Involvement of Gadolinium Chelates in the Mechanism of Nephrogenic Systemic Fibrosis: An Update

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Gadolinium

Gadolinium (atomic number Z = 64) belongs to the lanthanide series of elements. Its standard atomic weight is 157.25. Gadolinium was discovered in 1880 by the Swiss chemist Jean-Charles Galissard de Marignac, isolated by the French chemist Paul-Emile Lecoq de Boisbaudran in 1886, and named after the Finnish chemist Johann Gadolin, who, in 1794, analyzed the mineral gadolinite discovered at the Ytterby quarry, near Stockholm, by an amateur mineralogist.12 In addition to its medical imaging

Pharmacokinetics of gadolinium chelates

The pharmacokinetic behavior of GCs is of paramount importance for two reasons: (1) it strongly determines their imaging profile and efficiency and (2) it depends on certain physiologic functions, notably renal function, a feature that may play a major role in the mechanism of NSF.

GCs are highly hydrophilic molecules and share pharmacokinetic characteristics similar to those of water-soluble iodinated contrast agents. They can be regarded as tracers of the extracellular water, as shown by their

Physicochemical properties of gadolinium chelates

The effect of GCs on proton relaxation time and, consequently, their effect on the MR imaging signal depend on the large number of unpaired electrons of Gd3+ (n = 7). Because of its intrinsic toxicity, however, Gd3+ must be chelated by the administration of an appropriate ligand. Because Gd3+ is chelated, a thermodynamic equilibrium exists between the metal [M] (ie, Gd3+ in the present case), the ligand [L], and the chelate [ML]:[M]+[L][ML]Chemists involved in the field of GCs obviously try to

Free ligand

Because of their relatively low stability, pharmaceutic solutions of some GCs include a relatively large amount of free ligand or sodium salt of calcium complexes (see Table 1). These excipients are intended to ensure the absence of free Gd3+ cations in pharmaceutic solutions for the duration of their shelf lives.1, 2 According to the law of mass action (Equation 1), an excess in free ligand reduces the concentration of free Gd3+ and acts like a “gadolinium sponge.” The least stable agents

Hypotheses for the role of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis

The low prevalence of the disease makes investigations on its mechanism quite difficult. Although no fully validated mechanism for NSF has been established to date, major advances have been made in the past 2 years.

In one case report,42 the clinical condition improved after renal transplantation and subsequently relapsed after renal function was lost and dialysis was restarted. This report suggests a link between renal function and clinical signs associated with NSF. The role of renal failure

Summary

There has occasionally been some confusion attributable to failure to discriminate between two complementary aspects (ie, thermodynamic and kinetic stability) to describe the stability of GCs.1, 2Fig. 2 illustrates release of free Gd3+ from theoretic GCs, which differ in terms of their thermodynamic and kinetic stabilities. The time frame of Fig. 2 depends on pathophysiologic conditions, such as renal insufficiency, and possible storage in a deep compartment, such as bone tissue, with slow and

Summary

GCs are not similar in terms of stability. High kinetic stability provided by the macrocyclic structure combined with high thermodynamic stability minimizes the amount of free gadolinium released in tissue parenchymas. Although no fully validated mechanism for NSF has been established to date, major advances have been made in the past 2 years thanks to in vitro and in vivo models.

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