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Nephrogenic Sytemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a relatively new disease. The first cases were reported in 2000 and its association with magnetic resonance imaging (MRI) using gadolinium (Gd) contrast agent was first reported in 2006. During the next 3 years, more than 335 cases were recorded by the International Center for NSF Research.

NSF only affects those with severe renal impairment. Most diagnoses are made in patients with stage 5 chronic kidney disease (CKD, eGFR <15 mL/min). Most, but not all patients are dependent on dialysis when diagnosed. This disorder has never been described in individuals with normal renal function.

The most common first symptom of NSF is bilateral ankle edema and ankle weakness followed by hardening and thickening of the skin, which is visible as orange/brown plaques. The skin lesions then migrate upwards. Skin lesions remain largely confined to the limbs, sparing the torso and face. Loss of skin elasticity in the limbs is associated with joint stiffness that progresses flexion contractures. Definitive diagnosis currently depends on deep skin biopsy of an affected area. Autopsy has revealed that fibrosis is not confined to skin but present in underlying muscle and organs including heart, lung and liver.

No cure or effective treatment has been described, although reversal of renal disease and renal transplantation have been associated with improvement of skin lesions and halting of disease progression in some patients.

Approximately half of all MRI procedures are enhanced with a gadolinium contrast agent. Gadolinium is a rare earth metal, one of the lanthanide series. It has seven unpaired electrons resulting in its strong paramagnetic properties. Gadolinium is toxic to tissues. To counter this toxicity, Gd is bound to a chelation agent, which preserves its paramagnetic properties but makes it biochemically inert. Several different chelating agents have been used, but not all have been associated with NSF. Eighty five percent of NSF cases have been associated with the use of Gd-CA, gadodiamide (Omnsican™) and most of the remaining 15% have been associated with the use of gadoversetamide (OptiMark®) or gadopentate dimeglumine (Magnevist®).

Stability of chelate binding of Gd appears to play a significant role in the pathogenesis of NSF. Those Gd chelates that have been associated with NSF are less stable than those not associated with NSF. Release of Gd to tissues from these lower stability compounds is a necessary, but not sufficient trigger of NSF. Other factors must be involved because only a small minority (5-7 %) of patients with advanced renal disease exposed to Gd-enhanced MRI developed NSF.

In those with normal renal function, even the least stable Gd-CA products do not pose a threat, because they are normally rapidly eliminated with a half-life of 1.5-2 hours. However, in patients with advanced renal disease half-life is markedly prolonged to 30-120 hours in patients with advanced renal disease, increasing the likelihood of Gd dissociation from the chelae and accumulation of the toxic free metal in tissues

National guidelines for NSF prevention have been prepared in US, Canada, Europe and Japan. They are all based on the accepted premise that the only individuals at risk of NSF following administration of Gd-CA are those with acute renal failure and those with stages 3-5 CKD (e-GFR <60 mL/min/1.73 m2). The only foolproof strategy for identifying those at risk of NSF is to measure plasma creatinine and calculate eGFR of all patients immediately prior to administration of Gd-CA. Use of point of care testing for plasma creatinine in the radiology department can facilitate identifying those patients at greatest risk of developing NSF immediately prior to scan.

All guidelines advise that alternative diagnostic procedures should be considered, but if absolutely necessary the lowest possible Gd-CA dose should be administered. In the case of dialysis patients, the advice is to schedule MRI scan immediately prior to the next dialysis appointment to enhance immediate elimination of Gd-CA.

  1. Cowper S, Robin H, Steinberg S et al. Scleromyxoedema-like cutaneous diseases in renal dialysis patients. Lancet 2000; 356: 1000-01.
  2. Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis. Nephrol Dial Transplant 2006; 21: 1104-08.
  3. Schieren G, Wirtz N, Altmeyer P et al. Nephrogenic systemic fibrosis – a rapidly progressive disabling disease with limited therapeutic options. J Am Acad Dermatol 2009; 61: 868-74.
  4. Thomsen H, Marckmann P. Extracellular Gd-CA: differences in prevalence of NSF. Eur J Radiology 2008 66: 180-83.
  5. Leiner T, Kucharczyk W. NSF prevention in clinical practice: summary of recommendations and guidelines in the United States, Canada, and Europe. J Magn Reson Imaging 2009; 30: 1357-63.
  6. Korpi-Steiner N, Williamson E, Karon B. Comparison of three whole blood creatinine methods for estimation of glomerular filtration rate before radiographic contrast administration. Am J Clin Path 2009; 132: 920-26
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