Editor’s Note: Unfortunately, we misfiled this commentary and discovered our mistake too late to post this during the peak of NephMadness. Our apologies to Dr Schieda.
Nicola Schieda is an abdominal radiologist at The Ottawa Hospital and an Assistant Professor in Radiology at The University of Ottawa. He is actively involved in clinical research focusing mainly on the imaging of genito-urinary malignancies and studying various body MRI applications.
Competitors for the Contrast Region
Gadolinium-based contrast agents (GBCA) have been in clinical use for decades and have an integral role in magnetic resonance imaging (MRI) examinations. In general, GBCA have an excellent safety profile; however, they have been identified as the causative agent in nephrogenic systemic fibrosis (NSF). Due to the associations between NSF in patients receiving GBCA and renal impairment, the use of GBCA has been considered absolutely contraindicated in patients with acute kidney injury (AKI), severe chronic kidney disease (CKD), and receiving dialysis.
Nevertheless, the vast majority of documented NSF cases have occurred in patients who received linear non-ionic or older linear ionic GBCA (often repeatedly and/or at higher-than-recommended dosage). The incidence of NSF has substantially decreased over the past several years, and this is attributed mainly to physician awareness and avoidance of GBCA in at-risk patients, the use of newer macrocyclic and linear-ionic GBCA, and avoiding repeat injections and greater-than-recommended dosing. In Canada, for example, to our knowledge, the last officially documented case of NSF occurred in a 70-year-old patient who received an unspecified GBCA in 2011.
NSF is a serious late adverse reaction associated with exposure to GBCAs that can occur in patients with severe renal impairment and for which there is currently no known specific or consistently effective treatment. Based on current evidence, NSF occurs almost exclusively in patients receiving GBCAs that have stage 4 or stage 5 CKD (based on the KDOQI classification).
Therefore, severely reduced renal function is the most important patient-related risk factor which predisposes to NSF. The degree of renal insufficiency is also important, with a much greater incidence of NSF in patients with stage 5 CKD compared to stage 4 CKD. AKI is also considered a risk factor for NSF. Risk for NSF is also generally considered to be related to the molecular structure and stability of the GBCA used.
The majority of cases of NSF that have been reported are associated with three GBCAs: gadodiamide, gadopentate dimeglumine, and gadoversetamide. The incidence of NSF using newer linear and macrocyclic agents has decreased considerably.
It is difficult to accurately estimate the prevalence of NSF, but it is now considered a rare entity. Reported incidences of NSF vary but it is generally cited to be much less than 1% when using standard dosing and macrocyclic or newer linear GBCAs; however, the true prevalence of disease may be underestimated as GBCA was avoided nearly universally in at-risk populations for a time.
The Case Against Screening
Due to the exceedingly low risk of developing NSF after GBCA administration even in at-risk patient populations with impaired renal function and because dialysis would only be prescribed in patients already receiving dialysis, screening for renal dysfunction in institutions using macrocyclic and newer linear ionic agents to prevent NSF prior to GBCA administration is irrelevant, time consuming, and expensive. A recent study by Shankar et al demonstrated that foregoing screening of renal function (including measurement of serum creatinine in patients who are identified by screening questionnaire as potentially having renal impairment) would result in substantial cost savings.
Moreover, what is the point of screening if patients who are identified as having renal impairment will proceed to GBCA-enhanced MRI anyways because the test is considered medically necessary without initiating hemodialysis or switching from peritoneal to hemodialysis? To this end, the ACR updated Policy on Contrast Media suggests optional screening for outpatient before GBCA-enhanced MRI when a Class II (macrocyclic agent or Gadobenate Dimeglumine) are used. While cases of NSF have been reported in Class II agents, the exceedingly low risk does not warrant large-scale population-based screening for renal dysfunction, is not cost effective, and may result in suboptimal patient care, potentially delaying critical imaging tests.
The Case for Screening
Routine screening for CKD in asymptomatic adults before enhanced MRI is controversial. Obtaining blood samples to determine eGFR on all patients referred for GBCA-enhanced MRI leads to considerable expense for an anticipated minimal benefit, particularly considering the exceedingly low risk of developing NSF with macrocyclic and newer linear GBCA, and furthermore may not identify patients with AKI.
Another approach would be to ask patients if they have kidney disease or use a combination of bloodwork and surveys; however, patient awareness of their renal function is poor, and directly asking patients if they have CKD is likely not an effective approach to screening. A questionnaire developed by Choyke et al has been shown to effectively stratify patients by risk of NSF and includes only six questions. Using these six questions at the time of MRI scheduling and scanning to predict eGFR < 30 mL/min/1.73m2 in 665 patients, Sena et al found that answering “no” to all questions both times the questionnaire was administered had a sensitivity of 100% (95% confidence interval 59-100%).
While it is true that patients with impaired renal function would still undergo GBCA-enhanced MRI if medically indicated and clinically necessary without initiation of dialysis or switching from peritoneal to hemodialysis to reduce the potential risk of NSF, considering alternative tests would only be possible if the patients’ renal function was known. For example, a patient with unknown renal impairment and an incidentally detected liver lesion on an ultrasound examination could undergo further evaluation with a contrast-enhanced computed tomography (CT) evaluation rather than MRI; however, the switch from CT to MRI would only be possible if the patients’ renal function was known. Moreover, the decision not to screen outpatients for renal dysfunction due to exceedingly low rates of NSF when using Class II GBCA is more complicated in the era of gadolinium deposition in the brain.
Confounder: Gadolinium Deposition in the Brain
A recently described phenomenon of gadolinium deposition in the brain was first described in 2014 by Kanda et al using T1-weighted (T1W) MRI. Subsequent studies have confirmed, both on repeat imaging and autopsy studies, that these signal changes correspond to gadolinium deposition; this occurs in patients with normal renal function and intact blood brain barriers. Health organizations, radiological societies, and the medical imaging community as a whole have been challenged with understanding these rapidly evolving developments, and determining what (if any) practice changes are warranted. Both the USFDA and Health Canada have issued communications acknowledging the phenomenon of gadolinium deposition, with plans for future investigations and updates to product monographs.
In studies reporting gadolinium deposition and the various GBCAs approved for use in Canada, gadolinium deposition has been observed with both linear and macrocyclic agents on both imaging and autopsy studies of humans. Current guidelines/policy statements on gadolinium deposition recommend restricting use of GBCA (including the ACR/ASNR Guideline) only when medically necessary, and a majority recommend or infer to not exceed recommended dosages, to avoid repeated GBCA administration unless clinically indicated, and to monitor the literature and adapt recommendations as required. The USFDA also suggests considering the use of GBCA in at-risk populations. The guidelines are listed below:
How can one restrict the use of gadolinium, minimize repeated or excessive doses, and consider the use of GBCA carefully in at-risk populations (including those with renal impairment) when we no longer perform any screening to identify occult renal disease? In the era of gadolinium deposition, even though NSF cases have become quite rare, screening for renal function remains appropriate to minimize any potential deposition if at all possible.
– Post written by Nicola Schieda
As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.