both the Gd-chelates and Gd-based nanomaterials face is the risk of nephrotoxicity caused by the release of toxic Gd 3+ ions. 24 It is of great urgency to develop a kind of biocompatible, tumortargeting, and stable Gd-based nano-contrast agents with high relaxivity for T 1 -weighted tumor MRI.…”

d-Band Center of Rare Earth Oxides Determines Biotransformation-Induced Cell Membrane Damage

“…16−20 For instance, in the manufacturing and application of REOs NPs, long-term inhalation of rare earth dust can lead to pulmonary fibrosis among the occupational population (e.g., miners and polishers). 21,22 Diagnostic REO NPs such as gadolinium-based contrast agents have been identified as the key etiological agents of nephrogenic systemic fibrosis. 23−26 Moreover, REO NPs can cause organ damage in animals, including the brain, lungs, and liver.…”

“…As “industrial vitamins,” rare earth oxide (REO) nanoparticles (NPs) combine the characteristics of rare earth elements and nanomaterials and are widely used in fields such as energy, agricultural production, electronics, and biomedicine. − According to the latest data, both the production and consumption of REOs have grown by more than 10% annually over the past 5 years . Inevitably, application of REO NPs has aggravated their release into the environment and living organisms, and REO NPs are considered for environmental persistence and bioaccumulation. − REO NPs can enter the human body accidentally or intentionally through various exposure routes, especially occupational and iatrogenic exposure. − Once introduced into the human body, REO NPs can accumulate in the lungs, liver, and brain, posing a potential threat to human health. − For instance, in the manufacturing and application of REOs NPs, long-term inhalation of rare earth dust can lead to pulmonary fibrosis among the occupational population (e.g., miners and polishers). , Diagnostic REO NPs such as gadolinium-based contrast agents have been identified as the key etiological agents of nephrogenic systemic fibrosis. − Moreover, REO NPs can cause organ damage in animals, including the brain, lungs, and liver. − Despite growing evidence on the health hazards of REOs, insufficient understanding of the toxicity mechanism makes it difficult to predict and control the safety of REOs.…”