Nephrogenic systemic fibrosis (NSF), a systemic fibrosing disorder, was first recognized in 1997 and described as a new disease in 2000.

Initially considered a dermal disorder that occurred primarily in patients who require dialysis, NSF was subsequently defined as a systemic disorder that also developed in patients with non-dialysis-requiring CKD and acute kidney injury (AKI).

While underlying kidney disease was a common thread, early investigations failed to identify an etiology or trigger for NSF, although many associations were postulated, including hypercoaguable states, vascular injury, and certain exposures. Then, in 2006, researchers reported the first association of gadolinium-based contrast agents (GBCAs) and NSF in five patients with end-stage renal disease (ESRD), a finding that has been solidly confirmed by many others (Eur J Radiol. 2008;66:230-241).

NSF is a devastating disease, so there is great concern about its prevention in the medical community. Prevention of this currently untreatable disease is our duty as physicians, and we are working to protect patients from a process that is associated with such morbidity and increased mortality. As with any iatrogenic process, medicolegal implications emerge and medical malpractice suits raise the stakes further.

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To establish appropriate practice standards to avoid or limit the development of NSF, we need to understand the current data on factors that increase risk and to counter the natural tendency to completely avoid GBCA use in patients who would potentially benefit from its excellent diagnostic capacity.

I will attempt to address some of the issues of concern, recognizing that much of what I say is opinion that is influenced by limited data and incomplete information. Numerous reviews are available on the subject of NSF, so my comments will be limited to some of the more controversial issues.

What we know

We know that exposure to a GBCA is the trigger for NSF to develop, even though there are cases of NSF in which GBCA exposure has not been documented. This does not mean that GBCA use is not the trigger; cases of NSF without GBCA exposure probably reflect inability to document the exposure or the unlikely possibility of another less common trigger. There is no doubt that patients with underlying kidney disease are the only group at risk based on published literature and other available data. But does this risk extend to all types and levels of kidney disease?

Another important piece of information is that NSF remains a relatively uncommon disease despite a fairly large number of GBCA exposures in patients with kidney disease. The low numbers may in part reflect underrecognition of NSF (a result of unfamiliarity and mild cases), or they may indicate that GBCA exposure in patients with kidney disease is required but not sufficient to cause NSF. Are other cofactors required to allow the fibrosing process to proceed in various tissues?

Finally, we know that NSF is preventable if GBCA exposure is completely avoided, but this approach is impractical and not possible in all patients when definitive imaging requires use of this contrast agent. Thus, which agents and what approaches of GBCA use will maximally reduce the risk of NSF?

Kidney disease severity

As stated, patients with underlying kidney disease are at risk, but the inclusion of all patients with kidney disease in this group would result in an extremely large number. A review of the literature demonstrates that the vast majority of patients described as having NSF have dialysis-dependent ESRD, stage 5 CKD, and AKI.

Nearly 80% of NSF patients are on dialysis; the rest have primarily stage 5 CKD and AKI, and many of them require dialysis. The number of stage 4 CKD patients described as having NSF is small when one considers the number of stage 4 patients relative to those with stage 5 and ESRD in the population.

In fact, no patients with stages 1-3 CKD have been reported to have NSF in the published literature, and several studies that include patients who have stages 1-4 CKD and have been exposed to GBCA have not noted NSF as a complication.

In the HALT-Polycystic Kidney Disease and the Consortium for Radiologic Imaging for the Study of Polycystic Kidney trials, patients who had autosomal dominant polycystic kidney disease (ADPKD) with stages 1-3 CKD underwent 1,111 GBCA exposures with no cases of NSF reported, according to data presented by Chapman et al at the 2007 meeting of the American Association of Nephrology meeting in San Francisco. In another study, 592 patients with stages 3-4 CKD who were exposed to GBCA also did not develop NSF (Radiology.

2007;245:168-175.). Finally, 88 patients with stages 1-4 CKD who had 94 GBCA exposures, including 38 patients with stage 4 CKD, did not develop NSF (Invest Radiol. 2008;43:141-14). Thus, it appears that advanced kidney disease with a very low glomerular filtration rate constitutes the highest risk for NSF, while stage 4 CKD seems to be very low risk, and stages 1-3 CKD are associated with little or no risk.

GBCA exposure

As previously noted, compared with other conditions that affect patients with kidney disease, NSF is relatively rare. This suggests that other factors must be present to allow NSF to develop, as GBCA exposure and advanced kidney disease are necessary but not sufficient. A number of cofactors are possible. In a recent study, potential roles for increased serum calcium and phosphate concentrations, iron mobilization (or IV iron therapy), and high-dose erythropoietin (EPO) were recognized (Semin Dial. 2008;21:150-154).

Increased serum calcium concentration might promote gadolinium (Gd3+) transmetallation by competing with Gd3+ for its chelate. Although no established link to IV iron therapy exists, this metal may also compete with Gd3+ for its chelate and similarly induce transmetallation. Excess serum phosphate may bind free Gd3+ that is released by the process of transmetallation, allowing the Gd3+-phosphate complex to deposit in tissues. In fact, Gd3+-phosphate complexes are noted within the cells of some NSF tissues (J Am Acad Dermatol. 2007;56;27-30).

High-dose exogenous EPO may increase tissue fibrosis through that agent’s effects as a growth factor and mobilization of bone marrow-derived fibroblast precursors, which deposit in tissue containing Gd3+. However, the use of high EPO doses may simply reflect an inflamed, erythropoietin-resistant state, which as described later, may increase risk for NSF in GBCA-exposed patients.

Along with GBCA exposure, both underlying vascular injury and a pro-inflammatory state are important risk factors for NSF. As I have previously reported, different forms of vascular injury and pro-inflammatory states, such as infection, major surgery, and connective tissue disorders, are present in a large percentage of NSF patients.

Additionally, the GBCAs most commonly described in association with NSF, i.e., gadodiamide and gadopentetate, have also been shown to induce inflammation, perhaps contributing further to patient risk beyond just gadolinium exposure. Gadopentetate, a linear chelate, but not gadobutrol, a macrocyclic chelate, increased C-reactive protein in dialysis patients, suggesting that this pro-inflammatory effect may increase NSF risk in those exposed to the linear agents (Am J Kidney Dis. 2008; 51:976-986).

Providing further support for a pro-inflammatory effect is the finding by Steger-Hartmann et al that the nonionic linear chelate gadodiamide increased a number of pro-inflammatory cytokines in exposed animals that subsequently developed clinical and histologic NSF (Exp Toxicol Pathol. 2009 Jan 6; published online ahead of print).

One may speculate that vascular injury and inflammation increase NSF risk by two mechanisms. First, damaged, leaky vasculature allows Gd3+ that has become dissociated from its chelate during transmetallation to more readily enter the interstitial space and tissues, where it can promote fibrosis.

Second, underlying inflammation may enhance pro-fibrotic cytokine and chemokine synthesis by attracting circulating fibrocytes and perhaps other bone marrow-derived cells to Gd3+-containing tissues and increasing collagen production by fibrocytes and other local cells involved in tissue fibrosis. Figure 1 shows a hypothetical mechanism for the process and various factors involved in development of NSF.