Nephrogenic systemic fibrosis (NSF) is a rare, but a serious acquired disease characterized by fibrosis of the skin and soft tissues. The disease was first recognized in the USA in 2000, identifying a case from 1997. NSF was initially thought to be confined to the skin and was named nephrogenic fibrosing dermopathy (NFD). In some patients, however, since there is clinical involvement of organs other than skin such as lung, liver, heart and skeletal muscle, it is now commonly referred to as NSF. NSF starts by thickening and hardening of the skin of the extremities and sometimes of the trunk. Reddened or darkened patches, papules or plaques develop. Over time, the skin feels "woody", and the surface may have an appearance of texture of orange peel. Diagnosis is confirmed by the presence of specific histopathological features on skin biopsy. Patients may have burning, itching or severe sharp pains in areas of involvement, and may have swelling of the hand and foot with blister-like lesions. For many patients, the skin thickening inhibits flexion and extension of joints. Severely affected patients may have difficulty in walking, contractures of hand and feet, and muscle weakness. About 5% of patiens have a rapidly progressing severe disease course. In such patients, scarring of internal organs may lead to the impairment of their normal functions and death.

To date, NSF has only been identified in patients with: 1) acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m2), 2) acute renal disfunction due to hepato-renal syndrome or in the perioperative liver transplantation period. Its cause is unknown and there is no consistently successful treatment. Precise cause of NSF is still under investigation. The most consistent finding associated with NSF is severe renal impairment. Other associated risk factors are coagulation disorders, deep venous thrombosis, recent surgery, failed renal transplantation, systemic infections and cancer. In 2006, it was suggested that a gadolinium based contrast agent (GBCA) used in MR examinations might be the agent triggering NSF. Since then, many case series and case reports have been published regarding the possible association of GBCA and NSF. The mechanism by which GBCA might be trigerring NSF is not known for sure.

It is controversial whether the extent of risks for developing NSF are the same for all GBCAs. European health authorities (Commission on Human Medicines (CHM), Pharmacovigilance Working Party (PhVWP) of the Committee for Medicinal Products for Human Use and European Medicines Agency - EMEA) believe that GBCAs are associated with different levels of NSF risk based on their physicochemical and pharmacokinetic properties, and propose a step-wise approach to restricting the use of GBCAs. On the other hand, U.S. Food and Drug Administration declared that at present it is impossible to definetely determine whether different GBCAs have different levels of risk for developing NSF and requested the addition of the same boxed warning about risk of NSF to the prescribing information for all GBCAs.

In conclusion, NSF is a rare disease, however, it may have serious consequences. Patients with severe renal failure and those with history of liver transplantation are at greatest risk. There is no evidence that people with normal renal functions are at risk. Although it is suggested that GBCAs might trigger the disease, precise cause is unknown. There is no effective treatment for NSF; however, improvement of renal function may be helpful. Therefore, it is important that radiologists, nephrologists and other related health professionals familiarise themselves with the methods to avoid this debilitating and sometimes fatal disease.

3) Other references:
"Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation," by Elizabeth A. Sadowski, M.D., and colleagues will appear in the April print issue and is available now online at http://radiology.rsnajnls.org/cgi/content/full/2431062144v1.

"Gadolinium-based MR Contrast Agents and Nephrogenic Systemic Fibrosis," by Phillip H. Kuo, M.D., Ph.D., and colleagues is available in the March print issue or online at http://radiology.rsnajnls.org/cgi/content/full/2423061640v1.

http://www.rsna.org/Publications/rsnanews/feb07/upload/RSNANews_Feb07_Gadolinium.pdf

NSF Registry - Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007

Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency? G. Bongartz; Magn Reson Mater Phy DOI 10.1007/s10334-007-0071-5 (Springer) 22 April 2007

Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide, H. Thomsen; European Radiology, (2006) 16:2619-2621 DOI 10.1007/s00330-006-0495-8

Gadolinium - a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? T. Grobner; Oxford University Press on behalf of ERA-EDTA, Nephrol Dial Transplant 2006; 21:1104-1108 and Response to letter to the Editor, Nephrol Dial Transplant 2006; 21:3604-5

Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging, P. Marckmann, L. Skov, K. Rossen, A. Dupont, M. Damholt, J. Heaf, and H. Thomsen; American Society of Nephrology, 2006; JAmSocNephrol17:2359-2362,2006.doi:10.1681/ASN.2006060601

Editorial: Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? H. Thomsen, S.K. Morcos, and P. Dawson; Clinical Radiology (2006) 905-906

Gadolinium deposition in nephrogenic fibrosing dermopathy, A. Boyd, J. Zic, and J. Abraham; J Am Acad Dermatol, Articles in press, 2007 American Academy of Dermatology

Letter to the Editors: Gadolinium and nephrogenic fibrosing demopathy in pediatric patients, V. Dharnidharka, S. Wesson, and R. Fennell; Pediatric Nephrology, DOI 10.1007/s00467-006-0384-z (Springer)

Enhanced Computed Tomography or Magnetic Resonance Imaging: A Choice between Contrast Medium-Induced Nephropathy and Nephrogenic Systemic Fibrosis? Thomsen, H. S., Marckmann, P. and Logager, V.B., Acta, Radiologica, 48:6, 593-596 DOI 10.1080/02841850701370717

Important Drug Warning for Gadolinium-Based Contrast Agents Issued by Bayer HealthCare Pharmaceuticals Inc., Bracco Diagnostics Inc., GE Healthcare, and Mallinckrodt Inc.