Synopsis

The purpose of this study was to determine the gadolinium (Gd) retention in human bone tissue after administration of Gd contrast agent such as macrocyclic (Gd-DOTA) or linear (Gd-DTPA-BMA) chelate at a standard single clinical dose and to evaluate its correlation with renal function.

Introduction

Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd) -based contrast agents in particular with the stability of Gd-complex1-3. It is reported that the stability of macrocyclic chelate is higher than linear chelate. Thus, high intensity on brain MR images is suggested to have a relationship with increased cumulative dose of linear Gd-based contrast agent in patients with normal renal function4,5. Previous study had reported on the Gd concentration remained in human bone tissue after administration of standard clinical doses6. However, this study did not determine the renal function in each patient. It is important to estimate Gd concentration compare to thier renal function.

Methods

Enrollment period: Jul 13, 2012 – Nov 03, 2016

Subjects: 14 patients (11 men and 2 women, aged between 10 to 47 years old) who underwent contrast MRI examination prior to surgical removal of a bone tumor, who met the following applicability. Patients were randomly divided into 2 groups for MR scan (Gd-DOTA administration group and Gd-DTPA-BMA administration group).

This study was approved by IRB in Kobe University.

Applicability criteria:

Patient who consent to this examination

Patient who underwent surgery 7-14 days after the MRI

Patient who was measured eGFR (hematology tests must be performed) 30 days before surgery

Patient who is a 10-65-year-old male or female with a good performance status

Patient who has no severe renal dysfunction (eGFR 30 mL/min/1.73 m3 or higher)

Six-month interval from the last Gd enhanced MRI

Exclusion criteria

Patient with contraindication criterias of contrast agents.

Too small samples to analyse.

Patient who did not consent to this study.

Patient who is unsuitable for this study decided by investigator

Contrast agents

GBCA (Gadlinium Based Contrast Agent)

Gadoterate (Gd-DOTA, Magnescope/Dotarem)

Gadodiamide (Gd-DTPA-BMA, Omniscan)

Dose 0.1 mmol Gd/kg (clinical dose) intravenous injection

Bone sampling

Bone tumor removed surgically within 7‑14 days after the contrast enhanced MRI.

Normal bone tissue in margin of tumor

Bone sample was restored at -20℃ until ICP-MS Gd measurement

Gd determination in bone

Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

Elan DRC+（PERKINELMER, INC）

Agilent 7700x（Agilent Technologies Inc.）

Internal standard (In, Rh, Tb)

Data analysis

Gd concentration in bone tissue

eGFR

The number of days from MRI scan to surgery

Age

Statistical analysis by unpaired t test (Gd-DOTA group vs Gd-DTPA-BMA group)

Results

Gd concentration and patients background are shown in Figure 1.

The mean values of Gd concentration in bone tissue, eGFR, interval MRI to surgery after single dose of Gd-contrast agent are shown in Figure 2.

Gd concentration in bone in Gd-DTPA-BMA group was significantly higher than that in Gd-DOTA group at single dose injection. No difference in renal function was found in both group.

Patients in the Gd-DTPA-BMA group showed 5.0 times higher concentration of Gd accumulated in human being bone that the Gd-DOTA group in patients with normal renal function.

Discussion

Gd chelate stability was reported in various Gd based contrast agents, due to chelate structure and ionicity. The stability constant of Gd-DTPA-DMA and Gd-DOTA are shown in Figure 3.

•The difference in clinical symptom (clinically significant effect of Gd deposition in bone tissue) was not found. This result is similar as reported in previous studies on brain MR image^1,2).

•Linear Gd chelate showed higher accumulation of Gd than macrocyclic Gd chelate in normal renal function. The usage of Gd chelate should be carefully decided taking in consideration the age, disease, history of Gd enhanced scan (number of injection / type of Gd chelate / injection intervals / dose), and others.

•It remains unclear whether frequent Gd administration in patients with normal renal function is really tolerable, and whether the accumulation of Gd will consequently cause renal failure thus generating NSF.

Conclusion

Acknowledgements

References

1. Abraham JL, Thakral C, Skov L, et al. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol. 2007;158(2):273-280.

2. Port M, Idee JM, Medina C, et al. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008:21(4):469-490.

3. Sieber MA, Lengsfeld P, Frenzel T, et al. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol. 2008 ;18(10):2164-2173.

4. Kanda T, Ishii K, Kawaguchi H, et al. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material.Radiology. 2014;270(3):834-841.

5. Errante Y, Cirimele V, Mallio CA, et al. Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation. Invest Radiol. 2014;49(10):685-690.

6. White GW, Gibby WA, Tweedle MF. Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol. 2006;41(3):272-278.