Gadolinium and nephrogenic systemic fibrosis: time to tighten practice

The main concern for the radiologist is a growing body of evidence that clinical use of gadolinium-based contrast agents may trigger the disease. A number of patients with NSF seem not to have had any previous gadolinium exposure, but these are still under investigation. Grobner [22] was the first to report this association in January 2006. Grobner described nine patients with end-stage renal failure on dialysis who underwent MR angiography (MRA) with gadodiamide (Omniscan; GE Healthcare, Chalfont St Giles, UK); five (mean age 57.2±10.7 years) developed NSF after 2–4 weeks. All patients who developed NSF had confirmed metabolic acidosis, whilst all patients who did not develop NSF had normal pH and bicarbonate level at the time of the MRA. The average contrast agent volume used was 35 ml.

Marckmann et al. [23] reviewed case notes from their own nephrology department from August 2005 to May 2006 and found 13 patients with confirmed NSF, all exposed to gadodiamide. All patients were adults (33–66 years of age, mean 50 years), developed NSF 2–75 days (mean 25 days) after gadolinium exposure and had an eGFR <8 ml/min. From this cohort of renal patients the authors estimated an odds ratio between 32.5 and 47.6 for developing NSF following gadolinium exposure.

The link between gadolinium exposure and NSF has been further strengthened by two reports of gadolinium deposits in tissue samples of patients with NSF. High et al. [24] detected gadolinium in 4 out of 13 skin and soft-tissue biopsies from seven patients with documented NSF. All patients with NSF received gadolinium-based contrast medium prior to disease and the interval between dosing and biopsy could be determined with certainty only for two of four patients (age range 4–11 months). The same group reported in a research letter following quantitative analysis of the four tissue samples in which gadolinium was detected that the amount of gadolinium in the affected tissue of patients with NSF was approximately 35- to 150-fold the level of gadolinium in the bone of healthy volunteers with normal renal function. In a case report, Boyd et al. [25] found gadolinium deposits in areas of calcium phosphate deposition in blood vessels in a 68-year-old patient with NSF who had been previously exposed to gadodiamide.

Sadowski et al. [26] retrospectively reviewed data from 13 patients with confirmed NSF (eight males, five females, age 17–69 years), all exposed to gadodiamide. The median time between onset of NSF symptoms and last contrast-enhanced MRI examination was 11.5 days. The dose of contrast agent administered varied from 0.1 to 0.31 mmol/kg (actual) body weight. At the time of the contrast-enhanced MRI all 13 patients had CKD (eGFR <60 ml/min per 1.73 m²) and were hospitalized for a proinflammatory event (major surgery, infection or vascular event). The group with NSF had significantly lower eGFR, more proinflammatory events, and more contrast-enhanced MR examinations per patient (P<0.002) than did the control group. The incidence of NSF in this study and institution was 4.6% per year.

A review of six further NSF cases that were also related in time to gadodiamide administration has recently been published [27]. Patients were aged 23–71 years and the onset of symptoms consistent with NSF was between 19 days and 2 months after gadodiamide exposure. All patients had severe renal failure and were exposed to a gadodiamide dose ranging from 0.11 to 0.36 mmol/kg body weight. Despite having normal serum bicarbonate, five of the six patients had an elevated anion gap metabolic acidosis.

Broome et al. [28] have recently reported a retrospective study of 12 patients with NSF, all of whom received a double dose (0.2 mmol/kg body weight) of gadodiamide 2–11 weeks before the development of skin fibrosis. This group included eight men and four women (age 26–64 years) and all had renal insufficiency at the time of gadodiamide administration. The odds ratio for development of NSF in the gadodiamide-exposed patients compared with the gadodiamide-unexposed patients was 22.3 and the prevalence of NSF among gadodiamide-exposed dialysis patients was 4.0%. The odds ratio for development of NSF with double-dose compared to single-dose gadodiamide administration was 12.1. Ten patients were dialysed within 2 days of gadodiamide administration, but this failed to prevent the development of NSF.

Although the overwhelming majority (around 90%) of patients with gadolinium-associated NSF had been exposed to gadodiamide, there are now several reports of exposure to other gadolinium contrast agents. In a recent editorial in Radiology, Kuo et al. [29] reported 57 patients with NSF investigated by the United States Food and Drug Administration (FDA). In 43 of these the NSF was linked to gadodiamide; in 6 to gadopentetate dimeglumine (Magnevist; Berlex Imaging, Montville, N.J.); in 2 to gadoversetamide (OptiMARK; Mallinckrodt, St. Louis, Mo.); and in 3 to gadodiamide plus gadoversetamide; in 3 other patients, the associated specific gadolinium-based MR contrast agent was not definitively identified. Sadowski et al. [26] also reported one patient with confirmed NSF associated with both gadodiamide and gadobenate dimeglumine (MultiHance, Bracco Diagnostics, Milan, Italy). NSF related to specific gadolinium-based contrast agents is also monitored by the manufacturers, who have recently published several reports [30‐32]. In a retrospective study in Scotland of 1,826 haemodialysis patients, Collidge et al. [33] found a positive association between the cumulative dose of gadodiamide and the development of NSF. Patients who developed NSF had received a higher median cumulative dose of gadodiamide (0.39 mmol/kg vs. 0.23 mmol/kg in patients without NSF).

A case-control study by Marckmann et al. [34] conducted in 19 patients with histologically verified NSF and 19 matched controls found that increasing cumulative gadodiamide exposure, high-dose epoietin-b treatment and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related NSF in patients with renal failure.

Although not completely understood, several factors are known to contribute to the physiopathological mechanism in NSF. Gadolinium chelates are mostly eliminated through the kidneys. Renal impairment will therefore prolong the presence of these agents in the body, facilitating the release of the toxic free gadolinium ion (Gd³⁺) by dissociation from its chelate (chemical imbalance, acidosis, anion gap, inflammation) and its subsequent binding to endogenous ions. This chemical process, known as transmetallation, may be promoted by acidosis and anion gap, e.g. under inflammatory conditions [35‐40]. It has therefore been suggested that both the chemical stability of a particular chelate (cyclic compounds are more stable than linear ones in vitro) and the dose administered are risk factors for triggering NSF [28, 41]. Once released Gd³⁺ forms hydroxides and phosphates (insoluble at a pH >6.2) and these are probably engulfed by phagocytic cells [42]. This might affect the reticuloendothelial system, inhibiting the activity of certain enzymes with consequent foreign body and fibrous reactions [41, 43‐45]. Gadodiamide, the agent involved in NSF in most patients to date, is the least stable in terms of susceptibility to transmetallation in vitro, being an open-chain compound [46]. Free gadolinium ions may remain in the body for weeks to months, allowing more time for toxic effects [47]. Gadolinium is a well-known inorganic calcium channel blocker and its acute toxicity may also partly be explained via this mechanism [48, 49]. A review of the properties of commercial gadolinium contrast agents and their relation to NSF is presented in Table 1.

NSF in children has also been reported. Five patients under 18 years of age have thus far been reported (discussed below) out of a total of ten in the central database of the International Center for Nephrogenic Fibrosing Dermopathy Research (Dr. S. Cowper, personal communication). However, 13 possible patients have been reported to an online paediatric nephrology forum in June 2007 (https://​listhost.​uchicago.​edu/​mailman/​private/​pedneph/​) and these are still being investigated in relation to previous gadolinium exposure.

In 2003 Jan et al. [50] reported two paediatric patients with nephrogenic fibrosing dermopathy: a 16-year-old female patient with a life-long history of kidney failure and an 8-year-old boy with a 9-month history of membranoproliferative glomerulonephritis type II. Both patients had the clinical and histopathological features of NSF and no contrast-enhanced MRI procedures were known to be associated with these patients. However, this was before the publication of a possible link with gadolinium.

Jain et al. [51] reported two more patients with NSF in 2004: a 9-year-old boy on peritoneal dialysis and a 19-year-old male on haemodialysis with a 10-year history of previous failed renal transplants, both diagnosed with NSF on skin biopsies. The 9-year-old boy had a solitary MRA performed in June 2002, approximately 2 months prior to development of NFD. The history of the 19-year-old male was more complicated as he underwent 13 separate MRA procedures, all with gadolinium contrast agents, between April 2000 and August 2004. At least nine of the MRAs were performed prior to the NFD diagnosis in January 2003 [52]. Also, both patients had persistent metabolic acidosis in the months preceding the development of NSF, which may have been a contributing factor [22].

DiCarlo et al. [53] described another patient with histopathologically proven NSF. This patient was a 17-year-old male renal transplant recipient (15 years following transplant) who had recently begun peritoneal dialysis due to graft failure. No relationship to MRI investigations was mentioned.

Recently, Auron et al. [54] reported two patients with NSF. One of the patients was a 13-year-old boy previously reported at the age of 8 years by Jan et al. [50] in 2003 (discussed above). The second patient was a 20-year-old male who at the age 14 years was diagnosed with acute monoblastic leukaemia and 2 years later underwent bone marrow transplant and later developed kidney failure. No references to contrast-enhanced MRI are available from these reports.

Our own hospital has a large paediatric renal unit with up to 30 renal transplants per year. We have actively used MRI both for concurrent conditions and complications to CKD, as well as for providing a presurgical vascular road-map, using contrast-enhanced MRA (Gd-DTPA, Magnevist, Schering, Germany, 0.1–0.3 mmol/kg, i.v.). A review of all contrast-enhanced scans in children referred via our nephrology service (March 2002 to March 2007) showed that 75 nephrology patients (neonate to 18 years of age; median 9.6 years) had had 93 MRI scans with a follow-up of at least 6 months. There were no patients with NSF in this high-risk cohort.

Regulatory advice can be obtained from the websites listed in Table 2. The FDA has issued a general warning for all gadolinium-based contrast agents and advise against their use in patients with eGFR <30 ml/min per 1.73 m² and in all patients with acute renal insufficiency “unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging”. At the FDA’s request the manufacturers of gadolinium-based contrast agents have revised the product labels, which now include a new boxed warning and a new warnings section that describes the risk of NSF. The European Medicines Agency has so far not published any update of general contraindications, and is not in a position to do so since all but one gadolinium-based agent are licensed by individual member states’ regulatory bodies. However, the issue was discussed at a meeting of its pharmacovigilance group in June and May 2007, and issued specific advice as follows (http://​www.​mhra.​gov.​uk):

The use of Omniscan® and Magnevist® is contraindicated in patients with severe renal impairment (i.e. GFR or eGFR <30 mL/min/1·73 m²). Omniscan is also contraindicated in patients with renal dysfunction who have had, or who are awaiting, liver transplantation. For patients with moderate renal impairment (GFR or eGFR 30–59 ml/min/1·73 m²) or neonates and infants up to 1 year of age, Omniscan and Magnevist should be used only after careful consideration. All patients should be screened for renal dysfunction by obtaining a history and/or laboratory tests, especially before Omniscan or Magnevist are used. Haemodialysis shortly after administration of a gadolinium-containing MRI contrast agent in patients currently under haemodialysis may be useful for removal of contrast agent from the body. However, there is no evidence to suggest that haemodialysis can prevent or treat development of NSF. Careful consideration should also be given to the use of the other gadolinium-containing MRI contrast agents in patients with severe renal impairment.

There is an associated high morbidity and mortality with CKD, and imaging aids clinical management, such as assessment of secondary vasculopathies, infections etc, and surgical planning prior to renal transplantation. Patients at risk also include children with known or suspected CKD, as well as newborns and infants with renal immaturity or congenital cardiopathy. It seems plausible that impaired excretion, dissociation of the gadolinium chelate, and prolonged tissue retention of gadolinium is a trigger for NSF in patients with CKD. This risk increases with cumulative dose of gadolinium, with decreasing GFR <60 ml/min per 1.73 m², and in the presence of acidosis and proinflammatory conditions. The scarcity of reported children with NSF may well be due to the lower prevalence of CKD and secondary conditions in children. It is therefore imperative that paediatric practitioners are prudent and immediately tighten their local policies for use of intravenous gadolinium-based contrast agents.

It is difficult at present to suggest general guidelines, because:

It is often the case that MRI is requested after an inconclusive US examination. In our own experience, more meticulous patient preparation and dedicated rescanning of the patient with US can often give diagnostically adequate results. In patients with CKD not yet on dialysis CT is not a desirable alternative due to ionizing radiation and the nephrotoxicity of iodinated contrast agents. However, CT may provide an option in patients who are already on dialysis. MRI without intravenous contrast agent administration has not yet been validated for vascular anatomy prior to renal transplantation, but several techniques may be valuable, such as 3-D-balanced steady-state free precession imaging and time-of-flight angiography.

Patients with renal impairment may be referred for MRI from non-nephrology units and a crucial question is how to identify them. Our approach would be to include a mandatory tick box on the referral form requiring the referring clinician’s statement about renal function, and also to include a question about any known renal problems on the patient/guardian prescan checklist. This is a pragmatic approach, which will need revision after an initial phase.