Gadolinium-based contrast agents: Stimulators of myeloid-induced renal fibrosis and major metabolic disruptors

Abstract

Evidence for gadolinium-based contrast agent-(GBCA-) induced disease continues to mount. Risk factors for gadolinium-induced systemic fibrosis are entirely unexplored. Obesity-related renal injury is characterized by activation of glomerular mesangial cells and podocyte damage with alteration of lipid metabolism/lipid accumulation in both cell types resulting in matrix accumulation and eventual progression to glomerulosclerosis. We examined the consequences of GBCA treatment in the kidneys from mice with normal kidney function and the potential interplay between obesity and gadolinium exposure. We found that administration of GBCA (4 weeks) causes significant renal fibrosis and podocyte injury that are associated with metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis demonstrated that renal lipid metabolism and metabolic markers of collagen turnover are significantly altered by gadolinium. GBCA stimulates myeloid-derived fibrocytes to the kidney. Obesity was induced by feeding a group of mice a high fat diet (HFD) for 22 weeks. Groups were sub-randomized to GBCA treatment versus none for 4 weeks before sacrifice. HFD-induced fibrosis and podocyte injury were worsened by GBCA. Similarly, HFD-mediated hyperlipidemia and lipid metabolites were exacerbated by gadolinium. This is the first evidence that GBCA causes significant metabolic disorders and kidney injury in mice without renal insufficiency and that the injurious actions of GBCA are amplified by obesity. The understanding of the functional interplay between gadolinium and obesity will allow the development of therapeutic interventions or the establishment of effective preventive measures to reduce gadolinium-and obesity-mediated renal pathologies.

Gadolinium-Based Contrast Agent Use, Their Safety, and Practice Evolution

“…Myeloid C-C chemokine receptor 2 appeared to play an important role in fibrosis triggered by GBCA exposure (33,34). Furthermore, our animal studies uncovered metabolic disruptions caused by GBCA exposure (35).…”

Gadolinium Deposition Disease: A Case Report and the Prevalence of Enhanced MRI Procedures Within the Veterans Health Administration

“…6,7 Even in the setting of normal renal function, Gd-based contrast induces the formation of Gd-rich nanoparticles in the skin and kidney. 7,8 Far from being inert, Gd-based contrast agents induce systemic metabolic changes such as hypertriglyceridemia, elevations in lowdensity lipoprotein cholesterol, insulin resistance, and the Warburg effect (glycolytic/ energy switching) in the renal cortex concomitant with profound mitochondrial abnormalities. 8 We have discovered that the rate of Gd-enhanced procedures has increased immensely within the Veterans Health Administration (VHA) system in a subset of patients with designated kidney disease (Table 2).…”

“…Nonetheless, Gd is retained long-term in subjects with normal renal function, in symptomatic patients, permanently in the brains of patients, and in every organ we have tested with our animal models. 3,7,8,[10][11][12] Patients with normal renal function continue to report symptoms attributed to Gdbased contrast agents concomitant with retarded elimination. Numerous patients with normal renal function developed similar or novel symptoms that have been attributed to Gd concomitant with detectable urinary Gd years after exposure.…”

Wie gefährlich ist die Kontrastmittelexposition für die Nieren? Strategien der Nephroprotektion

“…Die klinische Relevanz dieser Ablagerungen ist jedoch noch nicht endgültig geklärt. Neueste Studien an Tiermodellen sehen jedoch noch weitere, bislang unbekannte Interaktionen von Gd im Körper, u. a. durch Beeinflussung des Fettstoffwechsels [42]. Inwieweit diese Interaktionen für die Nierengesundheit bedeutsam sind bzw.…”