ABSTRACT
The leitmotifs of magnetic resonance imaging (MRI) contrast agent-induced complications range from acute kidney injury, symptoms associated with gadolinium exposure (SAGE)/gadolinium deposition disease, potentially fatal gadolinium encephalopathy, and irreversible systemic fibrosis. Gadolinium is the active ingredient of these contrast agents, a non-physiologic lanthanide metal. The mechanisms of MRI contrast agent-induced diseases are unknown. Mice were treated with a MRI contrast agent. Human kidney tissues from contrast-naïve and MRI contrast agent-treated patients were obtained and analyzed. Kidneys (human and mouse) were assessed with transmission electron microscopy and scanning transmission electron microscopy with X-ray energy-dispersive spectroscopy. MRI contrast agent treatment resulted in unilamellar vesicles and mitochondriopathy in renal epithelium. Electron-dense intracellular precipitates and the outer rim of lipid droplets were rich in gadolinium and phosphorus. We conclude that MRI contrast agents are not physiologically inert. The long-term safety of these synthetic metal-ligand complexes, especially with repeated use, should be studied further.
Subject(s)
Coordination Complexes , Nanoparticles , Humans , Animals , Mice , Contrast Media/adverse effects , Contrast Media/chemistry , Gadolinium/adverse effects , Gadolinium/chemistry , Kidney/diagnostic imaging , Nanoparticles/adverse effects , Magnetic Resonance Imaging/methodsABSTRACT
Background: Gadolinium (Gd) usage in the Veterans Health Administration is increasing and patients with renal disease are frequently exposed. Gd is not entirely eliminated within 24 hours after administration, which may pose long-term adverse effects. Case Presentation: A Vietnam-era veteran aged > 70 years presented for evaluation of Gd-based contrast agent-induced chronic multisymptom illness. In the course of his routine clinical care, he was exposed to repeated Gd-enhanced magnetic resonance imaging studies. After his second Gd-based contrast agent exposure, he noted rash, pain, headaches, and hoarseness. Years after the exposure to the contrast agents, he continued to have detectable Gd in urine and serum. Conclusions: Practitioners should be aware of long-term intracellular Gd retention (including the brain) as patients increasingly turn to consultants with concerns about Gd deposition disease. Data from patient advocates demonstrate that Gd is eliminated in intermediate and long phases, which may represent a multicompartment model. The commercialization of Gd use in imaging studies is outpacing the science addressing the long-term consequences of harboring this alien, toxic, nonphysiologic rare earth metal.
ABSTRACT
The primary solute of the milieu intérieur is sodium and accompanying anions. The solvent is water. The kidneys acutely regulate homeostasis in filtration, secretion, and resorption of electrolytes, non-electrolytes, and minerals while balancing water retention and clearance. The gastrointestinal absorptive and secretory functions enable food digestion and water absorption needed to sustain life. Gastrointestinal perturbations including vomiting and diarrhea can lead to significant volume and electrolyte losses, overwhelming the renal homeostatic compensatory mechanisms. Dysnatremia, potassium and acid-base disturbances can result from gastrointestinal pathophysiologic processes. Understanding the renal and gastrointestinal contributions to homeostatis are important for the clinical evaluation of perturbed volume disturbances.
ABSTRACT
Dozens of millions of people are exposed to gadolinium-based contrast agents annually for enhanced magnetic resonance imaging. Gadolinium-based contrast agents are known nephrotoxins and can trigger the potentially fatal condition of systemic fibrosis. Risk factors are practically entirely undefined. We examined the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Age- and weight-matched mice were randomized to experimental diabetes (streptozotocin) and control groups followed by systemic gadolinium-based contrast agent treatment. Nox4-deficient mice were randomized to experimental diabetes and gadolinium-based contrast agent treatment. Skin fibrosis and cellular infiltration were apparent in both gadolinium-based contrast agent-treated and experimental diabetes groups. Similarly, both groups demonstrated renal pathologies with evidence of reactive oxygen species generation. Deletion of Nox4 abrogated both skin and renal pathology, whether from diabetes or gadolinium-based contrast agent treatment. These discoveries demonstrate the importance of Nox4 in gadolinium-based contrast agent- and diabetes-induced fibrosis.NEW & NOTEWORTHY A mouse model of gadolinium-based contrast agent- and diabetes-induced fibrosis was used to demonstrate the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Using these models, we established the role of Nox4 as a mediator of reactive oxygen species generation and subsequent skin and kidney fibrosis. These novel findings have defined Nox-4-mediated mechanisms by which gadolinium-based contrast agents induce systemic diseases.
Subject(s)
Contrast Media/adverse effects , Fibrosis/chemically induced , Gadolinium/adverse effects , NADPH Oxidase 4/drug effects , Renal Insufficiency/pathology , Animals , Diabetes Mellitus, Experimental/chemically induced , Fibrosis/pathology , Kidney/drug effects , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Mice , NADPH Oxidase 4/metabolism , Nephrogenic Fibrosing Dermopathy/chemically induced , Nephrogenic Fibrosing Dermopathy/pathology , Renal Insufficiency/chemically inducedABSTRACT
Changing medications within a drug class requires considering the indication and dosage, possible adverse effects, and drug-drug interactions.
ABSTRACT
Gadolinium-based contrast agents (GBCAs) have provided much needed image enhancement in magnetic resonance imaging (MRI) important in the advancement of disease diagnosis and treatment. The paramagnetic properties of ionized gadolinium have facilitated these advancements, but ionized gadolinium carries toxicity risk. GBCAs were formulated with organic chelates designed to reduce these toxicity risks from unbound gadolinium ions. They were preferred over iodinated contrast used in computed tomography and considered safe for use. As their use expanded, the development of new diseases associated with their use (including nephrogenic systemic fibrosis) has drawn more attention and ultimately caution with their clinical administration in those with impaired renal function. Use of GBCAs in those with preserved renal function was considered to be safe. However, in this new era with emerging clinical and experimental evidence of brain gadolinium deposition in those with repeated exposure, these safety assumptions are once again brought into question. This review article aims to add new perspectives in thinking about the role of GBCA in current clinical use. The new information begs for further discussion and consideration of the risk-benefit ratio of use of GBCAs.
Subject(s)
Contrast Media , Nephrogenic Fibrosing Dermopathy , Contrast Media/adverse effects , Gadolinium/adverse effects , Humans , Image Enhancement/methods , Magnetic Resonance Imaging/adverse effects , Nephrogenic Fibrosing Dermopathy/chemically inducedABSTRACT
ABI3BP is a relatively newly identified protein whose general biological functions are not yet fully defined. It is implicated in promoting cellular senescence and cell-extracellular matrix interactions, both of which are of vital importance in the cardiovascular system. ABI3BP has been shown in multiple studies to be expressed in the heart and vasculature, and to have a role in normal cardiovascular function and disease. However, its precise role in the cardiovascular system is not known. Because ABI3BP is present in the cardiovascular system and is altered in cardiovascular disease states, further investigation into ABI3BP's biological and biochemical importance in cardiovascular health and disease is warranted.
ABSTRACT
We tested the hypothesis that induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) are less able to adhere to the extracellular matrix (ECM) derived from failing human hearts with dilated cardiomyopathy compared to nonfailing human heart ECM. We also hypothesized that morphological development, cell beating rates, and mRNA levels of Nkx2.5 and cardiac troponin T would be altered after culturing the iPSC-CPCs on the failing heart ECM under cardiomyocyte differentiation conditions. We used microscopy to distinguish between adhered and unadhered cells, and to determine morphological development and cell beating. We used qPCR to determine mRNA levels. iPSC-CPCs show a significantly reduced ability to adhere to the ECM of failing hearts and higher expression of Nkx2.5 mRNA. However, morphological development, cell beating rates, and cardiac troponin T levels were not significantly altered in the cells cultured on the failing heart ECM. Our study shows that the failing heart ECM from patients with dilated cardiomyopathy impairs initial iPSC-CPC adhesion and may have a modest effect on the ability of the cells to transdifferentiate into cardiomyocytes.
ABSTRACT
Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.