Gadolinium-Based Contrast Agents: Updates and Answers to Typical Questions Regarding Gadolinium Use

Gadolinium-Based Contrast Agents in Patients With Nephrogenic Systemic Fibrosis

In the early 2000s, a small number of patients with advanced CKD and previous GBCA exposure showed signs of skin edema and erythema in their extremities that sometimes worsened into thickened, woody, and contracted skin.^4,5 In addition, the sclerosing process could extend to other organs and tissues, such as the lungs, diaphragm, esophagus, myocardium, skeletal muscle, and dura mater. This condition, termed NSF,^5,11 was primarily associated with the use of less stable linear GBCAs in patients with advanced CKD, and it rarely developed when cyclic GBCAs were used.⁹

The pathogenesis of NSF, previously reviewed by Cheong and associates,¹² most likely involves the dissociation of free and toxic Gd³⁺ through transmetallation by endogenous metal ions such as Zn²⁺ or Cu²⁺.

Increased awareness among practicing clinicians regarding the relationship among NSF, advanced CKD, and less stable linear (Group I) GBCAs has led to changes in clinical practice, including the use of more-stable GBCAs. Furthermore, clinical research uncovering the potential underlying mechanisms of NSF, together with guidance regarding GBCA use provided by the US Food and Drug Administration (FDA) and several professional societies,^7,10,13–17 has reduced or eliminated the incidence of NSF.^18–22 Beyond 2008, Attari and colleagues¹⁹ noted only 7 out of 639 biopsy-confirmed NSF cases after GBCA administration, further supporting a decline in the incidence of NSF.

With respect to NSF, macrocyclic (Group II) GBCAs have been relatively safe.^19,23–26 In the Gadobutrol in Renally Impaired Patients Study²⁵—a prospective international, multicenter, open-label study in which gadobutrol-enhanced MRI was used—no NSF was reported during the 2-year follow-up period; 284 of 908 patients (31.3%) had an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². In a recent meta-analysis of 16 studies, comprising 4,931 patients with stage 4 or 5 CKD who were given a Group II GBCA and were monitored for up to 72 months, no NSF was reported.²⁶

Few investigators have studied the safety of using gadoxetic acid (a Group III GBCA, primarily for hepatobiliary imaging),^27,28 although no NSF was noted during follow-up in patients who had moderate or severe CKD.²⁷ In studies of Group II gadobenate dimeglumine use in patients with severe CKD,^21,22,29 none of the patients developed NSF during the study period.

Gadolinium-Based Contrast Agents in Patients With Chronic Kidney Disease

In 2017, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency suspended the use of high-risk linear Group I GBCAs (gadodiamide, gadopentetate dimeglumine, and gadoversetamide),¹³ although gadopentetate dimeglumine can be used during an MRI arthrogram.¹³ Gadobenate dimeglumine and gadoxetic acid are now limited to hepatobiliary imaging only. Gadopentetate dimeglumine and gadoversetamide have been discontinued in the US, whereas gadodiamide is still available, albeit with a contraindication warning for patients with acute kidney injury (AKI) and those with an eGFR <30 mL/min/1.73 m².

Various professional societies have provided fairly similar recommendations regarding GBCA use in patients with CKD.^7,10,14–16 No special precautions are typically necessary for patients with stage 1, 2, or 3 CKD. Furthermore, when a Group II GBCA is being used for a clinically indicated study, it is unnecessary to measure eGFR or avoid GBCA administration in patients with advanced CKD who are not undergoing dialysis. For patients undergoing hemodialysis, the next treatment session can be scheduled as soon as possible after MRI, preferably within a few hours.

Group II (macrocyclic) GBCAs should be used whenever possible, given their exceedingly low to nonexistent risk for inducing NSF.^14–16,23 Hepatobiliary imaging may necessitate the only available class III GBCA (gadoxetic acid), which also imposes minimal NSF risk.^15,16,27,28

The MRI physician can play an important role in optimizing imaging protocols to minimize the required total GBCA dose. In general, when multiple GBCA doses are expected in an urgent situation, imaging should not be delayed simply because of NSF risk. When multiple doses are anticipated for elective imaging, a delay of longer than 24 hours or dialysis between doses in dialysis-dependent patients may improve GBCA clearance.⁷

In patients with advanced CKD or undergoing dialysis, the use of GBCA in MRI studies should be evaluated on a case-by-case basis. Specifically, clinicians should consider whether non–contrast-enhanced MRI will provide sufficient information or whether any other imaging method can provide information similar to that obtained from MRI with GBCA enhancement.

What is the Recommended Dose for a Single Session?

In general, only the FDA-approved GBCA dose should be administered during a single imaging session. The approved dose is 0.1 mmol/kg, except for the liver-specific gadoexetic acid dose (0.025 mmol/kg). Nonetheless, imaging physicians can make exceptions according to imaging requirements.¹⁰ The use of a lower-than-recommended GBCA dose for NSF prevention is not supported by evidence^15,16 and may compromise image quality.^16,23,30

What is the Recommended Time Interval Between Gadolinium-Based Contrast Agent Administrations?

In patients with normal renal function, GBCAs have a half-life of approximately 1.5 hours³¹; thus, more than 95% of an injected dose is eliminated within 24 hours.⁹ However, the mean half-life is prolonged to 5.6 hours in patients with moderate CKD and to 9.2 hours in those with severe CKD, and it can be as long as 30 hours when the GFR is <5 mL/min.^9,31 Hemodialysis removes GBCAs with ~70% clearance after 1 session and >95% clearance after 3 sessions.³² Thus, the following guidelines for the repeat administration of GBCA are recommended:

• In patients with normal renal function, GBCA can be readministered after 24 hours if a GBCA-enhanced MRI examination is clinically necessary.⁹ The European Society of Urogenital Radiology recommends at least 4 hours between GBCA injections in patients with an eGFR >30 mL/min/1.73 m².¹⁴ The most recent joint consensus statement from the American College of Radiology and the National Kidney Foundation states that “if multiple urgent Group II or Group III GBCA doses are indicated, subsequent dose(s) should not be delayed for fear of NSF.”⁷

• For patients undergoing hemodialysis, 3 dialysis sessions will clear >95% of a GBCA. For this reason, GBCA can be readministered one week later for a nonurgent, clinically indicated study.¹⁴

• For nondialysis outpatients with suspected advanced (severe) CKD, GBCA can be administered one week apart for a nonurgent, clinically indicated study, taking into account the prolonged half-life of GBCA in patients with severe CKD.¹⁴

Is Routine Evaluation of Renal Function Necessary?

According to the most recent recommendations from the Canadian Association of Radiologists, eGFR estimation is no longer needed for outpatients, because Group II and Group III GBCAs are associated with an exceedingly low to nonexistent risk for NSF.¹⁶ The American College of Radiology and National Kidney Foundation consensus statement suggests that eGFR evaluation is not mandatory for any Group II GBCA, but that it is necessary for Group III GBCAs.⁷

It is important to ascertain whether an outpatient is undergoing dialysis so that the next dialysis session can be facilitated, preferably as soon as feasible, after GBCA administration.^7,15 For inpatients, even those given a Group II GBCA, the imaging team should be alert for AKI along with concurrent medical issues, because AKI is a risk factor for NSF.¹² An available alternative imaging method should be considered for patients with AKI. However, if MRI with GBCA is clinically indicated in the presence of AKI and no alternative imaging method is available, MRI with GBCA should be performed and not delayed, given the very low risk for NSF for a standard GBCA dose.⁷ In this situation, a Group II GBCA should be used. Figure 1 shows an overview of GBCA administration.

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Do Gadolinium-Based Contrast Agents Cause Acute Kidney Injury?

Administering an FDA-approved dose of GBCA is not generally associated with postcontrast AKI, especially in patients with normal renal function.^9,14,33,34 Using a higher-than-approved dose or an intra-arterial injection are well-described risk factors for GBCA-associated postcontrast AKI.^9,34

When Should Hemodialysis and Peritoneal Dialysis Be Performed After Gadolinium-Based Contrast Agent Administration?

Hemodialysis effectively removes GBCAs.³² Dialysis should optimally be performed as soon as possible after GBCA administration.^7,15,35 However, no clear-cut evidence supports the hypothesis that hemodialysis prevents NSF in at-risk populations.^15,36 Therefore, hemodialysis should not be initiated solely to prevent NSF.

Even though it is not feasible to perform dialysis as soon as possible after MRI with GBCA, the benefit of MRI with use of a GBCA outweighs the risk of NSF, so MRI should still be performed if clinically indicated. The patient should then continue with regularly scheduled dialysis after MRI.⁷

Peritoneal dialysis should continue after GBCA administration. Insufficient data are available to support switching from peritoneal dialysis to hemodialysis.³⁰

Is GBCA Administration Safe in Breastfeeding Mothers?

In women with normal renal function, <0.04% of a GBCA dose is excreted into breast milk within the first 24 hours after it is administered. Infants absorb <1% of this small amount from their gastrointestinal tract. The expected systemic dose absorbed by the infant is <0.0004% of the intravascular dose given to the mother; therefore, the likelihood of an adverse effect from such a small amount of GBCA absorbed from breast milk is remote,¹⁰ suggesting that no breastfeeding interruption is required after GBCA administration.^10,40,41

Gadolinium Deposition

Kanda and colleagues⁴² first reported the observation of T1-weighted hyperintensities in the dentate nucleus and globus pallidus during the brain MRI of patients with normal renal function who had received multiple doses of linear GBCAs in the past. In tissues with similar MRI findings, Gd deposits were detected by using spectroscopy and electron microscopy.⁴³ Gadolinium deposition in other brain regions and extracranial organs has also been reported, even in patients with normal renal function.⁷ Gadolinium deposition in the brain is thought to be a kinetic process,⁴⁴ suggested after studies in rodents revealed that the accumulation of intact Gd-chelate molecules of both linear and macrocyclic GBCAs in the brain was progressively eliminated over time. On the other hand, dechelated Gd (predominantly from linear GBCAs) binding to soluble macromolecules led to permanent deposition.^45,46

One proposed mechanism of Gd accumulation in tissues is competition with other metals for the contrast agent chelator.⁴⁷ The result is transmetallation, whereby endogenous metals such as Fe³⁺, Zn²⁺, Cu²⁺, and Ca²⁺ have a high affinity for the chelator and release Gd³⁺, which is deposited in the tissue as Gd phosphate.⁴⁷ The iron-rich basal ganglia are heavily invested with metal transporters that may favor the accumulation of insoluble Gd.

Studies that compare the degree of Gd deposition associated with various GBCAs are lacking.³⁰ A few autopsy and imaging studies of the brain have revealed evidence of Gd deposits from both Group I and II GBCAs, with much greater Gd deposition for Group I (linear) GBCAs than from Group II GBCAs, presumably reflecting the more stable nature of Group II GBCAs.^30,47 Although no negative health effects from Gd brain deposition have been identified,^13,17,23,30 further research and longer-term monitoring are warranted.

Recommendations for GBCA use that are specifically related to Gd brain deposition include using GBCAs only when medically necessary, not exceeding the recommended dose, and avoiding repeated GBCA administration unless clinically indicated.³⁰ Given that comparison studies of GBCAs are limited, the more stable Group II (macrocyclic) GBCAs are generally the best option, unless hepatobiliary imaging is required. When macrocyclic GBCAs are not available, or if the patient has a history of severe allergic reaction to Group II GBCAs, Group I linear agents may be used after the risk-to-benefit ratio is considered.³⁰