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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Clinical Features of Nephrogenic Systemic Fibrosis

NSF has been reported to affect people across a broad range of ages (8-86 years). The condition has no gender predilection. In a study by Jain and co-workers, all patients affected with NSF had a decreased GFR; 90% were on dialysis as a result of ESRD or AKI.^[52] Seven patients were reported to have CKD stage 3 or 4, and a disproportionate number of these individuals were renal or liver transplant recipients. The GFR of these patients was estimated using serum creatinine measurements. The true GFR of both liver and renal transplant recipients is usually lower than the estimated GFR,^[53,54] so it is possible that these patients had more severe CKD than was reported.

Skin involvement in NSF is symmetrical, with extensive waxy thickening and hardening of the extremities and torso. Skin can become hyperpigmented and take on a 'woody' texture with plaques and subcutaneous nodules. Unlike scleromyxedema, NSF tends to spare the skin of the head and neck, and is not associated with paraproteinemia.^[31] A review of published cases by Mendoza et al. showed that skin of the lower extremities was affected in 97% of cases, and the distribution was from ankle to mid thigh.^[55] The upper extremities were involved in 77% of cases, most commonly from the wrist to mid upper arm. Truncal involvement was reported in 30% of cases,^[55] and there have been reports of yellow scleral plaques in the eye.^[56] Joint contractures are a common result of progressive skin, as well as muscle and fascia, fibrosis, and lead to severe immobility.^[57,58]. Progression is rapid in a subset of patients, who can become bed or wheelchair bound as a result of contractures.

There is an increased risk of thrombosis manifesting as deep venous thrombosis, a pulmonary embolus, thrombosed arteriovenous access, or an atrial thrombus, in patients with NSF. Elevated levels of antiphospholipid and anticardiolipin antibodies, deficiencies of protein C, protein S and antithrombin III, and presence of factor V Leiden, have all been observed in such patients.^[52,59-62] Patients with liver disease and those who have undergone liver transplantation seem to be at increased risk of developing NSF. Originally thought to be confined to skin, it is now known that the fibrosis can be systemic and involve fascia, subcutaneous tissue, and other organs, including lungs, heart, muscle, kidneys, dura mater, and testes.^[63-66] In one case of NSF, progressive fibrosis of the diaphragm eventually led to death from respiratory failure.^[65]

Examination of skin biopsy samples from patients with NSF reveals haphazardly-arranged thickened dermal collagen bundles interspersed with increased numbers of plump fibroblasts and mucin deposition.^[31,67] The skin of some patients harbors osteoclast-like giant cells with focal areas of calcification^[68] and ossification.^[69] The histology resembles that of a healing wound. Fibrocytes positive for CD34 and procollagen-1 are found in affected tissue. These fibrocytes originate in bone marrow and are drawn to the dermis by an unknown stimulus (possibly gadolinium deposition). After migrating to the dermis, the fibrocytes differentiate into cells that resemble normal fibroblasts and could be responsible for the excessive fibrosis.^[64,70,71]