Group 2 gadolinium-based contrast agents seem to be safe even for patients with chronic kidney disease

Nephrogenic systemic fibrosis (NSF) is a rare disorder that has been observed in some patients with impaired renal function after exposure to a gadolinium-based contrast agent (GBCA) for magnetic resonance imaging (MRI). 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. After GBCAs were identified as a cause of the disorder in 2006, rule makers in Europe banned some of the less stable agents from the marked, while in the US the Food and Drug Administration (FDA) issued an advisory about the association of GBCAs and NSF in 2006 and subsequently issued a black box warning in 2007, instructing physicians to avoid the use of all GBCAs in patients at risk for NSF.

Given that kidney failure greatly increases the elimination half-life of GBCAs, it was postulated that gadolinium ions dissociate from their underlying binding ligand during the prolonged retention period, allowing tissue deposition and the eventual development of NSF. In 2010 FDA updated its gadolinium warning, specifying that 3 agents (gadopentetate dimeglumine, gadodiamide, and gadoversetamide) were responsible for most cases of NSF and therefore contraindicated in CKD . In the same update, the FDA stated that other GBCAs could be used cautiously under certain circumstances. Since screening and prevention measures have been put in place, NSF is now considered rare. Anyhow, 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 (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol). The researchers screened the literature for related studies, and excluded from the found citations (in total 2700) conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports and all studies not reporting group II GBCA administration.

In total, sixteen unique studies with 4931 patients were finally included in this systematic review and meta-analysis. 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.

The pooled incidence of NSF across all studies was 0 of 4931 (0%; upper bound of 95% CI, 0,07%). The authors conclude that "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.

It has been reported, that some patients have developed NSF after extended time following administration of GBCA (up to 8 years !). Also, the guidelines to exclude patients at risk from the use of GBCA may have systematically excluded the highest risk patients from the studied group of patients. It therefore seems reasonable to continue to apply safety rules such as:
only use the lowest possible dose, avoid repeated exposure, and patients treated with hemodialysis receive it shortly after GBCA administration.

These are only some of the questions that need to be addressed for obtaining a full understanding of the effects observed around the administration of GBCAs.

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