Contrast-medium–induced nephrotoxicity
Dr. Thomsen is a Professor in the Department of Diagnostic Radiology, Copenhagen University Hospital at Herlev, Herlev, Denmark. Dr. Morcos is a Senior Lecturer at the University of Sheffield and a Consultant Radiologist with North General Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK.
The term contrast-medium-induced nephrotoxicity (CMIN) is widely used to refer to the reduction in renal function induced by contrast media. It implies impairment in renal function (an increase in serum creatinine by >25% or >0.5 mg/dL) that occurs within 3 days following the intravascular administration of contrast media and the absence of an alternative etiology. 1 Contrast-medium-induced nephrotoxicity is considered an important cause of hospital-acquired renal failure. 2,3 This is not surprising because diagnostic and interventional procedures requiring the use of contrast media are performed with increasing frequency. In addition, the patient population subjected to these procedures is progressively older with more comorbid conditions. 4 Prevention of this condition is important in order to avoid the substantial morbidity and even mortality that can sometimes be associated with CMIN. Even a small decrease in renal function may greatly exacerbate morbidity and mortality caused by coexisting conditions. 5,6 Sepsis, bleeding, coma, and respiratory failure are frequently observed in patients with acute renal failure.
Clinical features
Serum creatinine often peaks within 3 to 4 days after the administration of contrast media. 7,8 Mild proteinuria and oliguria may also be observed. The majority of patients with CMIN tend to be nonoliguric except those with pre-existing advanced chronic renal failure. Heavy proteinuria is an unusual feature of CMIN. Fortunately, most episodes of CMIN are self-limited and resolve within 1 to 2 weeks. Several nonanuric episodes are probably undetected because the serum creatinine is rarely measured after administration of contrast media and these patients have no symptoms, especially patients who are examined on an outpatient basis. Permanent renal damage is rare and occurs only in a very few instances.
Radiographic features
A persistent nephrogram on plain radiography or computed tomography (CT) of the abdomen for 24 to 48 hours after contrast media injection has been described as a feature of CMIN. 9,10 However, its presence is not always associated with a reduction in renal function. 11,12 Also, gallbladder opacification is not correlated with the occurrence of CMIN. 13 However, presence of these signs should be followed by assessment of renal function and should discourage the administration of further doses of contrast media if the results are abnormal.
Incidence
The development of CMIN is low in people with normal renal function varying from 0% to 2%. 1,6,14 Pre-existing renal impairment increases the frequency of this complication. The incidence of CMIN has been reported to range from 12% to 27% in several prospective controlled studies. 1,4,14 In one study, an incidence as high as 50% was reported in patients with diabetic nephropathy undergoing coronary angiography in spite of the use of low-osmolar contrast media and adequate hydration. Dialysis was necessary in 15% of these patients. 15 In another study, the incidence was significantly higher in patients with diabetic nephropathy (19.7%) and in patients with nephropathy (5.7%) due to other causes, whereas it was <1% in patients with a serum creatinine level below 1.5 mg/dL. 14
Long-term renal effects of contrast media
High-osmolar contrast media can enhance the progression of glomerulosclerosis and renal failure in old, spontaneously hypertensive male rats. 16 However, the long-term effects of contrast media on renal function in humans are not known.
Predisposing factors
Patients at highest risk for developing contrast-media-induced acute renal failure are those with pre-existing renal impairment (>1.5 mg/dL), particularly when the reduction in renal function is secondary to diabetic nephropathy. 1,14 Diabetes mellitus per se, without renal impairment, is not a risk factor. 14 The degree of renal insufficiency present before the administration of contrast media determines, to a great extent, the severity of CMIN. Large doses of contrast media and multiple injections within 72 hours increase the risk of developing CMIN. The route of administration is also important and contrast media are less nephrotoxic when administered intravenously than when given intra-arterially in the renal arteries or in the aorta proximal to the origin of the renal blood vessels. The acute intrarenal concentration of contrast media is much higher after intra-arte-rial injection than after intravenous administration. Dehydration and congestive cardiac failure are risk factors, as they are associated with a reduction in renal perfusion, which enhances the ischemic insult of contrast media. In the past, multiple myeloma was considered a risk factor for CMIN. However, if dehydration is avoided, administration of contrast media rarely leads to acute renal failure in patients with myeloma. 17 The concurrent use of nephrotoxic drugs such as nonsteriodal anti-infiammatory drugs (NSAIDs) and aminoglycosides potentiate the nephrotoxic effects of contrast media. Nephropathy is found more frequently in patients with hypertension, hyperuricemia, or proteinuria than in patients without these factors. 18 The type of contrast media is also an important predisposing factor. High-osmolar contrast media are more nephrotoxic in comparison to low-osmolar and isosmolar contrast media. 7,8,14
Identifying patients at risk of CMIN
Patients with pre-existing renal impairment are at particularly high risk of CMIN. In spite of the limitations of this measurement, serum creatinine is often used to determine the state of renal function and to identify high-risk patients. This section will address the value of serum creatinine in the assessment of renal function and when this measurement should be performed before contrast-medium injection.
Validation of serum creatinine measurements
Serum creatinine is not an ideal marker of renal function. The serum creatinine level depends on muscle mass and is not usually raised until the glomerular filtration rate has fallen by at least 50%. Endogenous serum creatinine clearance as a measure of glomerular filtration rate is also inaccurate (especially when renal function is low, because of a compensatory increase in tubular secretion), which limits its validity as a glomerular filtration marker. Radionuclide techniques are preferable, 19 but each of these tests is labor-intensive and impossible to perform in all patients undergoing contrast-enhanced imaging. Alternatively, renal function can be estimated by using specially derived predictive equations. The most accurate results are obtained with the Cockroft-Gault equation, whereas the most precise formula is the Modification of Diet in Renal Disease (MDRD) study equation. 20 Unfortunately, the predictive capabilities of these formulae are suboptimal for ideal patient care. 20 However, compared with a simple serum creatinine measurement, these methods are far superior for assessing renal function. Another alternative is to use cut-off values for serum creatinine as an indicator of several levels of renal impairment. However, the use of cut-off values (especially the low levels) will include several patients with normal renal function, and the use of high cut-off values will exclude patients with renal impairment. 21 Despite the inaccuracies of serum creatinine measurements, it is an adequate measure for identifying those patients at risk for CMIN, because patients with normal serum creatinine (<1.5 mg/dL) have almost no risk. 14
When should serum creatinine be measured?
A questionnaire designed to elicit a history of renal disorders as well as additional risk factors for CMIN may identify patients with normal serum creatinine in whom blood testing would be unnecessary. 18 The majority of patients (85%) in this study 18 had normal serum creatinine values (<1.3 mg/dL for women, 1.4 mg/dL for men). All except 2 patients (99%) who gave negative answers to the questionnaire had serum creatinine levels
<1.7 mg/dL. A strong association was found between raised serum creatinine values and a history of renal disease, proteinuria, prior kidney surgery, hypertension, gout, and diabetes. Only 6% of patients with negative answers to the 6 questions had abnormal serum creatinine levels. In a study of 2034 consecutive outpatients referred for CT examinations, only 3.2% (66 patients) had elevated serum creatinine levels (>2.0 mg/dL) and the majority (97%) of these patients had risk factors for CMIN. 22 Two of the 66 patients (0.1% of the total number of patients) with a raised creatinine level had no identifiable risk factors. Serum creatinine was measured in a prospective study involving 640 consecutive adult patients presenting to the emergency department with a clinical indication for intravenous administration of iodinated contrast medium. 23 Thirty-five (5.5%) patients had abnormal serum creatinine (>1.6 mg/dL). Of this group, 77% (27 patients) of them were considered to have risk factors for renal insufficiency. The remaining 8 patients (1.3% of the total number) had no identifiable risk factors for renal insufficiency. Thus, the majority of patients at risk of CMIN can be identified by appropriate questions, but a questionnaire does not completely exclude the presence of renal insufficiency.
Measures to reduce the incidence of CMIN
Several measures have been recommended to reduce the incidence of CMIN, 24,25 including: volume expansion, hydration with intravenous administration of normal saline solution (NaCl 0.9%) or half-strength saline solution (NaCl 0.45%), infusion of mannitol, pharmacological manipulation (administration of atrial natriuretic peptide, loop diuretics, calcium antagonists, theophylline, dopamine, dopamine-1 receptor antagonist [fenoldopam], acetylcysteine), use of low-osmolar nonionic contrast media instead of high-osmolar ionic contrast media, use of isosmolar contrast media instead of low-osmolar contrast media, use of gadolinium-based contrast media instead of iodine-based contrast media for radiography and CT, hemodialysis quicky after contrast administration, hemofiltration during and after contrast administration, an injection of a small volume of contrast medium, and avoiding short intervals (<48 hours) between procedures requiring intravascular administration of contrast media.
Extracellular volume expansion
Of all the measures mentioned above, extracellular volume expansion and use of low-osmolar contrast media have been found to be most effec- 1,26-29 This can be achieved with the intravenous injection of 100 mL/hour of 0.9% saline solution, starting 4 hours before contrast administration and continuing for 24 hours afterward. 1 In areas with a hot climate, more fiuid should be given. This regime is suitable for patients who are not in congestive heart failure and are not allowed to drink or eat before undergoing an interventional or surgical procedure. If there is no contraindication to oral administration, free fiuid intake should be encouraged. At least 500 mL of water or soft drinks before and 2500 mL during the following 24-hour period should be recommended orally. In addition, concurrent administration of nephrotoxic drugs, such as gentamicin and nonsteroid anti-infiammatory drugs, should be avoided. Mannitol and furosemide enhance the risk. 26
The main factors in the pathophysiology are considered to be a reduction in renal perfusion caused by a direct effect of contrast media on the kidney and toxic effects on the tubular cells, although the latter effect is contentious. 7
Pharmacological manipulation
Calcium channel blockers prevent the infiux of calcium ions through voltage-operated channels. This will cause a vasorelaxant effect in all vascular beds, including the kidney. In one study, a 3-day treatment with 20 mg of nitrendipine prevented the development of CMIN in patients with moderate renal impairment, 30 whereas in another study, a single dose (20 or 10 mg) given 1 hour before contrast medium administration failed to prevent CMIN. 31 Thus, the role of calcium channel blockers remains uncertain, and their protective effect in patients with advanced renal impairment has not been proven. Use of the vasodilators dopamine and arterial natriuretic peptide may even be harmful in patients with diabetic nephropathy. 32
Selective dopamine-1 receptor agonist (fenoldopam), in contrast to dopamine, increases both cortical and medullary blood fiow. One study has shown that fenoldopam offers some protection against CMIN, 33 whereas 2 studies showed that it offers no protection. 27,34 Furthermore, fenoldopam has several disadvantages: it has to be given intravenously, and it induces hypotension and requires regular monitoring of blood pressure. 25
Experimental studies have indicated that the endogenous vasoactive peptide endothelin may play an important role in mediating these events. Therefore, it was expected that endothelin antagonists 35 would reduce the incidence of CMIN in man, but a clinical study has shown the opposite effect 36 ; a nonselective endothelin receptor antagonist and intravenous hydration exacerbated CMIN when compared with hydration alone. However, there were several fiaws in this study. 37 The choice of the endothelin receptor antagonist was not appropriate. It was given only 12 hours after contrast medium injection, avoiding sustained drug cover.
The nonselective adenosine receptor antagonist theophylline has also been advocated to reduce the risk of CMIN. However, the results from published studies are confiicting. In one study, administration of 200 mg theophylline intravenously was shown to have a preventive effect, 38 whereas after 819 mg theophylline orally and daily for 3 days did not offer additional protective effect when compared with hydration alone. 39 Thus, the effectiveness of theophylline in preventing CMIN remains uncertain. In addition, theophylline may induce cardiac arrhythmia in patients with ischemic heart disease. 25
Administration of acetylcysteine, which is an antioxidant and a scavenger of oxygen-free radicals, has also been shown to be both effective in preventing CMIN in some studies 40-42 and to be without any effect in others. 27,43 One meta-analysis based on 7 studies (a total of 805 patients) concluded that the use of acetylcysteine reduced the risk of CMIN by 56%, 44 whereas a subsequent analysis based on 12 studies (1307 patients) concluded that conclusive data indicating that it offers effective protection are lacking. 45 In 7 of the 12 studies, no effect was found. In a meta-analy-sis, inconsistency of study results reduces the confidence about treatment recommendations. 46 Thus, pharmacological manipulation with renal vasodilators, receptor antagonists of endogenous vasoactive mediators, or cytoprotective drugs does not seem to offer consistent protection against CMIN.
Nonionic contrast media
The use of low-osmolar nonionic monomeric and, more recently, isosmolar nonionic dimeric contrast media has been recommended in high-risk patients to reduce the risk of contrast media nephrotoxicity. A multicenter study of 129 patients with renal impairment and diabetes mellitus (serum creatinine between 1.5 and 3.5 mg/dL) undergoing angiography with either the isosmolar dimer iodixanol or the nonionic monomer iohexol showed that CMIN developed only in 3% of the patients after the dimer and in 26% after the monomer. 47 The study concluded that the isosmolar dimer iodixanol is significantly less nephrotoxic in comparison with the nonionic monomers. In another study of patients with nephropathy due to various causes, CMIN developed in 4% after the isosmolar nonionic dimer and in 10% after a low-osmolar nonionic monomer. 48 In a further study, CMIN developed in 17% of patients with severe renal impairment who received intravenous injection of either a nonionic monomer or an isosmolar dimer for body or cranial CT. No difference in the incidence of CMIN between the monomer and dimer was found in this study. 49 Further studies are required to elucidate whether there is a significant difference in the nephrotoxic effects of the nonionic dimer in comparison with nonionic monomers. 50
Prophylactic hemodialysis or hemofiltration
Dialysis has been used in the prevention of CMIN. Hemodialysis and peritoneal dialysis safely remove both iodinated and gadolinium-based contrast media from the body. 51 The effectiveness of hemodialysis depends on many factors, including blood and dialysate fiow rate, permeability of dialysis membrane, duration of hemodialysis, and molecular size, protein binding, hydrophilicity, and electrical charge of the contrast medium. Generally, several hemodialysis sessions are needed to remove all contrast medium, whereas it takes 3 weeks for continuous ambulatory dialysis to remove the agent completely. There is no need to schedule the dialysis in relation to the injection of iodinated or MR-contrast media or the injection of a contrast agent in relation to the dialysis program. Hemodialysis does not protect poorly functioning kidneys against CMIN. 52- 55 In addition, hemodialysis may cause deterioration of renal function through activation of infiammatory reactions with the release of vasoactive substances that may induce acute hypotension.
Hemofiltration is a continuous form of renal replacement therapy and requires the intravenous infusion of a large volume of isotonic replacement fiuid (1000 mL/hour). This is exactly matched with the rate of ultrafiltrate production, so that no net fiuid loss or overload occurs. A recent study has shown that, in patients with chronic renal failure who are undergoing coronary interventions, periprocedural hemofiltration given in the intensive care unit (ICU) setting appears to be effective in preventing CMIN and reduces the rate of in-hospital events and in-hospital mortality. 56 However, it is very costly and requires an intensive treatment setting.
Gadolinium-based contrast agents for radiography in patients with renal impairment
Gadolinium-based contrast agents are believed to be safe and not nephrotoxic in the usual MRI doses up to 0.3 mmol/kg body weight. Therefore, it has been suggested that gadolinium-based contrast media could be used in place of iodinated agents for radiological examinations in patients with significant renal impairment. 57 However, the dose requirement for a satisfactory diagnostic study differs between MRI and radiography because different properties of the gadolinium are being used in each of the 2 techniques. The commonly used dose for body CT is 150 mL of a 300 mg I/mL (2.38 mmol I/mL) solution. The standard dose for contrast-enhanced MRI is 0.2 mL/kg body weight of a 0.5 mmol/mL gadolini-um-based contrast agent. For body CT, a patient weighing 70 kg would receive 120 mmol of the iodinated agent molecule and 360 mmol of iodine. For MRI, this same 70 kg patient would receive 7 mmol of the gadolinium-based agent molecule and 7 mmol of gadolinium. 57 Thus, the number of iodinated contrast agent molecules administered would be almost 17 times that of gadolinium-containing molecules, and the number of iodine atoms administered is 51 times that of gadolinium.
The results of a study involving 64 patients undergoing MRI with a gadolinium-based agent and a radiographic examination with an iodinated contrast medium indicated that gadolinium chelates are significantly less nephrotoxic than are iodinated agents. 58 Eleven of the 64 patients had a significant increase in serum creatinine after intravenous or intra-arterial administration of iodine-based contrast media, whereas none had increased serum creatinine levels after intravenous administration of a gadolinium-based contrast agent. However, the molar doses and concentrations of the iodine and gadolinium atoms were not comparable. In 3.5% of 195 patients with abnormal pre-examination creatinine clearance levels, acute renal failure (anuria) developed after gadolinium-based contrast medium administration; for MR-angiography the incidence was 1.9% and for digital subtraction angiography it was 9.5%. 59 Dialysis was required in 3 of the 7 patients who developed acute renal failure. The doses of gadolinium-DTPA ranged from 0.31 to 0.41 mmol/kg for MR angiography and 0.27 to 0.42 mmol/kg for digital subtraction angiography. Other reports have shown the nephrotoxic potential of gadolinium-based contrast media in high doses (>0.3 mmol/kg). 60-63 An experimental study in pigs has indicated that gadolin-ium-based contrast media are more nephrotoxic than are iodinated contrast media. 64 Thus, the use of gadolinium-based contrast media for radiographic examinations cannot be recommended to avoid nephrotoxicity in patients with renal impairment. 57
Conclusion
In patients with risk factors for CMIN, one should not: 1) give high osmolar contrast media; 2) administer large doses of contrast media; 3) administer mannitol and diuretics, particularly loop-diuretics; or 4) perform multiple studies with contrast media within a short period of time. It is very important that one: 1) makes sure that the patient is well hydrated (give ≥100 mL of liquid orally [eg, soft drinks] or intravenously [normal saline], depending on the clinical situation) per hour starting 4 hours before and continuing for 24 hours after contrast administration, in warm areas increase that fiuid volume); 2) uses low-osmolar or isosmolar contrast media; 3) stops administration of nephrotoxic drugs for at least 24 hours prior to contrast administration; and 4) considers alternative imaging techniques that do not require the administration of intravascular radiographic contrast media. 1