Nephrogenic Systemic Fibrosis (NSF): What It Really Means for Materials Scientists?

Noninvasive MR molecular imaging and targeted drug delivery systems, often referred to as theranostic agents, are being developed to enable improved detection, patient risk stratification, site-specific treatment and longitudinal monitoring [1]. Gadolinium (Gd), a paramagnetic lanthanide has been the dominant metal for T1 weighted MR contrast agents to produce bright signal in vivo. With seven unpaired electron (+3 oxidation state) in the outer d-orbital, it strongly influences the T1 relaxation times of the soft, biological tissues to which the metal has access. Gd exhibits a tendency to alter signal intensities by shortening the T1 time in its surroundings. The efficacy is measured by the relaxivity, which is dependent on the chemical properties of the metal, typically as a coordinated complex. Gadolinium is toxic in its free form [2]. The free ion (i.e. chloride, sulfate, or acetate form) has inadequate solubility in water in the neutral pH range, and is poorly tolerated in vivo. However in the clinics it is routinely administered in a chelated (linear or macrocylics) form such as DTPA or DOTA, still maintaining the strong relaxivity [3]. By far, in terms of their chemical properties, Gd is superior in comparison to the other paramagnetic metals e.g. manganese (Mn) and copper (Cu). Despite the long history of Gd blood pool contrast agents [4] and the preclinical success of nanotechnology platforms [5] based on this metal, the recent discovery of nephrogenic systemic fibrosis (NSF) has raised concern on currently approved MR contrast agents [6]. NSF is a serious and unexpected side effect of gadolinium blood pool agents observed in some patients with renal disease or following liver transplant [7]. It was first identified in 1997 in the US when a small group of renal transplant patients were found to have developed complications such as joint contractures, brawny in duration and hyper pigmentation of the skin in their extremities. The disease was initially referred to as ‘nephrogenic fibrosing dermopathy’; however, the close connection of visceral led to the name ‘nephrogenic systemic fibrosis’. Interestingly, all affected individuals were observed to have chronic kidney disease. Later, its association with Gd was clinically observed by Grobner et al. [8] and subsequently by others [9-10] (Figure 1). Patients with NSF develop thickening of the skin and connective tissues that can inhibit arm and leg movements and even lead to bone fractures. Approximately 5% of patients experience a rapidly progressive course, which may result in death due to widespread fibrosis [11]. The cause of NSF is unknown, and there is no effective treatment of this condition. All these findings prompted the FDA to issue a boxed warning of gadolinium blood pool agents specifying that gadolinium based contrast agents (GBCAs) increase the risk for NSF in patients with: 1) acute or chronic, severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2), 2) acute renal insufficiency of any severity due to the hepato-renal syndrome, or 3) in the perioperative liver transplantation period [12]. Although dialysis of patients may be considered promptly following GBCA administration, there is no evidence that hemodialysis prevents NSF. Linear chelates (e.g. Omniscan®, Magnevist® and OptiMARK®) are the most commonly reported agents differentiating them from macrocyclic molecules. In terms of the kinetic, thermodynamic, conditional stability as well as their tendency for transmetallation with zinc and other cations, macrocyclic chelates are superior to the linear forms [13]. Myriad of advancement has been made to create targeted nanoagents carrying high payload of paramagnetic Gd to characterize tissues based on the presence of pathognomonic biosignatures [14]. Some of these examples include e.g. metal chelates bearing liposomal vesicles [15] and lipoprotein micelles; [16] ανβ3-targeted paramagnetic polymerized liposome [17] and perfluorocarbon (PFC) nanoparticles; [18] paramagnetic micelles for macrophage imaging within atherosclerotic plaque [19] etc.