Upon receiving (along with two colleagues) the 1956 Nobel Prize in Medicine for discoveries concerning coronary catheterization, German physician Werner Forssmann predicted that the coming "age of cardiological and circulatory investigation" would reveal "surprising beauty."1 Forssmann, who had also explored the use of contrast media in angiocardiography, suggested that these new technologies could be applied to the kidney and other organs. But his enthusiasm was tempered by the recognition that the means could be dangerous. About contrast media, he expressly hoped that "further development will in many cases enable us to dispense with the massive and dangerous quantities of contrast media which at the moment we still need, and to manage instead with smaller, less harmful amounts." More than half a century later, his concern is still relevant.

Contrast medium-induced nephropathy (CIN)-a condition marked by an acute decline in renal function that follows the intravascular administration of contrast material and isn't attributable to other causes-can progress to irreversible renal dysfunction. It's reportedly the third-leading cause of acute kidney failure in hospitalized patients, affecting about 12%,2 and is associated with prolonged hospitalization and a high death rate.3, 4 Although the risk of CIN in the general population is relatively low-one review reported an incidence of 0% to 2%-and ends with excretion of the contrast medium, it's much higher in vulnerable populations such as people with both diabetes and chronic renal dysfunction, in whom the incidence ranges from 50% to 90%.5 Among patients having coronary angiography (more than 1 million annually in the United States6), the incidence ranges from 5% to 50%, depending on preprocedural renal function and other risk factors.7

In CIN, the contrast medium affects the nephrons, the basic structural and functional units of the kidneys. Two primary mechanisms are suspected: direct tubular cytotoxicity and renal ischemia.8, 9 While definitions of CIN vary, most experts agree that the condition is indicated by either an absolute increase in serum creatinine of at least 0.5 mg/dL from its preprocedure level or a relative increase of 25% or more.10 The increase typically occurs within 48 hours of the contrast medium injection, but the level may not peak for three to five days.

POSSIBLE CAUSES OF CIN

Renal ischemia. Intravascular administration of a contrast medium initially causes renal vasodilation lasting for one to three hours, followed by vasoconstriction. It's believed that contrast media heighten the activity of renal vasoconstrictors (such as vasopressin, angiotensin II, dopamine-1, endothelin, and adenosine) and decrease the activity of renal vasodilators (nitric oxide and prostaglandins).11 Some contrast media also appear to cause an influx of calcium ions into renal vascular smooth-muscle cells. This reduces renal blood flow, lowers the glomerular filtration rate (GFR), and leads to ischemia. The ischemia primarily affects renal medullary tissue, which normally has a lower partial pressure of oxygen (10 to 20 mmHg) than does cortical tissue (50 mmHg) and is therefore especially vulnerable to ischemia if hypoxia occurs.12 Contrast media are also known to cause erythrocyte aggregation, which results in increased blood viscosity and reduced oxygen delivery.13

Direct tubular cytotoxicity. It's also believed that contrast media are toxic to the epithelial cells lining the renal tubules, perhaps because contrast media increase the production of oxygen-derived free radicals and lower the GFR.7, 11, 14 Once tubular injury occurs, urinary proteins and granular and epithelial casts can obstruct the tubules.15 Renal blood flow and oxygenation decrease, while renal tubule workload increases.11, 12, 15

Application to practice. Although acute kidney failure can be oliguric, failure caused by CIN is most often nonoliguric8-meaning that the kidneys produce a normal amount of urine but cannot effectively eliminate nitrogenous waste or regulate electrolytes and the acid-base balance. Low sodium levels and casts and proteins in the urine may also go unnoticed.15 Therefore, the early identification of other signs-such as edema, weight gain, decreased urinary output, elevated blood pressure, and elevated serum creatinine level-and prompt intervention are crucial.

But because CIN can take several days to develop, patients might be discharged before its signs appear. Discharge teaching should emphasize the importance of oral hydration (provided that overall health status does not contraindicate increased fluid intake, as in congestive heart failure). Patients should call their primary care provider if they gain more than 1 kg (about 2 lbs.) per day, or if edema or other signs appear in the first days after the procedure.16 If CIN develops, treatment involves avoiding further exposure to nephrotoxic agents, restoring fluid and electrolyte balance, modifying diet according to electrolyte status and the degree of azotemia (a buildup of urea in the plasma), and, possibly, dialysis.7, 17

DETERMINING RISK OF CIN

Contrast medium-related risk factors include using a high volume of a contrast medium, an agent with high osmolarity, an ionic agent in a patient with diabetes or decreased renal function, and intravascular contrast medium twice in less than five days.18-21 Although any contrast medium injection poses some risk of CIN, intraarterial administration carries a higher risk than iv administration does, perhaps because the intraarterial route leads to "much higher" concentrations of the contrast medium in the renal vasculature and therefore to greater toxicity.5

The type and volume of contrast medium used may be the "most important modifiable risk factors" for CIN.22 Intravascular contrast media are in a base of either iodine or gadolinium and can be categorized by their osmolar and ionic properties. Osmolarity refers to the concentration of particles in a solution and is expressed in osmoles of solute particles per liter of solution. Contrast agents that have high osmolarity (1,200 to 1,400 mOsm/L water) pose a higher risk of CIN than those with low osmolarity (290 to 860 mOsm/L water). Because high-osmolarity agents are so much denser than human serum (the osmolarity of which is typically 275 to 285 mOsm/L water), they cause fluid to shift from the cells into the vascular compartment, upsetting renal homeostasis.

Contrast agents are also ionic or nonionic, depending on their atomic configuration. Nonionic contrast agents consist of three iodine anions (anions are ions with a negative electrical charge) and one neutral iodine atom; ionic contrast agents possess some combination of iodine anions and cations (cations are ions with a positive electrical charge). Iodine cations are thought to be nephrotoxic. Although ionic agents, first developed in the 1950s, are sometimes still used, they can increase the risk of CIN. They are especially dangerous to people with diabetes, renal dysfunction, or both. Nonionic agents such as iohexol (Omnipaque) were introduced in the mid-1980s and have largely replaced ionic agents; they typically have low osmolarity.18, 23 One nonionic agent, iodixanol (Visipaque), is also iso-osmolar (its osmolarity is about the same as that of human serum), but it's not yet known what benefits this affords.23

FIGURE 1. Two Possible Causes of Contrast Medium-Induced Nephropathy

No safe threshold has been established for the volume of contrast medium that should be given, but it's agreed that giving a high volume for one procedure or a lesser volume twice within five days increases the risk of CIN.18-21 For example, it's increasingly common for coronary angiography and angioplasty to be performed together in a single visit; such patients will receive a higher volume of contrast media (250 mL or more) than they would for angiography alone (about 100 mL).24, 25 The American College of Cardiology endorses the use of a "minimal amount" of contrast agent for all patients and postinjection assessment of serum creatinine levels for patients at risk for CIN.26

Patient-related risk factors include preexisting renal dysfunction, diabetes, hypovolemia, heart failure, advanced age (71 years or older), shock, and concurrent use of nephrotoxic drugs or drugs associated with decreased renal perfusion.5, 16, 18Preexisting renal dysfunction poses the highest risk.19, 22 Although a high serum creatinine level isn't by itself a definitive indicator of renal dysfunction, a value of more than 1.5 mg/dL is considered a strong indicator for the development of CIN.16, 27

Patients with one or more risk factors should have a 24-hour creatinine clearance test to provide a more accurate estimate of the GFR.28 The National Kidney Foundation uses the GFR in identifying five stages of chronic kidney disease (see Table 1, above).29 Patients who have either stage 3 chronic kidney disease or stage 2 with other preexisting risk factors are at moderate risk for CIN; patients who have stage 4 chronic kidney disease or stage 3 with other preexisting risk factors are at high risk.8, 30 For more, see Estimating the GFR, page 44.

TABLE 1. The Stages of Chronic Kidney Disease

Some drugs, including aminoglycosides, vancomycin (Vancocin), cyclosporine (Neoral and others), and amphotericin B (Amphocin, Fungizone), are known to be nephrotoxic and can increase the risk of CIN. Others, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, nonsteroidal antiinflammatory drugs, and diuretics, are thought to decrease renal perfusion.7, 12, 31

Application to practice. Since the GFR may drop by as much as 50% before an elevated serum creatinine level is noted, a one-time serum creatinine reading does not provide the most accurate picture of kidney function. However, because serum creatinine can be measured quickly and the test is relatively inexpensive, it's often used to provide a rough assessment of renal function before contrast medium injection.28 Some laboratories report both the serum creatinine level and an estimated GFR. The nurse should review the patient's laboratory results and history and alert the physician to any conditions or concurrently administered medications that warrant further investigation. Medications associated with an increased risk of CIN should be withheld for at least 24 hours, if possible, before contrast medium injection in at-risk patients.16

Postprocedural care is critical. Many facilities use flow sheets or procedural reports to track the administration of contrast media, including the type and volume given. Nurses should also monitor follow-up laboratory values and tell the physician about any elevated or abnormal results. Medications withheld before the procedure should be reviewed before administration resumes. For example, although metformin (Glucophage, Fortamet), used to control blood glucose, is not nephrotoxic, when it's given to patients with renal dysfunction, lactic acidosis may develop. It's currently recommended that this medication be withheld on the day of any procedure involving an intravascular contrast medium; it should be resumed only after the serum creatinine level has stabilized (typically 48 hours or more after the procedure).26

APPROACHES TO PREVENTION

To protect the kidneys and prevent injury in patients at high risk for CIN, cardiologists and interventional radiologists use one or more of the following approaches22, 24:

Prophylactic hydration. Most contrast agents promote diuresis because their osmolarity is higher than that of serum. Although it hasn't been proven empirically, it's generally believed that hydration before contrast medium injection helps to maintain intravascular volume, reduce stimulation of the renin-angiotensin-aldosterone system (RAAS), dilute the contrast medium, facilitate its elimination, and prevent obstruction of the renal tubules.22, 32

While no studies have compared patients given prophylactic hydration alone with patients not given it, it's generally agreed that hydration can help prevent CIN.4 Several studies have examined the use of pre- and postprocedural hydration either as an adjuvant to a drug or as the sole treatment.22, 32, 33 Hydration is considered so critical that investigators have always incorporated it into their studies of other strategies.33

The best administration route and fluid regimen remain unclear. Two studies found hydration by iv and oral routes to be comparable in preventing CIN in patients with stage 3 or 4 chronic kidney disease.34, 35 However, the oral fluids studied were different-one study used 0.9% saline (normal saline, or NS)34 and the other used plain water35-so it's unknown which, if either, is more effective. A third study comparing iv NS to unrestricted oral fluids (type and volume not reported) in 53 patients found the iv route to be superior to the oral route.36

It's difficult to determine the best time to start fluid administration and how long it should be continued. One review stated that in early canine studies, decreased renal perfusion persisted for as long as 20 hours after contrast medium administration4; it's not known how long it might last in humans. There is also disagreement on the best type of fluid to use for hydration. While solutions of NS and of half-NS in 5% dextrose (D51/2NS) are often used in iv hydration, the results of one large study in 1,620 patients showed the incidence of CIN to be significantly lower in the group receiving NS than in those receiving D51/2NS.37 One reason may be that NS, an isotonic solution, is thought to better expand intravascular volume and inhibit the RAAS than other solutions.4, 22

Sodium bicarbonate, used routinely in treating metabolic acidosis and restoring normal systemic pH, may also be added to iv hydration fluid. It's believed that CIN may result in part from the formation of oxygen-derived free radicals within the renal tubules, which an acidic environment promotes.33 The alkalinity of sodium bicarbonate may reduce free-radical formation, thus helping to prevent CIN.33

TABLE 2. Risk Factors for the Development of Contrast Medium-Induced Nephropathy

A large metaanalysis by Pannu and colleagues concluded that all patients at risk for CIN can be treated with either iv NS (1 mL/kg/hr for six to 12 hours before and after the procedure) or iv sodium bicarbonate 154 mEq/L in a solution of 5% dextrose and water (3 mL/kg/hr for one hour before and 1 mL/kg/hr for six hours after the procedure).4 Regardless of the regimen, the American College of Cardiology endorses prophylactic hydration for patients with known renal insufficiency.26

Application to practice. If the orders for contrast medium injection do not address prophylactic hydration and the patient has risk factors for CIN, the nurse should ask the physician whether fluid hydration is warranted. Unless contraindicated, oral fluids should be available to patients after the procedure.27 Patients receiving a sodium bicarbonate solution must be monitored for adverse effects, including metabolic alkalosis, hypernatremia, and if extravasation occurs, tissue necrosis.

Neutralization of oxygen-derived free radicals. Some research supports the use of acetylcysteine (Acetadote, Mucomyst), a drug with antioxidant and vasodilatory properties, to prevent CIN; other antioxidants such as ascorbic acid and statins are also under investigation. These agents may protect the epithelial lining of renal tubules, and prevent contrast medium-induced vasoconstriction, by neutralizing oxygen-derived free radicals created as a result of contrast medium injection.7, 38

Acetylcysteine administration to prevent CIN is an off-label use (it's approved for decreasing the viscosity of pulmonary secretions and to treat acetaminophen overdose and is formulated for inhalational, oral, and iv administration). It is thought to help prevent CIN by scavenging oxygen-derived free radicals and by increasing production of endothelial nitric oxide synthase, an enzyme that promotes renal vasodilation.23 Although the use of acetylcysteine in preventing CIN has been widely studied, evidence of its efficacy is inconclusive.4, 38 Still, many in the field favor its use, especially in patients with more than one risk factor. One recent review concluded that administering acetylcysteine to those at high risk "appears to be effective" in preventing CIN.3 And a large metaanalysis concluded that for patients with two or more CIN risk factors, acetylcysteine with concurrent iv saline hydration, as well as the use of a nonionic contrast medium, may be the best CIN-prevention strategy.4

While several studies have found a link between acetylcysteine use and reduced serum creatinine levels, its effect on the GFR is less clear, and among high-risk patients its use has not reduced the need for dialysis after contrast medium injection.39, 40These findings suggest that other markers of renal function are needed to establish conclusively its efficacy in preventing CIN. More study is needed.

Application to practice. Oral formulations of acetylcysteine are inexpensive and produce no known adverse effects. But although oral administration protocols have been established, the optimal iv doses are unknown. A typical preprocedural oral protocol is 600 mg twice on the day before and twice on the day of the procedure.41 At least one study suggests that the protective effects of acetylcysteine are dose dependent, and higher doses may be used in some cases.42 Concurrent prophylactic iv hydration is also recommended.19

Patients with renal dysfunction who require emergency angiography may be prescribed iv acetylcysteine. One rapid protocol involves an initial, 30-minute iv infusion of acetylcysteine 150 mg/kg in 500 mL NS immediately before contrast medium injection, followed by a second, four-hour infusion of acetylcysteine 50 mg/kg in 500 mL NS.43 For a 70-kg (154-lb.) patient, the total dosage would be approximately 14,000 mg.

Some researchers have studied both oral and iv routes of acetylcysteine. One study compared standard- and high-dose regimens in patients undergoing primary angioplasty.42 Patients in the standard-dose group were given a 600-mg acetylcysteine iv bolus immediately before contrast medium injection, followed by 600 mg orally twice daily for 48 hours after the procedure. Patients in the high-dose group received a 1,200-mg acetylcysteine iv bolus immediately before contrast medium injection, followed by 1,200 mg given orally twice daily for 48 hours after the procedure. Dilution and infusion times with the iv regimens weren't reported. The high-dose group had significantly better clinical outcomes, and the researchers concluded that the beneficial effects of acetylcysteine were dose dependent.

Adverse effects of acetylcysteine IV administration, which may include pruritus, urticaria, and flushing, should be reported to the physician, although these effects are often transient and dose related and require minor intervention, if any, with antihistamines.44 Because an optimal iv regimen has not been established, patients must be closely monitored for signs of anaphylaxis (such as angioedema or respiratory compromise) and fluid overload.43, 44 Oral acetylcysteine produces no known adverse effects.41

Ascorbic acid, or vitamin C, is a water-soluble vitamin used clinically in a dosage range of 200 mg to 12 g per day to acidify the urine, prevent scurvy, decrease the severity of the common cold, and supplement dietary intake. In one randomized study, researchers investigated the antioxidant and renal-protective properties of ascorbic acid in 231 patients with renal dysfunction who were undergoing angiography or coronary intervention.45 The experimental group received 3 g ascorbic acid orally at least two hours before contrast medium injection, followed by 2 g that night and 2 g again the next morning. The control group received a placebo on the same schedule. Both groups received similar types and volumes of contrast medium and hydration. The ascorbic acid group had significantly lower mean serum creatinine levels, better creatinine clearance rates, and a lower incidence of CIN than the placebo group. These results merit further study.20

Statins. A recent retrospective study examined the drug regimens of nearly 30,000 patients before and after percutaneous coronary intervention and found a significantly lower incidence of CIN in those who received preprocedural statins (CIN was defined as an increase in serum creatinine of 0.5 mg/dL or more postprocedurally).46 It's thought that statins neutralize the effects of oxygen-derived free radicals and decrease renal inflammation.

Calcium channel blockers. High-osmolarity contrast agents promote the influx of calcium ions into the vascular smooth muscle of renal arterioles, producing vasoconstriction. Calcium channel blockers may offer protection by dilating the afferent renal arterioles. Three calcium channel blockers-nifedipine, nitrendipine, and felodipine-have been studied for this purpose, administered sublingually in shorter-acting formulations (nifedipine) or orally in longer-acting formulations (nitrendipine and felodipine).24 The studies have shown some promise, but the sample sizes were small; larger trials are needed before these drugs can be recommended for preventing CIN.24 Patients taking them must be monitored for signs of hypotension and bradycardia.

Theophylline is an adenosine-receptor antagonist used to relieve bronchial spasm. Contrast media are thought to stimulate the kidneys to release adenosine, leading to severe vasoconstriction and subsequent renal medullary ischemia. Theophylline is believed to interrupt this process and improve renal perfusion.11 But studies have yielded conflicting findings on its prevention of CIN.7, 10

In a metaanalysis of nine studies investigating theophylline in CIN prevention, Bagshaw and Ghali described only one study reporting adverse effects-a transient and benign increase in heart rate following IV administration.47 However, they also noted that when used as a bronchodilator, the drug can induce cardiac ischemia, arrhythmias, and seizure. Therefore, more research is needed to substantiate its benefit in preventing CIN and to determine the optimal dose and route of administration.

Prostaglandin E1, a hormone-like active substance, has vasodilatory effects, and it's thought that it may act to prevent renal vasoconstriction. Because oral prostaglandin E₁ is associated with gastrointestinal intolerance, parenteral forms (the parenteral drug is also known as alprostadil) have been used in preventing CIN. A pilot study involving 130 patients with preexisting renal dysfunction found that those given iv prostaglandin E₁ before contrast medium injection had smaller increases in serum creatinine levels and better creatinine clearance than those who received a placebo, suggesting that prostaglandin E₁ may indeed have protective effects.48 Possible adverse effects with iv administration of this drug include tachycardia and hypotension. Further study is needed before prostaglandin E₁ can be recommended for CIN prevention.24

Other drugs sometimes used as renal vasodilators include dopamine, fenoldopam, and ANP. But the evidence for their efficacy is inconclusive at best. For example, fenoldopam, a vasodilator approved for rapidly reducing blood pressure in hypertensive emergencies, produces vasodilation in both renal cortical and medullary tissues, but while it has been found to prevent CIN in dogs, its efficacy in humans remains unclear.11, 24 And some studies have suggested that dopamine and ANP might even cause harm: dopamine appeared to worsen contrast medium-induced medullary hypoxia and ischemia,22 and ANP was associated with increased risk of CIN.7, 8 Until additional research can prove their merits, dopamine, fenoldopam, and ANP are not recommended as renal vasodilators in CIN prevention, and nurses are unlikely to find them used as such.22, 24 Fenoldopam is currently under investigation for use in targeted renal therapy, a more invasive strategy discussed below.49

Forced diuresis, involving iv administration of either furosemide (Lasix) or mannitol (Osmitrol), has been in declining use for preventing CIN since the mid-1990s. It was thought that forced diuresis would increase urine volume and tubular flow, decrease the time the contrast medium was in contact with the renal tubular walls, and reduce the consumption of oxygen by tubular cells.19, 23 But metaanalyses concluded that furosemide conferred no significant benefit and that the resulting hypovolemia could worsen outcomes22-24; mannitol was similarly problematic.24 Forced diuresis is considered ineffective in preventing CIN and is not recommended.

Invasive strategies used in CIN prevention have included hemodialysis, hemofiltration, and targeted renal therapy; of these, only targeted renal therapy appears to be under active investigation. Prophylactic hemodialysis begun immediately after contrast medium injection was investigated in patients with preexisting renal insufficiency; the goal was to prevent kidney damage by removing the contrast agent from the intravascular circulation. Studies yielded mixed results; adverse effects included hypovolemia and hypotension, resulting in decreased renal circulation.11, 22, 27Prophylactic hemodialysis is not currently recommended.

Patients who can't tolerate the rapid volume changes associated with hemodialysis may benefit from prophylactic hemofiltration-a type of continuous renal replacement therapy that's similar to dialysis but uses filtration and convection, rather than diffusion, to cleanse the blood while maintaining fluid volume by replacing lost fluid with an isotonic solution. It's capable of removing more and larger waste products than hemodialysis. One study among patients with chronic renal failure who were about to undergo coronary angiography or intervention found that hemofiltration resulted in a lower incidence of CIN.50 But because hemofiltration is invasive, limited in availability, and relatively expensive, this method is neither widely accepted nor recommended for CIN prevention.22, 41

Targeted renal therapy, a new strategy in CIN prevention, involves the direct infusion of nephroprotective agents such as fenoldopam and sodium bicarbonate into the renal arteries. Direct infusion ensures that more of the drug reaches the kidneys, and this method can reduce the systemic effects (such as hypotension) associated with systemic iv administration of some agents. Preliminary findings from an observational study of 112 patients suggest that targeted renal therapy holds promise: only 10% of patients at "very high risk" for CIN developed it, a much lower rate than the predicted incidence in this group.49

POSTPROCEDURAL CARE

The glomerular filtration rate (GFR) is a measure of the kidneys' ability to filter waste from the blood. More specifically, Stedman's Electronic Medical Dictionary defines it as "the volume of water filtered out of the plasma [as it passes] through the glomerular capillary walls [and] into Bowman capsules per unit time." The GFR cannot be measured directly; it's estimated using an equation and a serum creatinine laboratory value. The National Kidney Foundation (NKF) recommends using the Modification of Diet in Renal Disease (MDRD) Study equation, which factors in a patient's age, sex, and race and is adjusted for a mean body surface area of 1.73 m². The Cockcroft-Gault equation, developed to estimate serum creatinine clearance, is also useful in predicting the GFR and can be easier to use in a clinical setting. In young, healthy adults, a normal GFR ranges from 120 to 130 mL/min/1.73 m² and diminishes with age. (For free calculation tools, go to http://www.kidney.org/professionals/kdoqi/gfr.cfm For more on using these equations, see "Chronic Kidney Disease: An Overview," February 2005.)

In 2006 the NKF introduced a program to standardize creatinine results among assays,1 and a newer version of the MDRD equation has also been made available.2 Both MDRD equations may be inaccurate in apparently healthy patients with a low GFR or with low creatinine generation. A more accurate and reliable approximation of the GFR can be obtained by determining the creatinine clearance rate. That test involves a 12-to-24-hour urine collection and a single blood sample. Three values-total urine creatinine, total urine volume, and serum creatinine-are used to calculate the result.

1. Myers GL, et al. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clinical Chemistry 2006;52(1):5-18. [Context Link]

2. Levey AS, et al. Using standardized serum creatinine values in the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145(4):247-54. [Context Link]

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