Dr. Morcos is a Consultant Radiologist, Department of Diagnostic Imaging, Northern General Hospital, Sheffield, UK.
Patients with reduced renal function are at risk of developing contrast-induced nephrotoxicity (CIN) following a contrast-enhanced computed tomography (CT) examination with an iodinated contrast agent 1 and at risk of developing nephrogenic systemic fibrosis (NSF) after a contrast-enhanced magnetic resonance imaging (MRI) examination with an extracellular gadolinium-based contrast agent. 2 This article will present an overview of these 2 adverse effects as well as approaches to avoid these complications. The choice between contrast-enhanced CT or MRI in this group of patients will be discussed.
Contrast-induced nephrotoxicity implies that impairment in renal function (an increase in serum creatinine by more than 25% or 0.5 mg/dL) has occurred within 3 days following the intravascular administration of contrast and the absence of alternative etiology. 3
Incidence of CIN after intravenous injection
The precise incidence of CIN after the intravenous (IV) administration remains unclear because of the small number of studies that have investigated this issue. According to a recent review, only 40 studies could be identified over the last 40 years that investigated CIN after IV administration of iodinated contrast media. In contrast, there were >3000 reports on CIN after intra-arterial administration of contrast media over the same period. 1 According to this review, the incidence of CIN after IV injection varied from 0 to 21%. 1 However, 1 study reported an incidence as high as 42% in patients with advanced renal impairment (serum creatinine >2.5 mg/dL) before the contrast injection. 1 An incidence between 5% and 10% might be expected in a group of patients with different degrees of renal impairment before IV contrast administration. 1
Clinical importance of CIN
The effect of the development of CIN after IV contrast administration on a patient's morbidity and mortality is not clear and has not been adequately documented in the literature. However, CIN after intra-arterial administration is known to increase in-hospital morbidity and mortality. 4-6 Several reports have documented that CIN increases the incidence of nonrenal complications such as asepsis, lung infection, major adverse cardiac events, and delayed wound healing. 4,5 An increase in mortality among patients with CIN has also been documented. 6 It is more than likely that CIN that develops after IV contrast injection will have some deleterious effect, particularly on patients who suffer from advanced renal impairment (glomerular filtration rate [GFR] <30 mL/min) before contrast administration.
How to reduce the risk of CIN
In the author's opinion, the guidelines produced by the European Society of Urogenital Radiology (ESUR) in 1999 remain the most practical and effective approach to minimize the risk of CIN (Table 1), despite the large number of recent publications in this field. 3,7 Patients with renal impairment in whom the administration of contrast is deemed necessary should receive the lowest possible dose of isosmolar or low-osmolar nonionic contrast and hydration (100 mL/hour) for at least 4 hours before and after contrast injection. 3,7 The effectiveness of the prophylactic use of nephroprotective drugs such as acetylcysteines remains uncertain, and consistent protection has not been proven in the reports investigating the usefulness of these drugs. 5,8
Nephrogenic systemic fibrosis
This condition mainly affects patients with end-stage renal disease (ESRD). It was first reported in the literature in 2000 and was named nephrogenic fibrosing dermopathy. 2 However, it later became apparent that it is a multisystem disease and the fibrotic changes affect other organs such as lungs, heart, liver, and muscles, in addition to the skin. Hence, the name nephrogenic systemic fibrosis is now used instead of nephrogenic fibrosing dermopathy to reﬂect the multisystem nature of the disease. 2 In January 2006, an Austrian nephrologist reported 5 cases of NSF after contrast-enhanced MRI examination and, for the first time, suggested a possible causal relation between the use of gadolinium (Gd)-based contrast and NSF. 9 Since this publication, several reports have appeared in the literature that document the development of NSF in patients with advanced renal impairment following exposure to extracellular Gd contrast. 10-13
Nephrogenic systemic fibrosis affects patients with advanced renal insufficiency, including those on dialysis. The disease has also been reported in patients suffering from hepatorenal syndrome and those requiring liver transplantation. 2,13 Most cases of NSF have developed following the administration of Gd contrast. In a very few cases, exposure to Gd-based contrast could not be confirmed. The disease is characterized by scleroderma-like skin lesions that can be painful and puritic. The skin changes may progress to cause ﬂexion contractures at joints.
The skin lesions mainly affect the limbs and trunk but spare the head and neck. The fibrosis may also affect the liver, lung, heart, and muscles. The disease develops 24 hours to ≥3 months after receiving Gd contrast. The dose of Gd contrast varied from 18 to 50 mL per examination. Some of the severe cases of NSF have been associated with multiple exposures to Gd contrast. 10-13
The incidence of NSF in patients with ESRD who were exposed to Gd contrast is approximately 5%. 2,13 However, the precise incidence and extent of the disease remains uncertain. Nephrogenic systemic fibrosis has been reported world-wide with no ethnic, age, or gender preference. The majority of cases (>90%) were associated with the use of the nonionic linear Gd contrast agent gadodiamide (Omni scan, GE Healthcare, Princeton, NJ). A few cases have been reported with the nonionic linear Gd contrast gadoversetamide (OptiMARK, Tyco Healthcare/Mallinckrodt, St. Louis, MO) and the ionic linear Gd contrast gadopentetate dimeglumine (Magnevist, Bayer Schering, Germany). 13 A mild case of NSF has been documented following multiple exposures to gadoteridol (ProHance, Bracco Diagnostics, Inc., Princeton, NJ). 14
The implication of the epidemiology of NSF
The stability of a contrast agent reﬂects the ability of the chelate to retain the toxic gadolinium ion (Gd+++) in the molecule; strong binding between Gd+++ and the chelate indicates high stability. The stability of Gd contrast is likely to be an important factor in the pathogenesis of NSF, as the majority of cases were associated with the use of nonionic linear chelates that are the least stable molecules. 13 Only a single case of mild NSF has been reported with the macrocyclic agents that are more stable than the linear chelates. 15,16 No cases so far have been reported following the sole use of the most stable Gd contrast agent, the ionic macrocyclic chelate gadoterate meglumine (Dotarem, Guerbet, S.A., Paris, France). 13
Factors that determine the stability of Gd contrast
Shape (linear or cyclic)- A macrocyclic chelate offers a better protection and binding to Gd+++ in comparison to the linear structure. 16
Ionicity- Nonionic chelates are less stable than ionic ones. The replacement of a carboxyl group by a nonionic agent weakens the binding of the chelate to Gd+++, particularly in the nonionic linear molecule. 16
Markers of Gd-contrast stability- The following measurements are used in vitro to assess the stability of the Gd chelates: thermodynamic stability constant, conditional stability value, and dissociation half-life at pH 1.0. High values indicate high stability of the molecule. 15,16 The presence of a significant amount of excess chelate in the commercial preparation is an indirect marker of the instability of the molecule. 15,16 According to in vitro data, the least stable Gd chelates are the nonionic linear molecules. The commercial preparations of these molecules also contain the largest amount of excess chelates in comparison to other Gd contrast agents. The Gd contrast agent with the highest stability values and no excess chelates is the ionic macrocyclic preparation. 16 However, in vivo data that measures the amount of Gd retention in tissues ≥7 days after IV administration of Gd contrast in animals with normal renal function as a marker of stability showed no significant difference in the retention of Gd among macrocyclic agents. 17,18
Pathophysiology of NSF
Extracellular Gd contrast is eliminated from the body almost exclusively by the kidneys. In patients with renal impairment, the biological half-life is prolonged, which increases the possibility of transmetallation. In addition, molecules of low stability are prone to transmetallation with endogenous ions, leading to the release of free Gd. 16 Peripherally deposited Gd may act as a target for circulating fibrocytes, initiating the process of fibrosis. In addition, Gd in the tissues may cause the release of a variety of cytokines, particularly transforming growth factor beta (TGF ß), and activation of the enzyme transglutaminase 2 (TG2) that promotes fibrosis. 19,20 Recent studies have reported Gd deposition in skin biopsies of affected areas in patients with NSF. 21
Important risk factors for NSF
Advanced renal impairment (GFR <15 mL/min), the dose and type of Gd contrast used (the use of large doses, particularly of linear nonionic agents), the multiple repeat administration of Gd contrast, the presence of proinﬂammatory conditions (particularly vascular complications), the administration of high doses of erythropoetin, and hyperphosphatemia (which increases the chance of retaining ionized Gd in tissues) all have been reported as risk factors for the development of NSF. 12,22
How can the risk of NSF be reduced?
Patients with GFR <30 mL/min, including those on dialysis, should not receive nonionic linear chelates. The lowest possible dose of stable Gd contrast agents (macrocyclic chelates) should be used in these patients. 13 Contrast-enhanced MRI examination should be avoided whenever possible during pro-inﬂammatory events. 12 Although hemodialysis shortly after Gd contrast administration has not been shown to prevent NSF, patients on hemodialysis can be scheduled to have the dialysis session shortly after the MRI examination to reduce the Gd contrast load. 13 Patients on peritoneal dialysis are at particular risk, as the elimination of Gd contrast by peritoneal dialysis is rather slow. Continuous ambulatory peritoneal dialysis for 20 days eliminates only 69% of the injected dose. 23 Therefore, several rapid exchanges of the dialysis ﬂuid should be encouraged after contrast-enhanced MRI examination to speed the elimination of Gd. The ESUR has recently published guidelines on reducing the risk of NSF (Table 2). 13
The use of contrast in patients with renal impairment: Choosing CT or MRI
The following points should be considered in deciding whether a contrast-enhanced CT or MRI examination should be performed in a patient with reduced renal function.
1) Patients at high risk should be identified before contrast administration. Serum creatinine should be measured either routinely before contrast injection or selectively in patients with a history of renal disease, proteinuria, prior kidney surgery, hypertension, gout, or diabetes mellitus. 5,24,25 Serum creatinine can be used to determine the estimated glomerular filtration rate (eGFR) of the patient with the modification of diet in renal disease (MDRD) equation that is currently in wide use in many laboratories 24 :
- eGFR <60 mL/min is a risk factor for CIN.
- eGFR <30 mL/min is a risk factor for NSF. 13 2) The contrast administration has to be deemed essential for the patient's management, and the potential risk must be weighed against the benefits.
3) Consideration should be given to imaging techniques that may offer the same diagnostic information without the need to administer iodinated or Gd contrast agents:
- Ultrasound ± ultrasound contrast agents
- Noncontrast MRI studies
- CT without IV contrast
- CO 2 for angiography
- Isotope imaging
4) Clear communication with the patient is important, particularly to explain the reason for the choice of the examination. The patient should also be involved in the decision-making process. Explain potential risks to the patient without being an alarmist.
5) Knowledge and clinical wisdom should help the radiologist in answering the following questions:
- Which technique will offer the most accurate diagnostic information?
- What is the likelihood and seriousness of the risk?
- Do the clinical benefits justify the risk?
- How can the risk be minimized?
Balancing risk: CT and MRI
The chance of inducing CIN is much higher than of inducing NSF in patients suffering from renal impairment. The prevalence of CIN in patients with GFR <60 mL/min is approximately 10% after a contrast-enhanced CT examination 1,26 and increases to 30% to 40% in patients with GFR <30 mL/min. 1 On the other hand, NSF occurs mainly in patients with advanced reduction in renal function (GFR <30 mL/min), with an incidence of <5%. 2 In addition, all iodinated contrast agents have the potential to induce CIN, whereas NSF can possibly be prevented by using the lowest possible dose of a macrocyclic Gd contrast and avoiding repeat contrast administration within a short period of time. 13 The center that has reported the largest series of cases with NSF has not seen a single new case of NSF since they stopped using gadodiamide in March 2006 and switched to a macrocyclic MRI contrast. 26 In contrast, CIN cannot be completely avoided in spite of taking all necessary precautions. 5
Though NSF is a serious complication with no effective treatment, CIN remains a source of concern because it also increases patient morbidity and mortality. 6 A recent study reported that 4.8% of patients who developed CIN after a contrast-enhanced CT examination then developed irreversible renal impairment. 26 The further reduction in renal function is bound to adversely affect the long-term outcome for these patients. 26
Thus, considering the previously mentioned points, the balance of risk seems to be in favor of the use of contrast-enhanced MRI studies in patients with renal impairment. The incidence of NSF remains low, and the condition can be avoided by taking the correct precautions. 27
Administration of contrast to patients on dialysis
Patients on hemodialysis
Patients on hemodialysis are at an increased risk of developing NSF. Therefore, all necessary precautions should be implemented in these patients if a contrast-enhanced MRI examination is deemed necessary. 2,13 In contrast, CIN is irrelevant in hemodialysis patients, as the kidneys are already extensively damaged with no important residual renal function to protect. The administration of iodinated contrast agents to these patients usually has no important clinical consequence. 23
Patients on peritoneal dialysis
These patients are particularly at extra risk and require careful assessment and wise judgment in considering the use of contrast agents. Protecting residual renal function is clinically important, and therefore, CIN is better avoided. They are at increased risk of NSF because the prolonged half-life of Gd contrast increases the possibility of transmetallation and release of free Gd ions. 13
A contrast-enhanced MRI examination in patients with renal impairment is probably safer than contrast-enhanced CT, providing that the examination is essential for the patient's management and that all necessary precautions have been implemented. The possibility of inducing NSF might be eliminated with the careful selection of the Gd contrast to be administered, by avoiding large contrast doses, and by preventing multiple repeat contrast administrations.
- Katzberg RW, Barrett BJ. Risk of iodinated contrast material-induced nephropathy with intravenous administration. Radiology.2007;243:622-628.
- Thomsen HS. Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. EurRadiol.2006;16:2619-2621.
- Morcos SK, Thomsen HS, Webb JA, et al. Contrast-media-induced nephrotoxicity: A consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol.1999; 9:1602-1613; Comment in: EurRadiol. 2002;12:3026-3030.
- Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol.2000; 36:1542-1548.
- Morcos SK. Prevention of contrast media-induced nephrotoxicity after angiographic procedures. J Vasc Interv Radiol.2005;16:13-23.
- Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996;275:1489-1494; Comment in: JAMA. 1996;275: 1516-1517.
- Thomsen HS, Morcos SK. Contrast-medium-induced nephropathy: is there a new consensus? A review of published guidelines. Eur Radiol.2006;16: 1835-1840.
- Zagler A, Azadpour M, Mercado C, et al. N-acetylcysteine and contrast-induced nephropathy: A meta-analysis of 13 randomized trial. Am Heart J.2006;151: 140-145.
- Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;211104-1108.
- Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: Suspected etiological role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol.2006;172359-2362.
- Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol. 2007;2:264-267. Comment in: Clin J Am Soc Nephrol. 2007;2:200-202.
- Sadowski E, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: Risk factors and incidence estimation. Radiology. 2007;243:148-157. Comment in: Radiology. 2007;244:930-931; author reply 931-932.
- Thomsen HS. ESUR guideline: Gadolinium based contrast media and nephrogenic systemic fibrosis. Eur Radiol. 2007;17:2692-2696.
- Hayes E. NSF Update: Study concludes that NSF is widespread in high-risk patients, but diagnostic method raises questions. Available online at www.diagnosticimaging.com. Accessed August 23, 2007.
- Idée JM, Port M, Raynal I, et al. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: A review. Fundam Clin Pharmacol.2006;20:563-576. Erratum in: Fundam Clin Pharmacol. 2007; 21:335.
- Morcos SK. Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: Is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? Br J Radiol. 2007;80:73-76. Erratum in: Br J Radiol. 2007; 80:586. Comments in: Br J Radiol. 2007;80:581-582; author reply 584-585; Br J Radiol. 2007; 80:583-584; author reply 584-585.
- Wedeking P, Kumar K, Tweedle MF. Dissociation of gadolinium chelates in mice: Relationship to chemical characteristics. Magn Reson Imaging.1992;10: 641-648.
- Tweedle MF, Wedeking P, Kumar K. Biodistribution of radiolabeled formulated gadopentetate, gadoteridol, gadoterate and gadodiamide in mice and rats. Invest Radiol.1995;30:372-380.
- Jiménez SA, Artlett CM, Sandorfi N, et al. Dialysis associated systemic fibrosis (nephrogenic fibrosing dermopathy). Arthritis Rheum. 2004;50: 2660-2666.
- Parsons AC, Yosipovitch G, Sheehan DJ, et al. Transglutaminases: The missing link in nephrogenic systemic fibrosis. Am J Dermatopathol.2007;29:433-436.
- High WA, Ayers RA, Chandler J, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Derm atol. 2007;56:21-26. Comment in: J Am Acad Dermatol. 2007;56:710-712.
- Marckmann P, Skov L, Rossen K, et al. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant. 2007;22:3 174-3178.
- Morcos SK, Thomsen HS, Webb JA, Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR). Dialysis and contrast media. Eur Radiol.2002;12:3026-3030.
- Choyke PL, Cady J, DePollar SL, Austin H. Determination of serum creatinine prior to iodinated contrast media: Is it necessary in all patients? Tech Urol. 1998; 4:65-69.
- Thomsen HS, Morcos SK, Members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). In which patients should serum creatinine be measured before contrast medium administration? Eur Radiol. 2005;15: 749-754.
- Cheruvu B, Henning K, Mulligan J, et al. Iodixanol: Risk of subsequent contrast nephropathy in cancer patients with underlying renal insufficiency undergoing diagnostic computed tomography examinations. J Comput Assist Tomogr. 2007;31:493-498.
- Thomsen HS, Marckmann P, Logager VB. Enhanced computed tomography or magnetic resonance imaging: A choice between contrast medium-induced nephropathy and nephrogenic systemic fibrosis? Acta Radiol. 2007;48:593-596.