Long-Term Retention of Gadolinium in Bone

The purpose of the study is to further investigate the safety of six different commercially
used Gadolinium-containing contrast agents. In order to get a better view of internal organs
such as the brain, joints and other body regions contrast agents containing Gadolinium are
often administered during magnetic resonance imaging.

Gadolinium-containing contrast agents were introduced in the 1980s, and presently many
different products are in common use. Although these agents are well tolerated, in 2006 it
was reported that some patients with severe renal failure undergoing magnetic resonance
contrast imaging developed signs of a rare condition known as Nephrogenic Systemic Fibrosis
(NSF). NSF is an extremely rare disease that has predominantly been reported in patients with
severe kidney impairment, acute kidney insufficiency due to the hepatorenal syndrome (kidney
failure in patients with advanced chronic liver disease) or in patients with acute kidney
insufficiency, who have recently had or soon expect to have a liver transplantation.

In order to collect additional clinical data on a global scale and across different agents in
common use, this study was requested by the European Medicines Agency to further investigate
whether Gadolinium in human bone and skin are retained for a long time after administration
of Gadolinium-containing contrast agents. This study has been developed to evaluate
Gadolinium retention in patients with renal function ranging from stable to severely impaired
renal function who had previously received any of the six different contrast agents within a
magnetic resonance contrast imaging procedure and who are scheduled for an orthopaedic
procedure.

For this study the patients will not be administered any research medication.

Participating sites are located in Germany, Italy, Poland, Spain, Turkey, USA, Japan and
Republic of Korea.

Main Inclusion Criteria:

- Patient scheduled for an orthopaedic surgical procedure

- A minimum of 1 month has elapsed between Gadolinium contrast agent (GdCA) dose and
scheduled orthopaedic surgical procedure

- Patient belongs to one of the following subgroups with respect to the number of GdCA
doses received and the status of their renal function:

1. patient has stable impaired renal function (at least moderate impairment, eGFR ≤
60 ml/min/1.73 m2) and has received one GdCA injection at the standard dose
(0.025 mmol per kg body weight for Gadoxetic acid and 0.1 mmol per kg body weight
for all other agents) or

2. patient has stable impaired renal function (at least moderate impairment, eGFR ≤
60 ml/min/1.73 m2) and has received more than one injection of the same GdCA or

3. patient has stable normal renal function (eGFR > 60 ml/min /1.73 m2) and has
received one GdCA injection at the standard dose (0.025 mmol per kg body weight
for Gadoxetic acid and 0.1 mmol per kg body weight for all other agents) or

4. patient has stable normal renal function (eGFR > 60 ml/min/1.73 m2) who have
received more than one injection of the same GdCA

Main Exclusion Criteria:

- Patient has received different GdCAs.

- Patient has received intra-articular GdCA or per any other non-i.v. route

- Patient has received any investigational product or has participated in any other
clinical trial within 30 days prior to enrolling in this study.