Journal Departments

Q: Can the use of contrast materials for radiographic studies be harmful to patients with chronic kidney disease (CKD)?

A: In the past few years there has been considerable concern in the nephrology community about the use of gadolinium-based contrast agents that are used as a contrast agent in magnetic resonance imaging (MRI). Patients with Stages 3 and 4 CKD appear to be at increased risk. Although gadolinium has been widely used for several years, there is recent evidence that this agent plays a central role in the development of acute renal failure (ARF), nephrogenic fibrosing dermopathy (NFD) and nephrogenic systemic fibrosis (NSF). The latter two entities are acquired, idiopathic disorders that have been seen in patients with kidney disease and have only recently been recognized as distinct clinical pathological entities since 1997 with 177 cases worldwide (Grobner, 2006a).

Use of Gadolinium in CKD Population
Gadolinium is a paramagnetic metal ion and has the highest neutron absorbing properties of all the elements. These two characteristics make it highly suitable as a contrast agent. In MRI imaging, gadolinium allows for greater visualization of cellular and tissue pathology. Gadolinium is normally excreted through the urinary system within 6 hours post-infusion, but elimination becomes problematic for individuals with reduced kidney function. The half life is prolonged and may increase to 30-120 hours in this patient population (Grobner, 2006a).

Currently in the United States, five gadolinium contrast agents were approved by the United States Food and Drug Administration (FDA) between 1988 and 2004. These agents are gadodimide (Omniscan®), gadoversetamide (OptiMARK®), gadopentetate dimeglumine (Magnevist®), gadoteridol (ProHance®), and gadobenate dimeglumine (MultiHance®). More than 3,000 patients were involved in the FDA pre-market approval process. The most common symptoms exhibited with gadolinium infusion were sweating, rash, itching, hives, and facial swelling. These symptoms were generally considered to be allergic type responses and were not associated with specific renal toxicity. The number of patients with reduced kidney function that were included in Phase II and Phase III pre-market trials was limited. (FDA, 2007)

Use of Gadolinium and the Development Of Complications
NFD/NSF is a systemic, debilitating disease with prominent and visible effects in the skin that occurs exclusively in patients with kidney failure. According to the International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR), patients with NFD/NSF experience swelling and tightening of the skin with induration usually involving the distal extremities, but sometimes involving the trunk (Cowper, 2008). The skin is described as woody or resembling an orange peel (peau d’orange) and patients may experience burning or severe pain in the affected areas. It has been noted that the onset of symptoms can take a few days to several weeks after the contrast agent infusion and MRI procedure. The presumed causative agent is the gadolinium contrast. Some affected patients have reported such severe thickening of the skin that flexion and extension of the joints becomes difficult, which results in joint contractures. Most patients experience considerable pain in the area of the contractures. During the course of the disease, fibrosis of the internal organs, such as diaphragm, lungs, and abdominal muscles can occur leading to NFS, which may become fatal (Cowper, 2008).

Ergun et al. (2006) examined the safety of gadolinium in 91 patients with Stages 3 and 4 CKD. Several risk factors were noted for gadolinium-induced ARF. These included pre-existing diabetic nephropathy, low serum albumin and hemoglobin levels, older age, and reduced creatinine clearance. The investigators reported that 12.1% of the cohort developed ARF. However, they noted that 80% of the patients in the study received antihypertensive therapy such as angiotensin converting enzyme inhibitors, beta blockers, calcium channel blockers, diuretics, and other agents. They concluded that systemic hypertension, heart failure, and other etiologies of CKD were not risk factors for gadolinium-induced ARF.

A more recent study by Othersen, Maize, Woolson, and Budisavlevic (2007) examined the effects of gadolinium and the development of NSF in patients with reduced kidney function. The investigators studied 849 patients on renal replacement therapy (RRT) over a 5-year period and found that only 4 (1.5%) of the 261 patients exposed to gadolinium developed clinically significant diseases. They also examined 592 patients in Stage 3 or 4 CKD and found that none developed NSF after gadolinium exposure. The investigators noted that gadolinium exposure in patients with CKD is associated with NSF and indicated that that repeated gadolinium exposure can increase the incidence of NSF in this patient population. In spite of this association, the investigators are uncertain if gadolinium is the key factor in the pathogenesis of this disease.

Grobner (2006a) studied risk factors for development of NFD in nine patients with end stage renal disease receiving dialytic therapy. Five of the patients developed NFD, and four did not. All received Gd-DTPA-BMA (Grobner, 2006b). Grobner found that all five affected patients had metabolic acidosis (mean pH-value 7.29 ± 0.04) while the four unaffected patients had a normal pH (mean pH-value of 7.39 ± 0.01) (Grobner, 2006a). Additionally the mean time on dialysis was longer for the five patients affected (36 ± 12.5 months) than those not affected (23.75 ± 12.5 months).

Swaminathan and Shah (2007) propose that cumulative risk factors interplay with inflammation, stimulated hematopoietic environment, iron therapy, and hyperparathyroidism and may tie into a common pathogenic mechanism for fibrogenesis and development of NFD/NSF. These investigators suggest limiting doses of iron and erythropoietin-stimulating agents to doses that support the recommended targets.

Akgun, H., Gonlusen G., Cartwright, J., Suki, W., & Troung, L.D. (2006). Are gadolinium-based contrast media nephrotoxic? A renal biopsy study. Archives of Pathology and Laboratory Medicine, 130(9), 1354-1357.

Cowper, S.E. (2008). Nephrogenic fibrosing dermopathy [NFD/NFS Website]. Retrieved January 31, 2008, from http://www. icnfdr.org

Ergun, I., Keven, K., Uruc, I., Ekmekci, Y., Canbakan, B., Erden, I., et al. (2006). The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrology Dialysis Transplantation, 21, 697-700.

Food and Drug Administration (FDA), & United States Department of Health and Human Services. (2007). Information on gadolinium-containing contrast agents. Retrieved December 4, 2007, from http://www.fda.gov/ cder/drug/infopage/gcca/default.htm

Grobner, T. (2006a). Gadolinium – A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation, 21(4), 1104-1108. Retrieved January 31, 2008, from http://ndt.oxfordjournals.org/cgi/content/ extract/21/4/1104

Grobner, T. (2006b). Erratum. Gadolinium – A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation, 21(6), 1745. Retrieved February 2, 2008, from http://ndt.oxfordjournals.org/cgi/content/full/21/6/ 1745

Kuo, P., Kanal, E., Abu-Alfa, A., & Cowper, S. (2007). Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology, 242, 647. Retrieved January 19, 2008, from http://radiology.rsnajnls.org/cgi/content/full/ 2423061640v1

Othersen, J., Maize, J.,Woolson, R., & Budisavlevic, M. (2007). Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrology Dialysis Transplantation, 22(11), 3179-3185.

Swaminathan, S., & Shah, S. (2007). New insights into nephrogenic systemic fibrosis. Journal of the American Society of Nephrology, 18(10), 2636-2643.