Monday, June 5, 2023
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The FDA,[6] Danish Medicines Agency (DMA),[35] United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA),[92] and American College of Radiology (ACR),[93] among other organizations, have published recommendations regarding gadolinium use. Selected recommendations by these agencies have been chosen to frame our discussion of some of the more-controversial issues. The MHRA has submitted a public assessment report to the European Medicines Agency, but this statement does not represent the view of all member states. The DMA report is an independent Danish publication. The ACR recommendations were derived from a 'blue ribbon' panel and represent consensus of ACR members; they have not, however, been adopted as policy by the ACR.[94]
The FDA is the only agency to suggest that all gadolinium chelates are potentially linked to NSF.[6] The other three organizations mentioned above specifically implicate gadodiamide as being associated with the highest risk for NSF. This assertion is based on the fact that most cases of NSF are associated with this gadolinium preparation. The DMA and MHRA view gadodiamide as being contraindicated in patients with a GFR of less than 30 ml/min per 1.73 m2,[35,92] whereas the ACR recommends avoiding gadodiamide in patients with any degree of renal dysfunction.[93] Although the FDA does not state that any specific preparation is contraindicated, it does recommend that physicians carefully consider the need for any gadolinium chelate in patients with moderate kidney dysfunction to ESRD. The ACR and MHRA regard gadoversetamide and gadopentetate dimeglumine as being associated with an increased risk of NSF, but do not specifically recommend that these agents be avoided. As gadodiamide is the agent most often associated with NSF in reported cases, we agree with the ACR and Kuo et al.[95] that use of this preparation be avoided in patients with any degree of renal dysfunction. It is also prudent to avoid using gadoversetamide and gadopentetate dimeglumine until more data regarding their risk become available. These agents are reported to cause NSF and, like gadodiamide, have a linear structure and short dissociation half-lives.
The MHRA report states that serum creatinine concentration should be measured before gadolinium administration.[92] By contrast, the ACR recommends relying on information regarding kidney disease provided by the referring physician or by the patient via a questionnaire.[93] Given that even patients with advanced CKD are often unaware of their disease, we agree with the MHRA that a serum creatinine concentration should be obtained by the referring physician if a gadolinium chelate is to be administered. If a patient has any history of kidney disease, determination of serum creatinine level should be required by the radiology department within 30 days before the imaging procedure, or sooner if there is a clinical concern about recent deterioration in GFR (e.g. a preceding iodinated contrast study). We recognize that NSF is a rare occurrence in patients with stage 3 or 4 CKD, but we feel that this recommendation is justified given the serious consequences of the disorder.
The need for a gadolinium-based contrast study should be carefully considered in a patient with CKD stage 3 or greater and alternative imaging modalities should be considered. The lowest possible dose of gadolinium should be used because development of NSF might be dose related.[43] The use of gadolinium in angiographic studies as an alternative to iodinated contrast should be carefully evaluated because the dose required is often high and recent studies indicate that gadolinium is nephrotoxic (see Table 3).
Other recommendations that are consistent with those in published literature and prudent to adopt are that standard gadolinium doses should not be exceeded and repeat doses should not be given in less than 1 week, that gadodiamide should be avoided in patients with renal dysfunction who have had or are about to undergo liver transplantation, and that postponing the imaging study until renal function has recovered in patients with AKI should be considered.[92]
Perhaps the most controversial issue is the need for post-gadolinium hemodialysis; there is a marked difference of opinion on this topic among recommending bodies. The FDA originally stated that it might be prudent to promptly initiate hemodialysis after administration of gadolinium chelates to patients with advanced kidney dysfunction (stage 5 CKD or ESRD). The most recent FDA update (23 May 2007) recommended consideration of prompt post-gadolinium dialysis only in patients who were already on hemodialysis (the term "prompt" is not defined in the recommendation).[6] The FDA also stated that it is not known whether hemodialysis prevents NSF. The ACR advocates hemodialysis within 2 hours of gadolinium administration in patients already on hemodialysis.[93] There is, as yet, no evidence to support this recommendation. The MHRA does not consider hemodialysis to be indicated in such instances, due to a lack of evidence regarding its efficacy.[92] The risks associated with post-gadolinium hemodialysis are minimal for stable ESRD patients with functioning accesses; as such, the FDA recommendation is reasonable. The MHRA correctly asserts, however, that there is no evidence that hemodialysis will prevent NSF. Data reported by Broome and co-workers for three patients who developed NSF despite three consecutive daily hemodialysis sessions clearly show that NSF can still develop despite aggressive dialysis.[43] Assumptions about gadolinium removal from the body that are made on the basis of plasma concentration decay curves might lead to overestimation of the efficiency of gadolinium clearance by hemodialysis.
The risk of developing NSF after gadolinium exposure in patients with stage 3-5 CKD is unknown, but seems to be less than the 2.5-4.0% postulated for the ESRD population.[37,43] NSF has developed in two patients with stage 3 CKD;[44] one patient was a renal allograft recipient, the other a liver transplant recipient, and GFR was declining in both at the time of multiple exposures to gadolinium. It is probable that the true GFR of both patients was lower than that estimated using the Modification of Diet in Renal Disease equation.[96] The FDA's original warning in June 2006 and subsequent update in December of that year stated that patients with a GFR of less than 60 ml/min per 1.73 m2 were at risk of developing NSF after exposure to gadolinium. In the most recent update (23 May 2007), the GFR cutoff had been changed to less than 30 ml/min per 1.73 m2.[6] Five patients with stage 4 CKD have developed NSF after gadolinium administration.[43,44] All had been exposed to gadolinium several times. One patient had undergone renal transplantation, two had undergone liver transplantation, and two had advanced stage 4 CKD (estimated GFR 17-18 ml/min per 1.73 m2).
Taken together, these findings indicate that subgroups of patients with CKD stage 3 or 4 might be at increased risk of developing NSF after gadolinium administration. These subgroups include those exposed to gadolinium more than once, liver graft recipients, and patients for whom the Modification of Diet in Renal Disease equation might overestimate true GFR (e.g. organ transplant recipients and those with AKI superimposed on CKD). The risk of developing NSF increases as GFR declines through CKD stages 3, 4 and 5 to ESRD, with a very low risk in CKD stage 3 and a 2.5% risk per exposure for patients with ESRD. We agree with the MHRA that the evidence to date does not justify the risks that are associated with acute access placement and hemodialysis after gadolinium exposure. Every effort should be made to postpone any gadolinium-enhanced imaging procedures in patients with AKI. At our institution, gadoteridol was in use before the association between NSF and gadolinium chelates was recognized. We will continue to use gadoteridol in preference to other FDA-approved gadolinium chelates because patients receiving gadoteridol have the lowest reported incidence of NSF.
Decisions regarding the benefit of hemodialysis for gadolinium clearance are also difficult when managing peritoneal dialysis patients. Peritoneal dialysis seems to be an inefficient means of removing gadolinium. It should be pointed out, however, that this opinion is based on data derived from patients maintained on older chronic ambulatory peritoneal dialysis regimens. Improved clearance might be possible with more-aggressive cycler-based regimens, and this possibility warrants further study. That said, data from the Morbidity and Mortality Weekly Report indicating that the incidence of NSF in gadolinium-exposed peritoneal dialysis patients is 7.5 times higher than that in hemodialysis patients is alarming.[38] It seems prudent to avoid exposing peritoneal dialysis patients to gadolinium if possible, until the risk is further clarified. If gadolinium must be used, gadoteridol should be considered as the first choice of chelate. Initiating post-exposure hemodialysis should be considered, especially if the patient has a functioning access. Alternatively, the peritoneal dialysis prescription could be increased. It should be emphasized, however, that these approaches might not prevent NSF and there are no data to support them.
