Table 2.

Opportunities to recognize the association of gadodiamide administration with NSF development in Denmark (2002–06) [6]

Event	Action	Initial response	Later action
2002
Index case develops acute skin toxicity immediately after undergoing a gadodiamide-enhanced MR at Herlev Hospital	Case reported to Danish Medicines Agency	Patient’s findings are categorized by the manufacturer as being consistent with underlying disease	Manufacturers are no longer asked to adjudicate adverse event report descriptions
Second NSF case undergoes skin biopsy	Pathologist reviews the biopsy	Pathologist reads the biopsy as being consistent with foreign body reaction	Re-read of the biopsy in 2006 confirms the diagnosis of NSF
Second NSF case	Case reported to the manufacturer of gadodiamide by a dermatologist and a rheumatologist	Manufacturer classifies the case as exacerbation of underlying autoimmune disease	Biopsy reviewed by Shawn Cowper of Yale University Medical School and confirms NSF diagnosis
2003
Second Danish NSF case dies and Danish Patient Insurance Association awards large financial compensation	Danish Patient Insurance Association sends report of financial compensation to the manufacturer and states that patient’s death was probably a result of the gadodiamide administration	Manufacturer classifies the death as a consequence of underlying immunological disease	Patient diagnosed with NSF after death—in 2006
Manufacturer updates Periodic Safety Update Report (PSUR)	The PSUR does not list the first two NSF patients’ deaths as serious adverse drug reactions	The PSUR listing could have included the 2002 and 2003 cases as potential fatal adverse drug reactions	Patient’s deaths re-classified as a serious adverse drug reaction in 2006
2004
Similar clinical findings for a CKD patient undergoing a gadodiamide-enhanced MR procedure in Texas	Radiologist in Texas telephones manufacturer to query whether any similar cases have been reported	Manufacturer does not link this case with the two index cases from Herlev Hospital in 2002	FDA requests in 2006 that the manufacturer review this case for possibility of NSF diagnosis
Manufacturer sends a PSUR to Danish regulatory authorities	All serious adverse drug reactions identified by the manufacturer are described	Details of the two Danish patients and the one Texas patient are not included in this 2004 PSUR prior to 2006	The three patients are re-classified in 2006 as having had biopsy confirmed NSF and are added to a 2006 PSUR
2005
A radiology resident published a Herlev Hospital retrospective study of 104 CKD patients who underwent gadodiamide-enhanced MR procedures in 2002 and 2003	Medical records and angiograms are reviewed by radiologists at Herlev Hospital	Records of only two patients identify skin and muscle changes following the MR procedure. The records were reviewed for evidence of nephrotoxicity and changes in vascular findings within days of the procedure. Nephrologists attribute the changes to exogenous iron administration	After examining most of these patients in late 2006, the diagnosis of NSF is biopsy confirmed in eight patients who had gadodiamide administered between 2003 and 2005
A nephrology resident suspects that gadolinium might be the cause of acute skin changes and neuropathic symptoms of peritoneal dialysis patient exposed to gadodiamide in autumn 2005	Skin biopsy sent to a pathologist for examination for gadolinium in 2005	Methodology to identify gadolinium in skin biopsy is unavailable in 2005	Scanning electron microscopy identifies gadolinium in biopsy in 2007
Nephrologist suspects that common exposure might account for skin, muscle and joint changes in 10 CKD patients at Herlev Hospital	Medical record review is done. Summary table created in 2005 includes clinical findings and potential exposures	Gadolinium is listed as an exposure on only 2 of the 10 case summaries in the 2005 summary table	2006 re-review of the medical records identifies gadodiamide exposure on all 10 patients
A fourth CKD patient develops acute toxicity following the gadodiamide-enhanced MR procedure	Clinicians in Germany report the details of this patient to the gadodiamide manufacturer of acute toxicity following the gadodiamide-enhanced MR procedure	Clinical details are not linked by safety personnel at the manufacturer with the prior three reports	2006 re-review classifies this patient as having had NSF
2006
A Herlev Hospital nephrologist identifies 20 CKD patients with clinical diagnoses of NSF—all had undergone a gadodiamide-enhanced MR imaging procedure (early March 2006)	The Hospital nephrologist, Peter Marckmann, telephones the Danish Medicines Agency and describes the 20 CKD patients as having clinical diagnoses of NSF—all had undergone a gadodiamide-enhanced MR imaging procedure (early March 2006). These reports form the basis for the Danish Medicines Agency dissemination of a statement of concern and are forwarded to the European Medicines Agency, FDA, and to gadodiamide’s manufacturer	All 20 patients were later described in a written communication by the nephrologists to the DMA as clinically suspected NSF cases (Late March 2006). These reports form the basis for the Danish Medicines Agency dissemination of a statement of concern and are forwarded to the European Medicines Agency, FDA, and to gadodiamide’s manufacturer. (May 2006)	Skin biopsies confirm the NSF diagnosis in 13 of these patients. Findings are published as a rapid communication in August in the Journal of the American Society of Nephrology [22] in 2006.
Radiologists at Skejby Hospital hold a conference on NSF in 2006 (hosted by the manufacturer of gadodiamide)	No cases of NSF at Skejby Hospital based on clinician recall were identified. Radiologists conclude that gadolinium is unlikely to be the cause of NSF	Radiologists continued to administer gadodiamide to CKD Stages 4–5 patients until October 2006	2009 medical record re-review augmented by patient examination identifies 33 possible gadodiamide-associated NSF patients (10 are subsequently biopsy confirmed)