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Suggesting Gadolinium-based Contrast Media for CT in Azotemic Patients Is Not Based on Historical, Clinical, and Experimental Data

Ulf Nyman, MD, PhD^*, Barbara Elmståhl, MD, PhD, and Peter Leander, MD, PhD

^* Department of Diagnostic Radiology, Lasarettet Trelleborg, SE 231 85 Trelleborg, Sweden
e-mail: ulf.nyman{at}skane.se
Department of Diagnostic Radiology, Malmö University Hospital, Lund University, Lund, Sweden

Editor:

The substitution of gadolinium-based contrast media (CM) for iodine-based CM in computed tomographic (CT) examinations to prevent or reduce the risk of CM-induced nephropathy (1,2) does not take into account the historical development and basic characteristics of CM in relation to their toxicity.

The progress in clinical safety (general adverse effects and local organ toxicity) of iodine-based CM developed since the 1920s mirrors improvements in their animal toxicity and parallels the increasing ratio between the number of attenuating atoms (iodine) and osmotic active particles in CM—that is, attenuating capacity (the fundamental purpose of radiographic CM) relative to the risk of osmotoxic complications, including nephrotoxicity (3).

Gadopentetate dimeglumine, used by Dr Remy-Jardin and colleagues in studies in the June 2005 (1) and March 2006 (2) issues of Radiology; uroselectan (iodine-based CM developed in the 1920s); and a modern nonionic dimeric iodine-based CM (iodixanol) have the following ratio and intravenous median lethal dose, or LD₅₀, in mice, respectively: ratios of 1:3, 1:2, and 6:1 and LD₅₀ of 6, 16, and 200 mmol of the attenuating atom (gadolinium or iodine) per kilogram of body weight in mice (3,4). Thus, gadopentetate dimeglumine has 18-times higher potential osmotic effects and 33-times higher acute intravenous toxicity per attenuating atom (gadolinium or iodine) than does iodixanol. Gadolinium-based CM have also been proved more nephrotoxic than iodine-based CM in animal studies comparing both isoattenuating and equimolecular concentrations of gadolinium-based and iodine-based CM (5,6). The nephrotoxic potentials of gadolinium-based CM have also been demonstrated in humans (7,8), and a mixture of gadolinium-based CM and iodixanol was found to be more nephrotoxic than pure iodixanol (9). Findings of another study demonstrated equal nephrotoxicity of gadolinium- and iodine-based CM (10), although the concentration of the iodine-based CM should have been halved (6) for equal attenuation.

Fifty milliliters of 0.5 mol/L gadopentetate dimeglumine, the mean dose used by Dr Remy-Jardin and colleagues, represents a renal osmotic load of 75 mOsm (50 mL·0.5 mmol/mL·3 particles). By using the same model of scanner (Somatom Sensation 16; Siemens, Forchheim, Germany) as they did, we found the attenuation of 0.5 mol/L gadolinium-based CM to be roughly equal to 110 mg of iodine per milliliter at 120-kVp body CT (6). Fifty milliliters of 110 mg I/mL of iodixanol, a 5.5-g iodine dose isoattenuating with the gadolinium-based CM dose used by Dr Remy-Jardin and colleagues, represents an osmotic load of only 7.2 mOsm (50 mL·110 mg I/mL)/(6·126.9 – atomic weight of iodine). Thus, the osmotic load—considered an important pathophysiological mechanism in CM-induced nephropathy (11)—of gadopentetate dimeglumine is about 10 times that of iodixanol for the same attenuation.

We believe our presented basic facts about CM should discourage anyone from even starting experimenting with gadolinium-based CM for radiographic examinations in azotemic patients. Even the most fundamental requirements prior to human use include performing renal toxicologic animal studies in comparison with existing agents in concentrations and volumes resulting in the same effect for which they are intended. Thus, we are confused as to why Schering (Berlin, Germany) would support an off-label use of their own gadolinium-based CM.

	References

TOP References

 

1. Remy-Jardin M, Dequiedt P, Ertzbischoff O, et al. Safety and effectiveness of gadolinium-enhanced multi-detector row spiral CT angiography of the chest: preliminary results in 37 patients with contraindications to iodinated contrast agents. Radiology 2005;235:819–826.[Abstract/Free Full Text]
2. Remy-Jardin M, Bahepar J, Lafitte JJ, et al. Multi–detector row CT angiography of pulmonary circulation with gadolinium-based contrast agents: prospective evaluation in 60 patients. Radiology 2006;238:1022–1035.[Abstract/Free Full Text]
3. Dawson P, Cosgrove DO, Grainger RG, eds. Textbook of contrast media. Oxford, England: Isis Medical Media, 1999.
4. Nyman U, Elmståhl B, Leander P, Nilsson M, Golman K, Almen T. Are gadolinium-based contrast media really safer than iodinated media for digital subtraction angiography in patients with azotemia? Radiology 2002;223:311–318.[Abstract/Free Full Text]
5. Elmståhl B, Nyman U, Leander P, Chai CM, Frennby B, Almén T. Gadolinium contrast media are more nephrotoxic than a low osmolar iodine medium employing doses with equal x-ray attenuation in renal arteriography: an experimental study in pigs. Acad Radiol 2004;11:1219–1228.[CrossRef][Medline]
6. Elmståhl B. Are gadolinium contrast media really less nephrotoxic iodine agents in radiographic examinations? a comparison in relation to their ability to attenuate x-rays in a pig model [dissertation]. Lund, Sweden: Lund University Faculty of Medicine Doctoral Dissertation Series 2006:9. http://theses.lub.lu.se/scripta-archive/2006/01/05/med_1239/elmstahl_kappa.pdf. Accessed May 19, 2007.
7. Sam AD, Morasch MD, Collins J, Song G, Chen R, Pereles FS. Safety of gadolinium contrast angiography in patients with chronic renal insufficiency. J Vasc Surg 2003;38:313–318.[CrossRef][Medline]
8. Ergün I, Keven K, Uruc I, et al. The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrol Dial Transplant 2006;21:697–700.[Abstract/Free Full Text]
9. Briguori C, Colombo A, Airoldi F, et al. Gadolinium-based contrast agents and nephrotoxicity in patients undergoing coronary artery procedures. Catheter Cardiovasc Interv 2006;67:175–180.[CrossRef][Medline]
10. Erley CM, Bader BD, Berger ED, et al. Gadolinium-based contrast media compared with iodinated media for digital subtraction angiography in azotaemic patients. Nephrol Dial Transplant 2004;19:2526–2531.[Abstract/Free Full Text]
11. Heyman SN, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest Radiol 1999;34:685–691.[CrossRef][Medline]

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