It has been presupposed that the thermodynamic stability constant ( Ktherm) of gadolinium-based MRI chelates relate to the risk of precipitating nephrogenic systemic fibrosis. The present study compared low- Ktherm gadodiamide with high- Ktherm gadoteridol in cultured fibroblasts and rats with uninephrectomies. Gadolinium content was assessed using scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy in paraffin-embedded tissues. In vitro, fibroblasts demonstrated dose-dependent fibronectin generation, transforming growth factor-β production, and expression of activated myofibroblast stress fiber protein α-smooth muscle actin. There were negligible differences with respect to toxicity or proliferation between the two contrast agents. In the rodent model, gadodiamide treatment led to greater skin fibrosis and dermal cellularity than gadoteridol. In the kidney, both contrast agents led to proximal tubule vacuolization and increased fibronectin accumulation. Despite large detectable gadolinium signals in the spleen, skin, muscle, and liver from the gadodiamide-treated group, contrast-induced fibrosis appeared to be limited to the skin and kidney. These findings support the hypothesis that low- Ktherm chelates have a greater propensity to elicit nephrogenic systemic fibrosis and demonstrate that certain tissues are resistant to these effects.

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.

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.