The kidney urea cycle is perturbed by gadolinium‐based contrast agent treatment

Abstract

IntroductionGadolinium‐based contrast agents (GBCAs) are used extensively in magnetic resonance imaging. GBCA administration causes systemic fibrosis and long‐term retention of gadolinium in every vital (and non‐vital) organ, including the brain. Gadolinium‐based contrast agents are metabolic disruptors. GBCA administration leads to hyperlipidemia, insulin resistance, and renal disease on par of that induced by high fat diet‐induced experimental obesity (Do C et al, Toxicol Appl Pharmacol 2019 Jul 15;375: 32–45). Gadolinium‐based contrast agents induce glycolytic switching in renal cortex similar to that induced by a high fat diet. The urea cycle is requisite for urinary concentration in the mammal and for elimination of nitrogenous waste. Because high fat diet can also alter the urea cycle, we investigated the impact of gadolinium‐based contrast agent treatment on the urea cycle using metabolomic data.MethodsWild‐type C57/BL6 mice were randomized by age and weight into either a 60% saturated fat diet (20% protein, 20% carbohydrate) ad libitum (n = 20) or control chow (n = 20) for 20 weeks. At Week 17 groups were then sub‐randomized into untreated (n = 10) or GBCA‐treated (n = 10) (Omniscan, 2.5mmol/kg, intraperitoneally) subgroups for the remaining 4 weeks. Kidneys were isolated from mice and then snap frozen in liquid nitrogen. Metabolites were profiled by liquid chromatography‐mass spectrometry (Metabolon, Morrisville, NC). Comparisons were performed by two‐way ANOVA with post‐hoc Tukey HSD.ResultsGBCA treatment (P ≤ 0.05) reduced citrulline relative to the non‐treated group. GBCA treatment decreased aspartate relative to no treatment (P ≤ 0.001). Although high fat diet increased renal aspartate, the effect was reduced by the combination with gadolinium‐based contrast agent. Arginosuccinate was reduced by high fat diet with respect to the control (with similar trends for gadolinium treatment and the combination). Fumarate (also a tricarboxylic acid cycle metabolite) was greatly reduced by high fat diet and the combination with gadolinium‐based contrast agents (P < 0.0015 and P < 0.05, respectively). Although there was a trend for gadolinium to reduce urea levels relative to control, this effect of gadolinium was reversed in the setting of high fat diet (P < 0.005).ConclusionThese studies have been instrumental in defining the metabolic impact of GBCAs. Our results imply that high fat diet activates argininosuccinate lyase (thereby increasing L‐arginine). Gadolinium‐induced suppression of citrulline is either suppression of arginosuccinate synthetase or an increase of ornithine transcarbamoylase. The fact that gadolinium‐based contrast agents impact the same metabolic pathway as an experimental high fat diet suggest that there are physiologic disruptions (potentially pathologic) that will be aggravated by the combination, and that metabolic syndrome is a risk factor for gadolinium‐induced disease.Support or Funding InformationThe research was funded by the Veterans Administration Merit Award (I01 BX001958, BW); the National Institutes of Health Grant R01 DK‐102085 (BW); and the DCI/Kidney Institute of New Mexico.