Nephrogenic systemic fibrosis: more questions and some answers.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that may develop in patients who have advanced reduction in renal function. A causal relation between gadolinium (Gd(3+))-based contrast agents (Gd-CA) and NSF is probable and is supported by the accumulating data in the literature. From those data, the prevalence of NSF is seen to be significantly higher after exposure to gadodiamide than any other gadolinium-based agent. Gd-CA are either linear or macrocyclic chelates and are available as ionic or non-ionic preparations. The molecular structure, whether cyclic or linear, and the ionicity determine the stability of Gd-CA. Linear chelates are flexible open chains which do not offer a strong binding to Gd(3+). In contrast, the macrocyclic chelates offer a strong binding to Gd(3+) by the virtue of being pre-organised rigid rings of almost optimal size to cage the Gd(3+) atom. Non-ionic preparations are also less stable in comparison to the ionic ones, as the binding between Gd(3+) and the negatively charged carboxyl groups is stronger than that with amides or alcohol in the non-ionic preparations. According to stability constants and kinetic measurements, the most stable Gd-CA is the ionic-macrocyclic chelate Gd-DOTA and the least stable agents are the non-ionic linear chelates gadodiamide and gadoversetamide. The stability of Gd-CA seems to be an important factor in the pathogenesis of NSF. Gd-CA of low stability are likely to undergo transmetallation and release free Gd ions that may deposit in tissues and attract circulating fibrocytes to initiate the process of fibrosis. There have been no cases of NSF reported in the peer-reviewed literature after the exclusive use of the stable macrocyclic Gd-CA. This minireview covers the clinical and pathological features of NSF and updates the current understanding of the pathophysiology of this condition.