Special issue: Nephrogenic systemic fibrosis

“Bad times have a scientific value. These are occasions a good learner would not miss” Ralph Waldo Emerson (1803–1882) MRI contrast agents have been routinely used to enhance various structures, organs and lesions in the body for over 20 years now. There is strong evidence that these agents are highly efficacious, and routine clinical practice seems unthinkable without them. Almost all MR contrast agents are based on chelated heavy metals from the lanthanide group of elements, mainly gadolinium (Gd3+). Gadolinium is a rare earth metal that is known to be highly toxic in the free, unchelated form. However, when caged in a chelating molecule (from the Greek “χηλαι”, meaning “lobster claw”), gadolinium chelates can be safely administered by means of intravenous injection because the kidneys rapidly excrete them. Since the late 1980s, many toxicological and pharmacokinetics studies have been conducted by the major contrast vendors with various gadolinium-based contrast agents (GBCA). In all of these studies an extremely favorable safety profile was found. Therefore, the recent discovery of the association between administration of GBCA and nephrogenic systemic fibrosis (NSF) came as a surprise to almost everyone involved, although in retrospect maybe we should not have been so surprised. Perhaps after giving GBCA to over 200 million patients and rarely experiencing any adverse effects of any kind, we thought we could administer these drugs with impunity. On the other hand, would we not expect some adverse effects eventually to surface? We were injecting a heavy metal (albeit as a chelate), in ever larger doses, often multiple times, and often in patients with severely compromised renal excretion, knowing that these agents were primarily excreted by the kidneys. NSF is a rare, idiopathic systemic fibrosing disorder and is characterized clinically by pain, dermopathy, and joint contractures. NSF affects the skin, skeletal muscle, esophagus, lungs, heart, and kidneys. The first suggestion of the link between GBCA and NSF by Grobner et al. 3 years ago (1), sparked intense interest in this subject, illustrating just how important MR contrast media are today. It is now clear that NSF is a condition that almost exclusively affects patients with severely limited renal function. However, despite the deluge of publications on this subject—as of October 9, 2009, there were over 438 publications available on PubMed—surprisingly little is known about the exact pathogenesis of the disease, and who exactly is at risk for developing the disease. The discovery of NSF has been unfortunate for patients, and particularly patients with acute or chronic kidney disease (CKD) with severely impaired renal function. Worldwide, regulatory agencies have issued warnings on the use of GBCA in patients with severe CKD, which has led to a virtual cessation of use of contrast-enhanced MRI in this vulnerable patient group. Patients with CKD are a difficult population for the imaging community. MRI has always been and remains of high value in this patient group, because it is well known that administration of iodinated contrast agents is contraindicated, especially in the presence of residual renal function. Because of all the attention NSF has attracted, many clinicians are now ordering CT examinations instead of MRI. Many radiologists have experienced situations in their own practices where contrast-enhanced MRI examinations on their patients have been substituted with contrast-enhanced CT because of fear of NSF with GBCA-MRI only to have these patients go on to develop renal failure due to contrast induced nephropathy (CIN). While the desire to avoid NSF is understandable, care should be taken that contrast-enhanced MRI is not withheld in more patients than absolutely necessary. Paradoxically, the current FDA advice to only give GBCA to patients with estimated glomerular filtration rates (eGFR) greater than 60 mL/min/1.73 m2 may do more harm than good as there is no evidence of NSF occurring in patients with eGFR >30 mL/min/1.73 m2. The FDA guidelines can lead to patients in the eGFR 30–60 mL/min group being exposed to the high risk for negative effects from the administration of iodinated contrast agents, even though they have a negligible risk for development of NSF. Furthermore, whereas the FDA regards all GBCA as having an equal risk for inducing NSF, the FDA guidelines take no account of the chemical structure of the compound, and especially of the kinetic stability, which seems to be an important factor to consider. To date, no unequivocal NSF cases have been reported in patients who exclusively received macrocyclic agents with high kinetic stability, although some reports have suggested this possibility (2) . It is indeed highly likely that there is a relation between GBCA and NSF. The incidence of biopsy-confirmed NSF cases has dropped to nearly zero after the FDA warning and the institution of similar measures by the European Medicines Agency and similar regulatory bodies in other parts of the world. There have been no cases of NSF with onset after August 2008 reported by any of the GBCA vendors. Convincing proof is lacking that NSF can develop without administration of GBCA. NSF only occurs in patients with severe renal impairment (eGFR < 30). The few cases of NSF in cases with eGFR > 30 have been in situations of acute renal failure where the GFR was decreasing rapidly and did not accurately reflect renal excretory function (4, 5). Accumulating evidence suggests that GBCA with low kinetic stability confers a higher risk for NSF (4, 5). No unequivocal NSF cases have been reported after sole administration of GBCA with high kinetic stability. Higher cumulative doses of low kinetic stability GBCA confer a higher risk for NSF in patients with severely impaired renal function (6-8). Risk is relative, not absolute. Not only is the risk of NSF with GBCA-MRI small compared with the risk of CIN with iodinated CT, but also with risk of severe allergic reactions with iodine and allergic reactions with GBCA. The concern about NSF has masked our concerns for GBCA's other potential adverse effects. A survey of major American centers published in 1999 by Murphy et al indicated an incidence of severe allergic reactions to GBCA of approximately 20 cases per million doses administered (9). This is approximately 10-fold greater than the incidence of NSF. And what of the risk of making an incorrect diagnosis because the most appropriate imaging study was not done? Why do some patients with severely impaired renal function get NSF, whereas others, with similar degrees of impairment, do not? In fact, the vast majority of patients with severely impaired renal function do not get NSF, even when administered a high dose of low kinetic stability GBCA. This remains one of the most puzzling questions in the NSF saga. Which patients need to be screened for renal disease, and what is the safest and most cost-effective way to do this? Is a questionnaire sufficient? Or does every patient need to have their creatinine measured before a contrast-enhanced MRI examination can be performed? Or should laboratory screening only apply to certain subgroups of patients? Is the class of macrocyclic GBCA inert regardless of renal function, and can they be administered safely in patients with stage 4 and 5 CKD without causing NSF? At what level of renal function do the risks for NSF outweigh the risk for complications associated with administration of iodinated contrast agents? In other words: Is the newest generation of iodinated contrast agents safe or unsafe in patients with CKD? Can these agents be administered safely? In this special issue of the Journal of Magnetic Resonance Imaging, we present a series of review articles with the aim of summarizing the current knowledge about NSF in relation to administration of GBCA, and to answer some of the questions posed above. The issue begins with a summary of Dr. Jeff Weinreb's excellent keynote lecture as given at the 17th annual meeting of the ISMRM in May of this year (10). Subsequent articles cover a wide variety of related topics, ranging from a basic primer on gadolinium chemistry (11), the role of thermodynamic and kinetic parameters in gadolinium chelate stability (12), the biodistribution of GBCA, including gadolinium deposition (13), and biological effector mechanisms (14-16), to the clinical spectrum of NSF (17), to practical insights on measurement of renal function (18) as well as a review on how to remove gadolinium by dialysis (19). We present current guidelines for injection of GBCA as used in the United States, Canada, Europe (20) and Japan (21). Furthermore, risk factors for NSF are reviewed (22), and NSF is discussed in the context of renovascular (23) and liver disease (24). The issue of relative risk of NSF versus CIN is addressed in the excellent review by Martin and other experts on this topic (25). Finally, retrospective reviews of data from China (26) and the United States (27) confirm the safety of low-dose contrast-enhanced MRI, even in patients with renal impairment. It is our sincere hope that the material selected for this special issue will help with the further understanding of the relationship between the administration of GBCA and the development of NSF, and that the material in this issue will form the basis for further research and subsequent rational choices in patient management that ultimately lead to better clinical care for patients. We hope that by bringing together the most recent insights regarding the pathogenesis and strategies on how to avoid NSF in patients at high risk, contrast-enhanced MRI will again be used whenever indicated, except in that very small number of patients that are truly and significantly at risk. As Emerson eloquently stated: “Bad times have a scientific value. These are occasions a good learner would not miss”. We extend our gratitude to Dr. Leon Partain, Editor-in-Chief, for his support for this project and his insightful suggestions, and to the dedicated and skilled editorial office staff Martha Tanner, Barbara Sammons, and Kerry King. Finally, we would like to thank the contributors, all of whom are highly regarded experts in the field, for their time and effort to create this special issue of the Journal.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.