What Nephrologists Need to Know About Gadolinium

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Author(s)

Jeffrey G Penfield, MD

Staff Physician, Section of Nephrology, Veterans Affairs North Texas Health Care System, Dallas, Texas; Assistant Professor of Medicine, Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas

Disclosures

Disclosure: Jeffrey G. Penfield, MD, has disclosed no relevant financial relationships.

Robert F Reilly, Jr, MD

Professor of Medicine; Fredric L. Coe Professor of Nephrolithiasis Research; Chief, Division of Nephrology, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Disclosures

Disclosure: Robert F. Reilly, Jr., MD, has disclosed no relevant financial relationships.

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Link between Gadolinium and Nephrogenic Systemic Fibrosis

Several groups have examined the potential link between gadolinium administration and NSF. Deo et al.^[37] studied a group of patients treated in a dialysis practice in Bridgeport, CT. Three cases of NSF were identified during an 18 month period that ended 1 July 2006; two of these patients had received gadodiamide and one had received gadopentetate dimeglumine. The incidence of NSF among all hemodialysis patients in this study was 4.3 cases per 1,000 patient years. The risk of developing NSF was 2.4% per gadolinium exposure.^[37] In another study, 33 cases of NSF were reported in the St Louis, MO, area. Nineteen confirmed cases were evaluated in more detail in a case-controlled study.^[38] Four patients had been exposed to gadolinium more than 1 year before diagnosis of NSF and one individual had no known exposure. The remainder had received gadolinium within a year of diagnosis. Two patients had AKI and the remainder were chronic dialysis patients. In multivariate analysis, the only statistically significant risk factor for NSF was gadolinium exposure within 12 months of diagnosis (odds ratio 8.97). The attack rate for peritoneal dialysis patients was 4.6 per 100 patients and was 0.61 per 100 for hemodialysis patients. The number of peritoneal dialysis patients in this study was small, but evidence from a study by Joffe et al. of poor clearance of gadolinium chelates during peritoneal dialysis supports this finding.^[39]

Khurana and co-workers^[40] reviewed the case records of six patients who had developed NSF between 19 days and 2 months after gadodiamide exposure. One patient had AKI, one patient had AKI superimposed on advanced CKD, another was on hemodialysis, and three had stage 5 CKD but were not yet on dialysis. This report emphasizes that NSF occurs in patients with reduced renal function and is not confined to the dialysis population. In a study in Denmark, 13 people developed NSF between 2 and 75 days after exposure to gadodiamide.^[41] The odds ratio for exposure was 32.5 in these patients compared with patients with endstage renal disease (ESRD) who had not been exposed. No association of NSF with acidosis was detected. The same authors reported no new cases of NSF at their institution since the use of gadodiamide was discontinued in March 2006.^[42] The total number of NSF cases related to gadodiamide that they have observed has now increased to 24. The extra cases are the result of delayed diagnosis of NSF that was caused by exposure to gadodiamide before its use was discontinued at their institution (P Marckmann, personal communication).

Broome et al.^[43] reported 12 patients who developed NSF after gadodiamide exposure. A total of 559 MRI exams were performed on 168 dialysis patients. The 12 patients who developed NSF (301 gadodiamide exposures) were compared with those who were not exposed to gadodiamide (258 MRI exams). Four of the twelve patients were liver transplant recipients with AKI secondary to hepatorenal syndrome. The odds ratio for exposure to gadodiamide was again high, at 22.3, and the prevalence of NSF among gadodiamide-exposed dialysis patients was 4%. Patients receiving gadodiamide doses of 0.1 mmol/kg and those receiving doses of 0.2 mmol/kg were compared. The odds ratio for developing NSF for those on the higher dose was 12.1, indicating that the risk of developing the condition is dose dependent. Daily dialysis, starting on the day of gadolinium administration, for 3 days did not prevent NSF in three patients.

In another series, thirteen patients developed NSF after being exposed to gadolinium; all received gadodiamide, and one was exposed to both gadobenate dimeglumine and gadodiamide.^[44] These patients were compared with a group of 4,236 individuals who received gadolinium but did not develop NSF. Affected patients had higher serum creatinine concentrations and had undergone a greater number of contrastenhanced magnetic resonance exams than those who did not develop NSF. Those with NSF were also affected by more proinflammatory events (defined as surgery, thromboembolic vascular events, or systemic infections), emphasizing the potential contribution of inflammation to the development of NSF. This series of patients also included two individuals with CKD stage 3 plus AKI. One was a liver transplant recipient, the other a renal transplant recipient. The authors emphasized that AKI in the setting of a proinflammatory event could have contributed to the development of NSF in these two patients.

Marckmann et al.^[45] reviewed 19 cases of gadodiamide-induced NSF to identify potential cofactors. The primary risk factor for NSF was an increasing cumulative dose of gadodiamide. The investigators also observed a statistically significant correlation between NSF and elevated serum calcium and phosphorus concentrations, and between NSF and higher doses of epoetin beta. There was no correlation of NSF with acidosis, use of angiotensin-converting-enzyme (ACE) inhibitors, or serum parathyroid levels.

At least 96 reported cases of NSF have been associated with gadolinium-containing contrast media. The type of gadolinium chelate used was reported for 63 cases; all but one patient received gadodiamide (this individual received gadopentetate dimeglumine) and one patient received both gadodiamide and gadobenate dimeglumine. There are no published case reports linking gadoversetamide (OptiMARK^®; Mallinckrodt, Hazelwood, MO) with NSF, although six cases have been reported to MedWatch, the FDA safety information and adverse event reporting program. MedWatch reports are generated by volunteer clinicians and are not peer-reviewed. As of 17 January 2007, 85 cases of NSF associated with gadodiamide, 21 cases associated with gadopentetate dimeglumine, and 6 cases associated with gadoversetamide, had been reported to the FDA. NSF has also been reported to develop after sequential administration of gadodiamide and gadobenate dimeglumine, as well as after sequential administration of gadodiamide and gadoteridol.^[6] Only two patients who developed NSF without any known exposure to gadolinium are reported in the literature.^[38,46]