Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats

Abstract

ObjectivesThe purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain.Materials and MethodsA comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur.ResultsAfter the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 μmol/L) at this time point. Plasma Gd concentration was then around 1 μmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups.ConclusionsRenal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.

Dechelation (Transmetalation)

“…It is clear from the evaluation of animals receiving such agents that renal dysfunction (with the correlate in patients being mild or moderate chronic kidney disease) potentiates deposition of gadolinium not only in the cerebellum but also in the brain and bones. 61 These results are fully consistent with a prior clinical study, 62 thus stressing the translational value of most nonclinical studies.…”

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

“…In renally impaired rats, when compared with rats with normal renal function, gadolinium uptake, after multiple injections of gadodiamide, was potentiated in the cerebellum, brain, and bones. 34 This study also showed that plasma gadolinium was predominately in a disassociated, soluble form. Total Gd concentration in the brain correlated with renal function.…”

“…46 Evidence-from both clinical and preclinical studies-to date favors that patients with impaired renal function are at higher risk for gadolinium accumulation in the brain and in bone, with this conclusion applying only to the group of agents that have such gadolinium deposition, the linear chelates. 34 Both cited studies furthermore noted deposition of gadolinium in the choroid plexus (beyond what was previously established, specifically the dentate nucleus and the globus pallidus). The Cornell and Columbia groups subsequently published a study of patients receiving 35 or more linear GBCA administrations with normal renal function.…”

Region of Interest Selection in Nonclinical Studies of Accumulated Gadolinium-based Contrast Agent–induced T1 Hyperintensity in Deep Cerebellar Nuclei

“…One reason for using contrast material, nonetheless, is improved image quality. We have shown that ferumoxtyol significantly improves aortic annulus image quality compared with unenhanced MR angiography, resulting in better measurement reproducibility (3). A second possible reason is imaging time reduction.…”