#NephMadness 2018: Gadolinium Toxicity – Gaps in Knowledge

Brent Wagner, MD

Dr. Wagner is the inaugural Director of the Kidney Institute of New Mexico, the Renal Section Chief of the New Mexico Veterans Administration Health Care System, and an Associate Professor of Medicine in the Division of Nephrology at the University of New Mexico Health Science Center. His research interest is in the molecular and cellular mechanisms of gadolinium-based contrast agent-induced diseases, including ‘nephrogenic’ systemic fibrosis. Follow him @Wagner_Nephro.

Competitors for the Contrast Region

Contrast is Nephrotoxic vs Contrast is NOT Nephrotoxic

Gadolinium in CKD4 vs Iodinated Contrast in CKD4

“We’re taking single studies and drawing massive conclusions, and I don’t think we’re there yet in terms of chemical stabilities and macrocyclic versus linear. There’s not a lot of data,” for the safety of gadolinium-based contrast agents. — Dr. Robert McDonald, September 8, 2017, United States Food & Drug Administration (USFDA) Medical Imaging Drugs Advisory Committee (MIDAC) meeting.

No matter what you have read, we don’t know the precise glomerular filtration rate where the disease cannot occur—what we know has been based on retrospective, non-experimental case reports. We don’t know how gadolinium-based contrast agents trigger the disease; several different brands have been tied to the condition. We don’t know the threshold of the gadolinium contrast agent or the conditions that lend themselves to the disease.

Not all patients with end-stage kidney disease (ESKD) develop ‘nephrogenic’ systemic fibrosis even after multiple doses, yet others with chronic kidney disease (CKD) — with enough intact kidney function where dialysis is not needed — can succumb to the disease after just a single dose (and sometimes symptom onset will occur years after gadolinium-based contrast agent exposure).

“Gadolinium exposure in organ donors may cause nephrogenic systemic fibrosis in transplant recipients never exposed to gadolinium,” N. Scheinfeld, Assistant Attending at St. Luke’s Roosevelt Hospital Center and Assistant Clinical Professor of Dermatology at Columbia University.

‘Nephrogenic’ systemic fibrosis has been discovered in transplant recipients of solid organs (i.e., heart and kidney) who were not exposed to gadolinium (but it was not reported whether the donors were). Patients have developed ‘nephrogenic’ systemic fibrosis after single, label doses of gadolinium-based contrast. Among the first 13 patients where a gadolinium-based contrast agent was linked to ‘nephrogenic’ systemic fibrosis, the doses that elicited the disease was well within the label range (from 9 to 25 mmol). Clearance of the gadolinium-based contrast agent with conventional dialysis does not prevent the disease.

If we consider that ‘nephrogenic’ systemic fibrosis can be triggered by a solid organ transplant from a donor who was exposed to gadolinium-based contrast and in patients with CKD—10% of patients with ‘nephrogenic’ systemic fibrosis have not had hemodialysis; at the University of Copenhagen, this figure was 60%—after just a single dose, then we accept that the facts do not support the argument that there is dose-dependence. This is important because two critical factors for acquisition of the disease have not been defined:

1) the degree of kidney dysfunction, nor

2) the threshold of gadolinium required.

There are undefined risk factors that are lurking.

Table. Properties and categorization of the gadolinium-based contrast agents.
Brand name Generic name log (Ktherm)* log 7.4 (Kcond) Structure Valence Primary clearance route 2016 Packages sold ACR group# EMA risk category||
Gadovist Gadobutrol 21.8 15.5 Macrocyclic Non-ionic Urine 2852245 II Low
MultiHance Gadobenate dimeglumine 22.2 18.4 Linear Ionic Urine 2249498 II Low
Dotarem Gadoterate meglumine 25.2 19.3 Macrocyclic Ionic Urine 932290 II Low
Magnevist Gadopentetate dimeglumine 22.5 18.4 Linear Ionic Urine 863932 I High
ProHance Gadoteridol 23.8 17.2 Macrocyclic Non-ionic Urine 717479 II Low
Omniscan Gadodiamide 16.9 14.9 Linear Non-ionic Urine 653058 I High
OptiMARK Gadoversetamide 16.8 15 Linear Non-ionic Urine 408142 I High
Eovist Gadoxetic acid 23.5 18.7 Linear Ionic Urine/ hepatobiliary 121118 III Medium
Ablavar Gadofosveset trisodium 22.1 18.9 Linear Ionic Urine 0 III Medium

* log (Ktherm) refers to the in vitro thermodynamic equilibrium of Gd3+ and the proprietary ligand

log 7.4 (Kcond) refers to the Ktherm as measured at pH 7.4

Data obtained from Appendix A, Drug Utilization Tables, USFDA MIDAC September 8, 2017 Briefing Information, page 188.

# The American College of Radiology (ACR) Manual on Contrast Media classification of gadolinium-based contrast agents relative to ‘nephrogenic’ systemic fibrosis is based on observational data. Group I encompasses the agents associated with the greatest number of ‘nephrogenic’ systemic fibrosis cases. Group II includes the agents associated with “few, if any unconfounded cases of” ‘nephrogenic’ systemic fibrosis. Group III are the “agents for which data remains limited regarding [‘nephrogenic’ systemic fibrosis] risk, but for which few, in any unconfounded cases of [‘nephrogenic’ systemic fibrosis] have been reported.”

|| The European Medicines Agency (EMA) categorizes the gadolinium-based contrast agents mainly according to their structure, i.e., linear or macrocyclic.

_____________________________________

With respect to causation of ‘nephrogenic’ systemic fibrosis, the ACR and the EMA categorized gadolinium-based contrast into different groups (see table above). This distinction was based on cases of ‘nephrogenic’ systemic fibrosis for the former, and by chemical structure for the latter. Neither is based on prospective, experimental data. These classification systems are based on the unproven assumption that liberation of gadolinium from the chaperone molecules is the sole step in triggering ‘nephrogenic’ systemic fibrosis cascade.

Is there a reason why the ACR class II agents have not been linked to ‘nephrogenic’ systemic fibrosis other than the hypothetical in vitro dissociation kinetics? Consider that the market share of the class II agents in 2006 was only 7.6%. Macrocyclic gadolinium-based contrast agents—this was only ProHance at the time—represented just 4.9% of this market share. The 2007 FDA black box warning applied to all gadolinium-based contrast agents, even classes II and III. Therefore, the highest risk population, those with known acute or chronic kidney impairment, were largely (not entirely) protected from exposure to all classes of gadolinium-based contrast agent exposure. Consider that the ACR group II agents have not been strongly linked to ‘nephrogenic’ systemic fibrosis because there was a marked change in diagnostic practice: far fewer patients with kidney disease were exposed to a gadolinium-based contrast agent of any type.

The 2017 USFDA MIDAC meeting was convened because of safety concerns about gadolinium much more far reaching than patients suffering from kidney dysfunction. All gadolinium-based contrast agents deposit in the brain. There is no known safety margin for gadolinium retention.

“The question in terms of gadolinium retention is, does this intrinsic stability correlate with gadolinium disassociation in the setting of retention? And the answer is we only have limited information on this,” Karen Bleich, MD, Division of Medical Imaging Products, 2017 FDA.

“Regardless of renal function and apparently regardless of patient status or type of contrast agent, if a gadolinium-based contrast medium is administered, a very small quantity of that gadolinium will remain in the patient for an indeterminate and possibly long period of time,” Matthew S. Davenport, Department of Radiology, University of Michigan, Ann Arbor.

We are facing more of a problem than just ‘nephrogenic’ systemic fibrosis. We are facing the unintended consequences of potential pathophysiologic effects of the retention of gadolinium-based contrast agents that may take years or decades to manifest regardless of renal function. An overall assessment of safety should not focus on a single property of these contrast agents.

Should gadolinium-based contrast agents be used just as liberally as they were in 2006 or should a risk/benefit analysis be considered for contrast-enhanced magnetic resonance imaging regardless of the ACR categorization?

‘Nephrogenic’ systemic fibrosis has occurred after just single doses in patients with impaired kidney clearance. Gadolinium is retained in numerous tissues regardless of kidney function and regardless of the chemical structure of the contrast agent. ‘Nephrogenic’ systemic fibrosis has become manifest years after administration. Gadolinium-based contrast agents can induce fibrosis in the skin of animals with normal kidney function. Gadolinium-associated plaques are a newly-discovered phenomena and have been discovered in patients with normal kidney function. Gadolinium was detected in bone 3 to 8 days after magnetic resonance imaging contrast exposure regardless of the American College of Radiology group. After multiple gadolinium-enhanced studies, the metal and high CD34 immunoreactivity (a fibrocyte marker and criterion for the diagnosis of ‘nephrogenic’ systemic fibrosis) were found in a patient with normal kidney function. Does any of this suggest that gadolinium deposition disease and ‘nephrogenic’ systemic fibrosis are, indeed, a continuum?

These facts lend themselves to the hypothesis that the threshold of gadolinium to induce disease, whether it has been transchelated or not, is miniscule. This disease is incurable, devastatingly painful, crippling, and potentially fatal. ACR group II and III agents are still gadolinium-based. These group II and III agents did not earn their statuses in the same arena as the high-risk, group I agents (ProHance was the only contender that was in use, with only 4.9% of the market share, when ‘nephrogenic’ systemic fibrosis was linked to gadolinium in 2006).

Thereafter, there was a sharp decline in the administration of gadolinium-based contrast agents in the highest-risk patients—i.e., those with known kidney impairment. If we accelerate the exposure of these high-risk patients to the ACR group II and III agents, then we will be conducting a dangerous experiment (in the face of accumulating evidence that gadolinium-induced disease does not recognize our artificially-defined border, i.e., an eGFR of 30 mL/min/1.73 m2).

– Post written by Brent Wagner. Follow him @Wagner_Nephro

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.

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