Gadolinium-Based Contrast Safe for Patients With CKD

Nicola M. Parry, DVM

December 10, 2019

Patients with chronic kidney disease (CKD) who receive a gadolinium-based contrast agent (GBCA) have a low risk of developing nephrogenic systemic fibrosis (NSF), a systematic review and meta-analysis published online December 9 in JAMA Internal Medicine has shown.

"Findings suggest that the risk of nephrogenic systemic fibrosis from group II gadolinium-based contrast agent administration in stage 4 or 5 chronic kidney disease is likely less than 0.07%," write Sean A. Woolen, MD, from the University of Michigan, Ann Arbor, and colleagues.

"[P]otential diagnostic harms of withholding group II gadolinium-based contrast agents for indicated examinations may outweigh the risk of nephrogenic systemic fibrosis in this population."

NSF is a rare disorder that may occur in patients with acute kidney injury or stage 4 or 5 CKD who have been exposed to GBCAs.

The characteristic features of NSF include diffuse skin thickening and fibrosis. In severe cases, systemic involvement may affect the heart, lungs, liver, and skeletal muscle. The lesions are irreversible, progressive, and sometimes fatal.

The risk for NSF to individual patients remains poorly understood. With this in mind, Woolen and colleagues assessed the incidence of NSF in patients with stage 4 or 5 CKD after exposure to a group II GBCA.

The investigators included studies that involved patients with "stage 4 or 5 CKD with or without dialysis, administration of an unconfounded American College of Radiology classification group II GBCA (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol), and incident NSF as an outcome."

They excluded conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports, and manuscripts not reporting total group II GBCA administrations.

Overall, the final study cohort comprised 16 studies that included 4931 patients.

These studies were published from May 2008 through April 2019, had a collective study period of 1997 through 2017, and had retrospective cohort (11 of 16 [69%]) and prospective cohort (5 of 16 [31%]) designs.

Most of the 16 studies were conducted in Europe (8 of 16; 50%) and the United States (7 of 16; 44%). Seven (44%) were multicenter studies.

Across all 16 studies, the pooled incidence of NSF in patients with stage 4 or 5 CKD who had received a group II GBCA was 0%.

The upper bound of the 95% confidence interval for this estimate was 0.07%.

According to the authors, the upper bound of risk among the GBCAs involved ranged from 0.12% (for gadobenate dimeglumine; 0 of 3167) to 1.59% (for gadoteridol; 0 of 230).

This range reflects sample size, they add.

"These data support recent updates to ACR [American College of Radiology] and European Society of Urogenital Radiology guidelines liberalizing use of low-risk GBCAs for indicated examinations" for patients with stage 4 or 5 CKD, Woolen and colleagues conclude.

In an invited commentary, Saugar Maripuri, MD, and Kirsten L. Johansen, MD, both from Hennepin County Medical Center, Minneapolis, Minnesota, concur that these findings support the assertion that risk for NSF is extremely low in this patient population.

However, they also highlight some of the limitations of this study.

First, although dialysis patients have the highest risk of developing NSF, it is not known how many of the included GDBA exposures occurred in patients with stage 4 or 5 CKD, they note.

Second, they stress that a pooled risk estimate does not reflect differences in risk according to level of kidney function.

"Nonetheless, one cannot ignore the fact that not a single reported case of NSF occurred in nearly 5000 patient exposures," they write.

Although the data favor use of group II GBCAs for patients with CKD, a disconnect persists between the more conservative approach taken by the US Food and Drug Administration (FDA) and the more permissive guidelines from the ACR.

Maripuri and Johansen explain that in 2010, the FDA updated its gadolinium safety communication, warning that three agents (gadopentetate dimeglumine, gadodiamide, and gadoversetamide) were associated with most cases of NSF and thus were contraindicated in patients with CKD. However, other GBCAs could be used cautiously under certain circumstances.

"This incongruity may be mirrored by a disconnect between nephrologists and radiologists," they say, "with the former concerned that the lack of cases may be driven by avoidance of GBCAs in high-risk patients and the latter more convinced by the biochemical case for safety of newer GBCAs."

In view of the emerging data, the editorialists' opinion is that group II GBCAs may be used cautiously in at-risk patients, including those receiving dialysis. They recommend, however, that patients be given the lowest possible dose and that repeated exposures be avoided. Those undergoing hemodialysis should receive treatment shortly after GBCA exposure, they add.

Although they acknowledge that changing practice behavior could be challenging, they emphasize that nephrologists may need to come to terms with the natural tendency to focus more on avoiding errors of commission than errors of omission.

"Perhaps the combination of zero events and a solid biochemical rationale will help get us there," Maripuri and Johansen conclude.

The study authors' and editorialists' relevant financial relationships are listed in the original articles.

JAMA Intern Med. Published online December 9, 2019. Abstract, Commentary

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