**3.1 Pathogenesis of NSF**

*Rare Earth Elements and Their Minerals*

**Figure 5.**

**Figure 6.**

*Gadoteridol (ProHance).*

*Gadobutrol (Gadovist).*

**Gadolinium-DO3A**: The nonionic open-chain metal chelates and neutral macrocyclic gadolinium chelates have been synthesized. Two of them such as gadobutrol (Gadovist) (**Figure 5**) and gadoteridol (ProHance) (**Figure 6**) have been launched as extracellular MRI contrast agents. Both agents are derivatives of

Thermodynamic stability constants and relaxivities in water at 20 MHZ and

Nephrogenic systemic fibrosis (NSF) is a multi-systemic fibrosing disease that has been characterized by thickening and tightening of the skin and subcutaneous tissues. NSF also includes fibrosis of the skeletal muscle, lung, liver, testis, or

First described in 1997, NSF was initially known as nephrogenic fibrosing dermopathy because of its classic presentation of symmetric, brawny, or erythematous indurated cutaneous plaques that develop in the setting of renal insufficiency [13, 22, 23]. Grobner's published case reports have found an association of NSF with GBCAs exposure when a meticulous chart review was performed. Currently, over 250 documents reporting NSF cases have been registered by Shawn Cowper of Yale University, which have linked 85% of its cases to gadodiamide (Omniscan) [23–25].

1,4,7-tricarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A).

40°C of commercially available gadolinium chelates.

**3. Nephrogenic systemic fibrosis (NSF)**

myocardium with possible fatal outcomes.

**54**

The exact pathogenesis of NSF is still unclear. However, there are some evidences suggesting that it likely involves the migration of CD34 and procollagen-1 positive, circulating fibrocytes from the blood to the engaged tissue as proposed by Cowper. These fibrocytes likely activate a fibrotic response through cytokine production and T-cell activation. Several reports have shown increased expression of transforming growth factor β1 and CD68-factor XIIIa within the affected skin and skeletal muscle which are also essential markers associated with wound healing and fibrosis [26, 27].

In addition, evidence of in vivo transmetallation has been provided by a preclinical trial in which rats exposed to repeated high-dose GBCAs injection developed an NSF-like skin lesion consisting of epidermal ulceration, acanthosis, dermal fibrosis, and CD34 fibrocytic infiltration with high concentrations of gadolinium in the skin. These findings were more severe with gadodiamide (Omniscan) than gadopentetate (Magnevist) [28]. The differences in conditional thermodynamic stability constants and stimulatory response of gadodiamide on fibroblasts may explain the higher incidence of NSF with gadodiamide (Omniscan). The medical literature report of NSF and this additional evidence seem to indicate a stratified risk within the class of GBCAs. The transmetallation of the gadolinium chelate would occur because of exchange of Gd3+ ions for endogenous metals (such as Zn, Cu, and Ca), and then free Gd3+ ions are released from the chelate. Patients with severe or end-stage renal disease are more likely to undergo in vivo transmetallation because of markedly prolonged clearance of GBCA. This theory has been substantiated by detection of gadolinium within tissue months after GBCA exposure. And transmetallation of Gd-DTPA with endogenous Fe(II)/Fe(III) is possible in human blood plasma. Telgmann concluded that transmetallation may be a trigger of NSF if free Fe(III) ions were accessible during a prolonged pathway of Gd complexes with linear ligands through the patient's body [29].
