Gadolinium-induced nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis is a new disease whose incidence has peaked and receded over the past decade. It occurs in the presence of significant renal impairment, either acute or chronic (MDRD creatinine clearance of <30 mL/min/1.73 m(2)), and is associated with the administration of gadolinium-based contrast (GBC). Since 2006, the incidence of this disease has decreased markedly in patients with renal impairment, mainly owing to protocols that have not administered GBC to patients with creatinine clearances of less than 30 mL/min/1.73 m(2), and in some cases with the use of less toxic and lower doses of GBC. The purpose of this article is to review the current status of GBC use for imaging in patients with kidney disease.     

Gadolinium and nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is characterized by red skin areas or plaques that over several weeks successively develop to painful thickened skin with a 'woody' texture, resembling 'peau d'orange'. Starting at the extremities, it may spread to the trunk, and may progressively inhibit flexion of adjacent joints. In skin biopsies of affected areas, thickened collagen bundles, mucin deposition, and proliferation of fibroblasts and elastic fibers are seen. Originally described as nephrogenic fibrosing dermopathy (NFD) because of its primarily cutaneous manifestation, this entity was then named NSF because of systemic involvement of other organs like lungs, myocardium, or striated muscles. The pathogenesis of the disease is not yet known, but our observations suggest a close association between development of NSF and exposure to gadolinium-containing contrast agents, thereafter confirmed by other authors. Recently, gadolinium was demonstrated to be detectable in skin tissue samples of affected patients. In this short review, the development of NSF and its sequential association with the exposure to gadolinium-containing contrast agents is presented. The mechanisms likely to cause NFD/NSF are discussed.     

Gadolinium and nephrogenic systemic fibrosis: an update

Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. It can be severely debilitating and sometimes fatal. There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Risk factors include renal impairment and proinflammatory conditions, e.g. major surgery and vascular events. Although there is no single effective treatment for NSF, the most successful outcomes are seen following restoration of renal function, either following recovery from acute kidney injury or following renal transplantation. There have been ten biopsy-proved pediatric cases of NSF, with no convincing evidence that children have a significantly altered risk compared with the adult population. After implementation of guidelines restricting the use of gadolinium-based contrast agents in at-risk patients, there has been a sharp reduction in new cases and no new reports in children. Continued vigilance is recommended: screening for renal impairment, use of more stable gadolinium chelates, consideration of non-contrast-enhanced MRI or alternative imaging modalities where appropriate.     

New insights into nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis is a new disorder reported almost exclusively in patients who have renal insufficiency and are exposed to contrast media formulated with gadolinium. High morbidity and mortality are associated with this severely disabling and painful condition. The acute phase begins upon exposure to gadolinium contrast media, characterized by a systemic inflammatory response involving iron mobilization, and then as a progressive, chronic phase in which fibrosis develops. Proposed is a unifying model of cumulative risk factors in which the interplay of systemic inflammation and stimulated hematopoietic environment associated with hyperparathyroidism and erythropoietin may tie to a common pathogenic mechanism of fibrogenesis. Because there are no uniformly effective interventions to treat nephrogenic systemic fibrosis other than successful renal transplantation, prevention by avoiding gadolinium contrast media in patients with chronic kidney disease is vital. On the basis of suspected pathogenesis, it is also reasonable to limit erythropoietin and iron therapy to dosages ensuring recommended targets and adequately control hyperparathyroidism. Herein is reviewed what is currently known about this subject.     

Gadolinium and nephrogenic systemic fibrosis: association or causation

SUMMARY:   With widespread availability of magnetic resonance imaging (MRI), it has become standard practice for patients with severe renal impairment or previous severe reactions to iodine-containing contrast media to receive gadolinium-based MRI contrast agents instead of traditional radiographic contrast agents, particularly for magnetic resonance angiography. However, there is growing concern about the use of gadolinium contrast agents in the presence of severe renal insufficiency, because of increasing reports of nephrogenic fibrosing dermopathy (NFD)/nephrogenic systemic fibrosis (NSF), associated with the exposure to certain gadolinium-containing contrast agents. In this review we explore the causal link between gadolinium exposure and NSF, using an established system of epidemiological criteria proposed by Bradford Hill. Though the current evidence makes gadolinium a strong suspect as an aetiologic agent for NSF in the presence of severe renal failure, the die is not cast yet. At this stage there needs to be cautious approach to the use of gadolinium-containing contrast agents in the presence of severe renal failure (glomerular filtration rate <30 mL/min per 1.73 m²).     

Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis

AIMS: To further characterize the clinical signs and symptoms of nephrogenic systemic fibrosis, a new and serious disease affecting renal failure patients and caused by some Gd-containing contrast agents, including gadodiamide. MATERIAL: 22 cases of gadodiamide-related nephrogenic systemic fibrosis followed at the nephrology department of Copenhagen University Hospital Herlev. METHOD: Retrospective cohort study based on medical records, personal interviews and physical examinations. RESULTS: Typical first signs of the disease were skin discoloration, induration and warmth, itching, constant pain and other neuropathic symptoms localized to the lower legs. First sign appeared in a median of 14 days (range 0 a 53 days) after gadodiamide exposure. Associated early symptoms included sleeplessness and transient, diffuse hair loss. The predominant late symptom was symmetrical skin stiffness of extremities with or without restricted joint motion. Ten of 22 patients (45, 95% CI: 27 a 66%) were severely disabled due to contractures on the average of 29 months after being exposed to gadodiamide. Four patients died (18, 95% CI: 6 a 41). Patients perceived that intensive physiotherapy was effective in limiting disabling contractures. CONCLUSIONS: Signs and symptoms of nephrogenic systemic fibrosis vary over time and between patients. The disease leads to severe disability in a significant proportion of affected patients. Intensive physiotherapy may limit the development of contractures.     

Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?

Nephrol Dial Transplant April 2006; 21: 1104–1108     

Treatment of nephrogenic systemic fibrosis: limited options but hope for the future

Nephrogenic systemic fibrosis has now been linked to gadolinium-based contrast exposure in those with compromised kidney function. When present, symptoms can be quite devastating for the patient including severe pain and immobility. Unfortunately there is a lack of a universally effective therapy at this time and the literature, reviewed in this article, is comprised of primarily case reports and small case series allowing few conclusions to be drawn. It is widely recognized that supportive management with physical therapy and aggressive pain management is essential. Resolution of renal function in acute kidney injury appears to attenuate disease in most cases and transplantation has been associated with variable success. Therapies with anecdotal benefit include extracorporeal photopheresis and intravenous sodium thiosulfate. Other interventions have shown limited success. As the mechanism becomes more readily understood, it is hoped that targeted therapy might prove more effective than currently available remedies. In all likelihood prevention will prove to be most effective in avoiding this devastating complication.     

Case-control study of gadodiamide-related nephrogenic systemic fibrosis.

BACKGROUND: Nephrogenic systemic fibrosis may be caused by gadolinium (Gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients exposed to gadodiamide develop nephrogenic systemic fibrosis. METHODS: We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were retrieved from medical records. RESULTS: Cases had been exposed to a mean gadodiamide dose of 0.29 mmol/kg (range 0.18-0.50) shortly before first signs of nephrogenic systemic fibrosis. Controls had been exposed to 0.28 mmol/kg (0.13-0.49). Cumulative gadodiamide exposure while in chronic kidney disease stage 5 was significantly higher among cases compared with controls (0.41 vs 0.31 mmol/kg, P = 0.05) and among severe cases (n = 9) compared with non-severe cases (0.49 vs 0.33 mmol/kg, P = 0.02). Severe cases developed primarily among patients in regular haemodialysis therapy at exposure. Cases had higher serum concentrations of ionized calcium and phosphate than controls and tended to receive higher doses of epoietin-beta than controls at time of exposure. Severe cases were treated with higher doses of epoietin-beta than non-severe cases at exposure (10.8 vs 4.4 10(3) IU/week, P = 0.02). CONCLUSIONS: Increasing cumulative gadodiamide exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.     

Clinical improvement of nephrogenic systemic fibrosis after kidney transplantation

Nephrogenic systemic fibrosis (NSF) has been observed with increased frequency in recent years. Progressive hardening of the skin advancing to severe woody induration and the development of thickened hyperpigmented plaques on the extremities and the trunk are the main clinical features. Further progression of the disease results in flexion contractures of the upper and lower extremities, resulting in immobilization and severe morbidity. In this study, we reviewed our experience with seven end-stage renal disease patients who were referred to our center between January 2004 and June 2005 for kidney transplant evaluation or for diagnosis and treatment of their deteriorating condition. Diagnosis in all patients was confirmed by skin and muscle biopsy. Three of these patients underwent renal transplantations, and softening of the skin and improved mobility of the joints was noted after kidney transplantation. Three of the four patients who remained on dialysis showed further deterioration of their NSF despite a trial of immunosuppressive therapy. Improvement after transplantation could be secondary to immunosuppression, increased renal clearance and/or more effective fluid management.     

Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease

BACKGROUND.: In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark's identification and subsequent rapid eradication of NSF. METHODS.: NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002-11). RESULTS.: In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide's renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION.: A confluence of factors led to the development and eradication of NSF in Denmark.     

Patient characteristics and risk factors for nephrogenic systemic fibrosis following gadolinium exposure

Nephrogenic systemic fibrosis (NSF) is a systemic illness, which only affects patients with kidney failure. NSF risk increases with progressively lower levels of kidney function. It is characterized by red skin areas or plaques that develop over several weeks to painful thickened skin with a "woody" texture, resembling "peau d'orange." It may ultimately cause flexion contractures of joints. Skin biopsy reveals thickened collagen bundles, mucin deposition, proliferation of fibroblasts and elastic fibers, without inflammation. Originally described as nephrogenic fibrosing dermopathy (NFD), because of its primarily cutaneous manifestation, it was renamed NSF because of the involvement of various organs like the lungs, myocardium, or striated muscles. The pathogenesis of the disease is not known yet, but recently we suggested a strong association between development of NSF and exposure to gadolinium-based contrast (GBC) agents, thereafter confirmed by other authors. As a consequence of our recent observations, medical authorities imposed restrictions that exclude patients with advanced levels of renal insufficiency from potentially important magnetic resonance imaging studies with gadolinium. Unfortunately, the only alternatives in many situations (examination of brain, lungs, vasculature) are imaging modalities using iodinated radiocontrast agents. Thus, clinicians are faced with weighing the potential risk of NSF from GBC exposure against the risk of acute kidney injury-associated with radiocontrast media. In this dilemma, clinicians must identify patients at high-risk to develop NSF. Known risk factors critical for the development of NSF after exposure to GBC agents (certain chelates and higher doses) are end-stage renal disease requiring dialysis, especially those with little or no residual renal function, and advanced kidney disease not on dialysis. Other potential risk factors include metabolic acidosis, iron overload/intravenous iron, divalent ion disturbances, endothelial/vascular injury, and high erythropoietin doses. Further studies are required.     

Treatment with corticosteroids does not seem to benefit nephrogenic systemic fibrosis

Sir, Nephrogenic systemic fibrosis (NSF) is a formerly unknown disease,which has become more and more recognized. It affects patientswith kidney failure and, to a great extent, mimics systemicsclerosis [1]. An     

Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis is a severe disabling disease that can follow gadolinium-based contrast exposure. In this study we analyzed the clinical and laboratory records of patients with nephrogenic systemic fibrosis who had a history of exposure to gadolinium-based contrast media and identified their cardiac and vascular events. At autopsy, we found that the heart, blood vessels, and skin of three patients who died of cardiac and/or vascular complications had appreciable amounts of gadolinium, iron, and aluminum as measured by inductively coupled plasma-mass spectrometry and confirmed by x-ray fluorescence. Of the 32 patients with nephrogenic systemic fibrosis studied, 10 died at a median of 112 days after diagnosis. Cardiovascular events contributed to the mortality of 9 patients and included congestive heart failure, recurrent arrhythmias, hypotension, stroke, limb ischemia, posterior ischemic optic neuropathy and sudden death. Our results show that increased cardiac and vascular complications along with short survival in nephrogenic systemic fibrosis are associated with metal accumulation in the heart, blood vessels, and skin of these patients.