Nephrogenic Systemic Fibrosis Is Mediated by Myeloid C-C Chemokine Receptor 2

Abstract

Gadolinium-based contrast agents are implicated in several pathologic abnormalities (long-term retention in vital organs such as the skin and the brain) and are the cause of a sometimes fatal condition in patients, nephrogenic systemic fibrosis. Bone marrowederived fibrocytes and the monocyte chemoattractant protein-1 inflammatory pathway have been implicated as mediators of the adverse effects induced by gadolinium-based contrast agents. Mechanistic studies are scant; therefore, a mouse model of nephrogenic systemic fibrosis was established. Dermal cellularity was increased in contrast-treated green fluorescent protein (GFP) chimeric mice. GFP in the skin and fibrosis were increased in the contrast-treated chimeric animals. Monocyte chemoattractant protein-1 and CC chemokine receptor 2 were increased in the tissues from contrast-treated mice. CC chemokine receptor 2edeficient recipients of GFP-expressing marrow had an abrogation of gadolinium-induced pathology and displayed less GFP-positive cells in the skin. Wild-type animals that received CC chemokine receptor 2edeficient bone marrow had a complete abrogation of dermal pathology. That GFP levels and expression increase in the skin, in tandem with a fibrocyte marker, supports the blood-borne circulating fibrocyte hypothesis of the disease. As of now, fibrocyte trafficking has yet to be demonstrated. Importantly, our data demonstrate that the monocyte chemoattractant protein-1/C-C chemokine receptor 2 axis plays a critical role in the pathogenesis of nephrogenic systemic fibrosis.

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

“…Gadolinium-based contrast agents-often inappropriately assumed to be inert-increased glycolysis (Figure 5a), similar to what has been found in cancerous cells (Porporato, Dhup et al 2011). Concomitantly, gadolinium-based contrastproven biologically-active substances (Wagner, Tan et al 2012, Do, Barnes et al 2014, Drel, Tan et al 2016, Do, Drel et al 2019, Leyba and Wagner 2019)dysregulate energy production in the cortex. Citrate was elevated in the tissue, yet the glycolytic intermediates were suppressed with an elevation of lactate, suggesting that oxidative phosphorylation is impaired (Figure 11).…”

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

“…We also observed gadolinium deposition in multiple organs including skin, kidney and heart and found evidence of bone marrow-derived fibrocytes in these tissues (31,32). 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

“…[4][5][6] Systemic fibrosis is mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor 2. 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.…”

“…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).…”