Evaluation of Gd Retention in Human Bone and Skin After MultiHance or ProHance Administration Compared With Control

Each subject enrolled will already be scheduled to undergo a hip, shoulder or knee
replacement, limb amputations or other orthopedic surgical procedures and each subject
enrolled in the non-control group will have retrospectively undergone one or more
administrations of MultiHance or PROHANCE with the last dose administered at least 1 month
before their scheduled surgery. In order to classify the subjects' renal status, the serum
creatinine (SCr) value and/or estimated glomerular filtration rate (eGFR) at the time of last
MRI with MultiHance or ProHance must be available and collected. The control subjects'
documented SCr values will be collected prior to enrollment in the study.

The bone and skin tissue sample(s) collected (during the subjects surgery) will be blinded to
gadolinium based contrast agent (GBCA) exposure and sent to a central laboratory where they
will be tested for gadolinium (Gd) and other analytes including calcium, phosphorous, sodium,
iron, zinc, and potassium. The Gd deposition of the resected bone and skin tissue will be
analyzed by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The bone and skin tissue
will also be analyzed for other analytes using ICP-MS. These sample(s) will be stored at the
central laboratory.

A separate sample of the skin tissue collected (during the subjects' surgery) will also be
sent to a central dermatopathologist who will be blinded to GBCA exposure and test for any
possible NSF related abnormalities. These skin tissue sample(s) will be stored with the
central dermatopathology laboratory.

Inclusion Criteria:

SUBJECTS WHO RECEIVED MULTIHANCE or PROHANCE:

- Is scheduled to receive hip, shoulder or knee replacement surgery, limb amputations or
other orthopedic surgical procedures

- Has undergone at least one MULTIHANCE or PROHANCE administration at least 1 month
before his/her scheduled surgery

- Has a documented SCr for calculation of eGFR and/or documented eGFR at time of last
MRI with MULTIHANCE or PROHANCE

- Provides written Informed Consent and is willing to comply with protocol requirements

- Is willing to undergo deep skin tissue sampling during scheduled hip, shoulder or knee
replacement surgery, limb amputations or other orthopedic surgical procedures

- Is ≥18 years of age

SUBJECTS WITH NO EXPOSURE TO GBCA:

- Is scheduled to receive hip, shoulder or knee replacement surgery, limb amputations or
other orthopedic surgical procedures

- Has no history of GBCA administration

- Provides written Informed Consent and is willing to comply with protocol requirements

- Is willing to undergo deep skin tissue sampling during scheduled hip, shoulder or knee
replacement surgery, limb amputations or other orthopedic surgical procedures

- Has prior SCr and/or eGFR at time of enrollment

- Is ≥18 years of age

Exclusion Criteria:

SUBJECTS WHO RECEIVED MULTI HANCE or PROHANCE:

- Has undergone any GBCA including MULTIHANCE or PROHANCE administration less than 1
month before his/her scheduled surgery

- Has ever been suspected of, or diagnosed with, NSF

- Has been suspected or diagnosed, prior to inclusion in this study, with bone cancer or
any other osteoblastic or osteoclastic disease, such as septic, infectious or ischemic
disease affecting physiological bone structure that has caused the bone to be
diseased, prior to inclusion in this study

- Is unable or unwilling to be examined by dermatologists or to undergo laboratory/other
diagnostic evaluations should development of NSF be suspected.

- Has received any GBCA other than the one under evaluation at any time prior to
inclusion in this study (e.g., a MULTIHANCE subject should not receive any other GBCA
including PROHANCE)

SUBJECTS WITH NO EXPOSURE TO GBCA:

- Has received any GBCA at any time prior to inclusion in this study

- Has ever been suspected of, or diagnosed with, NSF prior to the enrollment

- Has been suspected or diagnosed with bone cancer or any other osteoblastic or
osteoclastic disease, such as septic, infectious or ischemic disease affecting
physiological bone structure that has caused the bone to be diseased prior to
inclusion in this study

- Is unable or unwilling to be examined by dermatologists or to undergo laboratory/other
diagnostic evaluations should development of NSF be suspected.