Radiologia Brasileira - Publicação Científica Oficial do Colégio Brasileiro de Radiologia

Claudia da Costa Leite

Associate Professor, Department of Radiology, Head for the Magnetic Resonance Sector at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil. E-mail: claudia.leite@hcnet.usp.br

Up to some time ago, we radiologists have been using gadolinium in patients affected by renal insufficiency, and this was done very confidently, with assurance that we were utilizing a safe alternative for assessment of these patients.

The Food and Drug Administration (FDA) warning, on June/2006, (http://www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html), concerning nephrogenic systemic fibrosis (NSF)/nephrogenic fibrosing dermopathy obliges us to revise our concepts on safety in the use of gadolinium. After the RSNA 2006, the medical team in our institution started discussing the indication for gadolinium use in patients with renal insufficiency, but up to then strict rules for utilizing gadolinium-based contrast agents in these cases had not been established yet. So, in June/2007, a patient with this disease was admitted to the Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo, and I must confess that, seeing for the first time a patient affected by this syndrome associated with gadolinium administration, I have got that old sensation: "this will not happen here". The impact has been so effective that currently in our institution the creatinine clearance is preventively evaluated prior to the administration of gadolinium to patients with moderate or severe renal insufficiency. It might be said that the scenario is critical and that every physician must be aware of the possibility of NSF development.

Until February this year, 200 cases of NSF were described. This disease is systemic, and, just as its name indicates, is characterized by widespread tissue fibrosis. Originally, it was known as nephrogenic fibrosing dermopathy because of its dominant cutaneous findings (http://www.pathmax.com/dermweb).

This condition develops in patients who receive intravenous gadolinium-based contrast agents to enhance the quality of magnetic resonance imaging or angioresonance, angiography or angio-CT, and who present with moderate (stage 4) renal dysfunction (creatinine clearance < 60 ml/min/1.73 m²) or severe (stage 5) renal dysfunction (< 15 ml/min/1.73 m²), particularly those requiring dialysis (http://www.massmedboard. org). Also, the development of NFS is reported in patients affected by hepatorenal syndrome⁽¹⁾, and, in these cases, the renal function assessment becomes even more difficult, because the liver fails to produce creatinine, and therefore creatinine blood levels do not reflect the renal picture. The precise cause of NSF in patients with renal disease — usually in those requiring dialysis —, after administration of gadolinium, is still to be known; however, tissue biopsies in cases of NFS detect the presence of gadolinium in the specimens. The effects are dose-dependent and cumulative, so the risk for developing NFS increases with multiple administration of paramagnetic contrast agents. The condition is progressive and develops rapidly (about 2–12 weeks following the gadolinium administration), and sometimes may result in patients becoming confined to a wheelchair because of joints contractures, muscular weakening and arthralgia. The extremities skin hardening and joints contracture leads to immobility. Besides the skin, the involvement of other tissues like lungs, skeletal-muscle system, heart, diaphragm, and esophagus also have been described, although the patients may be asymptomatic. Although the disease may stabilize, there is no report of remission. Up to the present moment, the majority of cases was associated with gadodiamide (Omniscan^®; GE Healthcare, Princeton, NJ), however, there are cases associated with gadopentetate dimeglumine (Magnevist^®; Berlex Imaging, Montville, NJ) and gadoversetamide (OptiMARK^®; Mallinkrodt, St. Louis, MO) or these agents in association, both in doses of 0.1 mmol/kg and more⁽²⁾.

Therefore, the necessity of gadolinium must be carefullyevaluated in the setting of renal disease. Many questions must beanswered for a correct indication of these so useful contrastagents for imaging diagnosis in these patients: How do renalinsufficiency and gadolinium interact for triggering NSF? How doother risk factors (such as electrolytic disorders with increasein calcium, potassium and zinc levels) affect this process? Ismetabolic acidosis necessary for NSF to occur? Why did the firstreports emerge in 1997, when gadolinium-based contrast agents hadalready been used in patients with renal insufficiency forseveral years?

Meanwhile, the FDA suggests the following recommendations:

– Gadolinium, especially at high doses, should only beutilized if undoubtedly necessary in patients with severe renalfailure (glomerular filtration rate < 15 ml/min/1.73 m²).The most prudent course would be to institute dialysisimmediately after the gadolinium administration although there isno data to define the utility of this procedure to prevent NSF.In patients with renal insufficiency, the gadolinium excretoryrates reach, on average, 78%, 96% and 99% respectively in thefirst to third hemodialysis sessions. Notwithstanding thedevelopment of NSF is associated with only some gadolinium-basedcontrast agents, the FDA recommends prudence in the use ofgadolinium.

There is no report about development of NSF in patientswithout renal disease and the literature reports that 90% ofcases involved dialytic patients, and in the others, patientswith stage 4 or 5 chronic kidney disease. Even in patients withsevere or end-stage renal disease, the chances to develop NSFseems to be around 3-5%; however, considering the severity of thedisease, extreme prudence isrecommended⁽³⁾.

Kuo et al., in a study published in the March/2007 issue ofthe Radiology journal⁽²⁾, suggest thefollowing steps to be adopted in these cases:

1) Evidence of renal disease absence: creatinine serum levels,creatinine clearance, electrolytes should be checked, besidesconsidering decreased doses for elder, hypertensive and diabeticpatients, in the absence of previous data.

2) Discussing with the ordering physician alternative imagingdiagnosis methods for these patients. Benefits and risks shouldbe evaluated on an individual bases for each patient.

3) In cases of moderate or severe renal insufficiency wheregadolinium is prescribed, a term of informed consent should besigned both by the ordering physician and the patient or his/herlegal representative.

4) If administration of gadolinium-based contrast agent isdeemed necessary, the lowest dose as possible should beconsidered.

5) During the MRI examination any non-contrast enhancedsequence that may be helpful should be performed aiming atminimizing the necessity of contrast agent.

6) In patients undergoing hemodialysis, this treatment shouldbe ensured as soon as possible, ideally within three hours afterthe administration of the gadolinium-based contrast agent. Asecond dialysis session should be performed within 24 hours,provided it is clinically safe for the patient.

7) In patients undergoing peritoneal dialysis, it is necessaryto assure that the patient has no periods with dry abdomen.Additional dialysis cycles are recommended within the 48-hourperiod following gadolinium administration.

8) Administration of gadolinium is not recommended forpatients in whom there may be relatively protected spaces fromwhich gadolinium chelates may not be cleared, such as theamniotic fluid.

9) In patients who have already been diagnosed with NSF, a newgadolinium injection is not recommended.

NSF is a disfiguring and debilitating disease with noeffective treatment or preventive regimen⁽¹⁾.The severity of this disease leads us to remember the hippocraticprecept — primum non nocere — and in patientswith moderate to severe renal insufficiency gadolinium may beassociated with severe consequences.

Acknowledgments: Professor, Doctor Edson Amaro Júnior and Doctor Paula Arantes, by the revision of this editorial.

References

1. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007;188:586–592.

2. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology2007;242:647–649.

3. Kanal E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol 2007;188: 1447–1474.