Contrast-Induced Nephropathy
Contrast-Induced Nephropathy
Contrast-induced nephropathy refers to a reduction in renal function after the administration of an ICA. The standard diagnostic criteria for contrast-induced nephropathy is a greater than 25% increase in baseline serum creatinine concentration within 3 days of receiving an ICA after other possible causes have been ruled out. Serum creatinine will usually peak within 3 to 7 days and return to baseline (or a new baseline) within 14 days. In many patients, the course is usually benign; however, the development of contrast-induced nephropathy can prolong hospital stay, increases the need for dialysis, and increases overall mortality.50, 51
The major risk factors for contrast-induced nephropathy can be found in Table 2. Preexisting renal dysfunction is the greatest risk factor for developing contrast-induced nephropathy, and the risk becomes greater with increasing baseline renal impairment. The incidence of contrast-induced nephropathy is less than 5% in patients with normal renal function but can be as high as 50% in those with preexisting renal dysfunction.52 Compared with those with normal renal function, patients with a baseline serum creatinine concentration of 1.2 through 1.9 mg/dL, 2.0 through 2.9 mg/dL, and 3.0 mg/dL or more (to convert to μmol/L, multiply by 88.4) have a 2.4, 7.4, and 12.8 increased odds of developing contrast-induced nephropathy after administration of an ICA for a coronary intervention.53 In one report, the risk of developing contrast-induced nephropathy was 2%, 10.4%, and 62% for patients with a preprocedural baseline serum creatinine concentration of 1.2 mg/dL or less, 1.3 through 1.9 mg/dL, and 2.0 mg/dL or higher, respectively.54 Other patient factors include age, systemic diseases that predispose patients to renal dysfunction (eg, diabetes mellitus and hypertension), and factors that contribute to a reduction in cardiac output (eg, severe hemodynamic instability, dehydration, congestive heart failure, and myocardial infarction within 24 hours of receiving an ICA). Recent use of nephrotoxic drugs (eg, aminoglycosides) or drugs that alter renal hemodynamics (eg, nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors) may also predispose patients to the development of contrast-induced nephropathy.55
The nature of the ICA and volume administered can also influence the risk of developing contrast-induced nephropathy and appears to be greatest after the use of high-osmolar ionic monomers, especially in patients with preexisting renal disease. However, it is still unclear whether there is a difference in the risk of developing contrast-induced nephropathy after the use of either nonionic dimers or nonionic monomers.32 For a given ICA preparation, increased volume of ICA administered clearly increases the risk of nephropathy. In patients undergoing coronary angiography, each additional 100 mL of ICA increased the risk of subsequent development of nephropathy by 12%.53
The route of contrast administration may also have an effect on the development of nephropathy. Most clinical studies of contrast-induced nephropathy relate to intraarterial injection of contrast media, whereas corresponding studies of nephropathy after an intravenous contrast injection are somewhat lacking. Recently, some investigators have questioned the existence of clinically significant contrast-induced nephropathy from intravenous injection of iodinated contrast.56 Additional studies with adequate control groups will be necessary to answer this question.
The specific cause of contrast-induced nephropathy is not known; however, multiple factors are thought to contribute to renal impairment associated with ICA use. The ICAs can produce transient vasodilatation followed by prolonged vasoconstriction, which can last 1 to 2 hours, thus reducing renal perfusion. This vasoconstriction is hypothesized to be due to a direct effect of ICAs on the renal endothelial cells, causing an increased production of endothelin, prostaglandins, and adenosine. The ICA molecules are filtered at the glomerulus but not reabsorbed within the renal tubules. Most notable with the high-osmolarity ionic monomers, this results in increased tubular flow and, because of tubuloglomerular feedback (and direct renal vasoconstriction), in a decrease in glomerular filtration. The ICAs are also toxic to renal epithelial cells, causing an increase in the production of free radicals and activating apoptosis in the cells of the thick ascending limb of the loop of Henle.18 One must also note that a reduction in renal function after a radiologic study may not necessarily be due to contrast-induced nephropathy because another disorder included in this differential diagnosis is renal atheroembolic disease due to the use of an aortic catheter (ie, with coronary or cerebral angiography after femoral artery cannulation), which usually occurs days to weeks after a procedure; it is often associated with other manifestations of embolic events, such as digital or mesenteric ischemia.
Treatment should begin by preventing contrast-induced nephropathy in patients who are at increased risk57 (Table 2). In these patients, one should consider the possibility of alternate testing that would not involve the use of an ICA. If that is not possible, the total volume of low- or iso-osmolar ICA should be minimized. Contrast volume should be adjusted to body weight and serum creatinine as when total volume (in milliliters) of ICA exceeded 5 times (body weight [in kilograms]/baseline serum creatinine [in milligrams per deciliter]) the risk of the need for dialysis increased by a factor of 12.58 One should also consider avoiding the concurrent administration of nephrotoxic drugs with ICAs, and intravascular volume depletion should be treated. Other treatments include volume expansion, sodium bicarbonate, diuretics, N-acetylcysteine, dopamine receptor agonists, renal vasodilators, and prophylactic hemofiltration; we will discuss each of these.
Adequate hydration, and especially avoidance of dehydration, is critical for attenuating the risk of contrast-induced nephropathy.59 However, some patients may require careful hydration, such as those with congestive heart failure. At-risk patients may be hydrated with oral or intravenous fluids, at least 100 mL/h starting at least 4 hours before receiving contrast and continuing for at least 24 hours after contrast administration.59, 60 Furthermore, hydration with isotonic solutions (ie, 0.9% sodium chloride) has been shown to be superior at reducing the incidence of contrast-induced nephropathy (especially in women, those with diabetes mellitus, and those who received more than 250 mL of contrast), compared with hypotonic solutions (ie, 0.45% sodium chloride).61 Hydration with an isotonic sodium bicarbonate solution (154 mEq/L) might be superior to an equiosmolar solution of sodium chloride (154 mEq/L) at further reducing the incidence of contrast-induced nephropathy; in patients with chronic renal insufficiency, the reported incidence of contrast-induced nephropathy was 13.6% with sodium chloride hydration and 1.7% with sodium bicarbonate hydration (P=.02).62 A sodium bicarbonate solution can be prepared by adding 150 mL of 1-mEq/mL sodium bicarbonate to 850 mL of 5% dextrose in water. This solution is administered at 3.5 mL/kg for 1 hour before contrast exposure and 1.18 mL/kg/per hour for 6 hours after contrast exposure. Because free radical formation is promoted in an acidic environment, sodium bicarbonate is believed to attenuate contrast-induced nephropathy by increasing the pH of renal tubular fluid, thus decreasing free radical formation.62 Recently, From et al63 retrospectively reviewed 11,516 contrast exposures in 7977 patients and reported that sodium bicarbonate use increases the risk of contrast-induced nephropathy, in contradistinction to the prospective data obtained from 199 patients reported by Merten et al.62 Further study will be needed to sort out this discrepancy and determine whether sodium bicarbonate is beneficial in only certain subgroups of patients.64 Still, many recommend prophylactic sodium bicarbonate administration in high-risk patients.
Forced diuresis can have an adverse effect on the risk of developing contrast-induced nephropathy. Rates of contrast-induced nephropathy have been reported to be either similar65 or worse66 after use of furosemide compared with saline hydration alone. Addition of mannitol to saline hydration has shown benefit in reducing the risk of contrast-induced nephropathy.65, 66 These data are not surprising because furosemide and mannitol both increase tubular fluid flow, which can further decrease glomerular filtration via tubuloglomerular feedback, and both agents can also result in dehydration. In addition, mannitol increases renal oxygen consumption and is a renal vasoconstrictor. Thus, forced diuresis should be avoided in patients at risk for contrast-induced nephropathy.
Use of N-acetylcysteine, a free radical scavenger and renal vasodilator,67 has produced mixed results in the prevention of contrast-induced nephropathy. The largest and most recent meta-analyses showed a benefit from the use of N-acetylcysteine in high-risk patients; however, there was considerable variability in both dosing and efficacy.68, 69 As such, the authors refrained from making clinical recommendations based on their pooled data. N-acetylcysteine may show the greatest benefit when used in patients with severe preexisting renal dysfunction.70, 71 Furthermore, N-acetylcysteine has a relatively safe toxicity profile. Because its use is unlikely to cause harm and may provide protection against contrast-induced nephropathy, N-acetylcysteine could be considered. Generally, N-acetylcysteine is administered to adults orally as 600 mg twice per day for 2 days before receipt of an ICA, although doses up to 1200 mg twice per day have also been reported and might be more efficacious.69
Low-dose dopamine (<2 μg/kg/per minute) increases renal blood flow and reduces sodium reabsorption, thus inducing diuresis. Use of low-dose dopamine to prevent contrast-induced nephropathy has demonstrated mixed results and may be harmful in patients with diabetes mellitus.55, 72 Recent findings derived from larger investigations have shown that fenoldopam can reduce the incidence of ICA-induced nephropathy, especially if administered directly into the renal arteries.73, 74, 75 Direct administration into the renal vasculature has been shown to reduce the risk of systemic hypotension, possibly allowing higher doses of fenoldopam to reach the kidneys while avoiding systemic hypotension. Other agents, such as adenosine receptor antagonists and calcium channel antagonists, show mixed and inconsistent results in reducing the incidence of contrast-induced nephropathy.55 As such, the currently available literature does not support the use of low-dose dopamine, adenosine receptor antagonists, or calcium channel antagonists to reduce the incidence of contrast-induced nephropathy.
Hemodialysis is effective at removing the ICA from circulation, but the use of hemodialysis after exposure to an ICA has not been shown to reduce the risk of the subsequent development of nephropathy in patients with preexisting renal insufficiency.76 However, Marenzi et al77 showed that hemofiltration use before, during, and after the administration of ICAs in patients with severe renal dysfunction may show promise for reducing the incidence of contrast-induced nephropathy and in-hospital adverse events. Therefore, additional studies will be required to determine the utility of hemodialysis or hemofiltration as a preventive measure against contrast-induced nephropathy in at-risk patients.
In patients who develop contrast-induced nephropathy, the treatment is similar to the methods for prevention. Adequate hydration remains the mainstay of therapy with additional protective measures, such as avoiding other nephrotoxic drugs and possibly instituting hemodialysis, can be considered. Early consultation with a nephrologist might prove helpful. Fortunately, in most circumstances, contrast-induced nephropathy follows a benign course and often spontaneously resolves.
Contrast-induced nephropathy refers to a reduction in renal function after the administration of an ICA. The standard diagnostic criteria for contrast-induced nephropathy is a greater than 25% increase in baseline serum creatinine concentration within 3 days of receiving an ICA after other possible causes have been ruled out. Serum creatinine will usually peak within 3 to 7 days and return to baseline (or a new baseline) within 14 days. In many patients, the course is usually benign; however, the development of contrast-induced nephropathy can prolong hospital stay, increases the need for dialysis, and increases overall mortality.50, 51
The major risk factors for contrast-induced nephropathy can be found in Table 2. Preexisting renal dysfunction is the greatest risk factor for developing contrast-induced nephropathy, and the risk becomes greater with increasing baseline renal impairment. The incidence of contrast-induced nephropathy is less than 5% in patients with normal renal function but can be as high as 50% in those with preexisting renal dysfunction.52 Compared with those with normal renal function, patients with a baseline serum creatinine concentration of 1.2 through 1.9 mg/dL, 2.0 through 2.9 mg/dL, and 3.0 mg/dL or more (to convert to μmol/L, multiply by 88.4) have a 2.4, 7.4, and 12.8 increased odds of developing contrast-induced nephropathy after administration of an ICA for a coronary intervention.53 In one report, the risk of developing contrast-induced nephropathy was 2%, 10.4%, and 62% for patients with a preprocedural baseline serum creatinine concentration of 1.2 mg/dL or less, 1.3 through 1.9 mg/dL, and 2.0 mg/dL or higher, respectively.54 Other patient factors include age, systemic diseases that predispose patients to renal dysfunction (eg, diabetes mellitus and hypertension), and factors that contribute to a reduction in cardiac output (eg, severe hemodynamic instability, dehydration, congestive heart failure, and myocardial infarction within 24 hours of receiving an ICA). Recent use of nephrotoxic drugs (eg, aminoglycosides) or drugs that alter renal hemodynamics (eg, nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors) may also predispose patients to the development of contrast-induced nephropathy.55
The nature of the ICA and volume administered can also influence the risk of developing contrast-induced nephropathy and appears to be greatest after the use of high-osmolar ionic monomers, especially in patients with preexisting renal disease. However, it is still unclear whether there is a difference in the risk of developing contrast-induced nephropathy after the use of either nonionic dimers or nonionic monomers.32 For a given ICA preparation, increased volume of ICA administered clearly increases the risk of nephropathy. In patients undergoing coronary angiography, each additional 100 mL of ICA increased the risk of subsequent development of nephropathy by 12%.53
The route of contrast administration may also have an effect on the development of nephropathy. Most clinical studies of contrast-induced nephropathy relate to intraarterial injection of contrast media, whereas corresponding studies of nephropathy after an intravenous contrast injection are somewhat lacking. Recently, some investigators have questioned the existence of clinically significant contrast-induced nephropathy from intravenous injection of iodinated contrast.56 Additional studies with adequate control groups will be necessary to answer this question.
The specific cause of contrast-induced nephropathy is not known; however, multiple factors are thought to contribute to renal impairment associated with ICA use. The ICAs can produce transient vasodilatation followed by prolonged vasoconstriction, which can last 1 to 2 hours, thus reducing renal perfusion. This vasoconstriction is hypothesized to be due to a direct effect of ICAs on the renal endothelial cells, causing an increased production of endothelin, prostaglandins, and adenosine. The ICA molecules are filtered at the glomerulus but not reabsorbed within the renal tubules. Most notable with the high-osmolarity ionic monomers, this results in increased tubular flow and, because of tubuloglomerular feedback (and direct renal vasoconstriction), in a decrease in glomerular filtration. The ICAs are also toxic to renal epithelial cells, causing an increase in the production of free radicals and activating apoptosis in the cells of the thick ascending limb of the loop of Henle.18 One must also note that a reduction in renal function after a radiologic study may not necessarily be due to contrast-induced nephropathy because another disorder included in this differential diagnosis is renal atheroembolic disease due to the use of an aortic catheter (ie, with coronary or cerebral angiography after femoral artery cannulation), which usually occurs days to weeks after a procedure; it is often associated with other manifestations of embolic events, such as digital or mesenteric ischemia.
Treatment should begin by preventing contrast-induced nephropathy in patients who are at increased risk57 (Table 2). In these patients, one should consider the possibility of alternate testing that would not involve the use of an ICA. If that is not possible, the total volume of low- or iso-osmolar ICA should be minimized. Contrast volume should be adjusted to body weight and serum creatinine as when total volume (in milliliters) of ICA exceeded 5 times (body weight [in kilograms]/baseline serum creatinine [in milligrams per deciliter]) the risk of the need for dialysis increased by a factor of 12.58 One should also consider avoiding the concurrent administration of nephrotoxic drugs with ICAs, and intravascular volume depletion should be treated. Other treatments include volume expansion, sodium bicarbonate, diuretics, N-acetylcysteine, dopamine receptor agonists, renal vasodilators, and prophylactic hemofiltration; we will discuss each of these.
Adequate hydration, and especially avoidance of dehydration, is critical for attenuating the risk of contrast-induced nephropathy.59 However, some patients may require careful hydration, such as those with congestive heart failure. At-risk patients may be hydrated with oral or intravenous fluids, at least 100 mL/h starting at least 4 hours before receiving contrast and continuing for at least 24 hours after contrast administration.59, 60 Furthermore, hydration with isotonic solutions (ie, 0.9% sodium chloride) has been shown to be superior at reducing the incidence of contrast-induced nephropathy (especially in women, those with diabetes mellitus, and those who received more than 250 mL of contrast), compared with hypotonic solutions (ie, 0.45% sodium chloride).61 Hydration with an isotonic sodium bicarbonate solution (154 mEq/L) might be superior to an equiosmolar solution of sodium chloride (154 mEq/L) at further reducing the incidence of contrast-induced nephropathy; in patients with chronic renal insufficiency, the reported incidence of contrast-induced nephropathy was 13.6% with sodium chloride hydration and 1.7% with sodium bicarbonate hydration (P=.02).62 A sodium bicarbonate solution can be prepared by adding 150 mL of 1-mEq/mL sodium bicarbonate to 850 mL of 5% dextrose in water. This solution is administered at 3.5 mL/kg for 1 hour before contrast exposure and 1.18 mL/kg/per hour for 6 hours after contrast exposure. Because free radical formation is promoted in an acidic environment, sodium bicarbonate is believed to attenuate contrast-induced nephropathy by increasing the pH of renal tubular fluid, thus decreasing free radical formation.62 Recently, From et al63 retrospectively reviewed 11,516 contrast exposures in 7977 patients and reported that sodium bicarbonate use increases the risk of contrast-induced nephropathy, in contradistinction to the prospective data obtained from 199 patients reported by Merten et al.62 Further study will be needed to sort out this discrepancy and determine whether sodium bicarbonate is beneficial in only certain subgroups of patients.64 Still, many recommend prophylactic sodium bicarbonate administration in high-risk patients.
Forced diuresis can have an adverse effect on the risk of developing contrast-induced nephropathy. Rates of contrast-induced nephropathy have been reported to be either similar65 or worse66 after use of furosemide compared with saline hydration alone. Addition of mannitol to saline hydration has shown benefit in reducing the risk of contrast-induced nephropathy.65, 66 These data are not surprising because furosemide and mannitol both increase tubular fluid flow, which can further decrease glomerular filtration via tubuloglomerular feedback, and both agents can also result in dehydration. In addition, mannitol increases renal oxygen consumption and is a renal vasoconstrictor. Thus, forced diuresis should be avoided in patients at risk for contrast-induced nephropathy.
Use of N-acetylcysteine, a free radical scavenger and renal vasodilator,67 has produced mixed results in the prevention of contrast-induced nephropathy. The largest and most recent meta-analyses showed a benefit from the use of N-acetylcysteine in high-risk patients; however, there was considerable variability in both dosing and efficacy.68, 69 As such, the authors refrained from making clinical recommendations based on their pooled data. N-acetylcysteine may show the greatest benefit when used in patients with severe preexisting renal dysfunction.70, 71 Furthermore, N-acetylcysteine has a relatively safe toxicity profile. Because its use is unlikely to cause harm and may provide protection against contrast-induced nephropathy, N-acetylcysteine could be considered. Generally, N-acetylcysteine is administered to adults orally as 600 mg twice per day for 2 days before receipt of an ICA, although doses up to 1200 mg twice per day have also been reported and might be more efficacious.69
Low-dose dopamine (<2 μg/kg/per minute) increases renal blood flow and reduces sodium reabsorption, thus inducing diuresis. Use of low-dose dopamine to prevent contrast-induced nephropathy has demonstrated mixed results and may be harmful in patients with diabetes mellitus.55, 72 Recent findings derived from larger investigations have shown that fenoldopam can reduce the incidence of ICA-induced nephropathy, especially if administered directly into the renal arteries.73, 74, 75 Direct administration into the renal vasculature has been shown to reduce the risk of systemic hypotension, possibly allowing higher doses of fenoldopam to reach the kidneys while avoiding systemic hypotension. Other agents, such as adenosine receptor antagonists and calcium channel antagonists, show mixed and inconsistent results in reducing the incidence of contrast-induced nephropathy.55 As such, the currently available literature does not support the use of low-dose dopamine, adenosine receptor antagonists, or calcium channel antagonists to reduce the incidence of contrast-induced nephropathy.
Hemodialysis is effective at removing the ICA from circulation, but the use of hemodialysis after exposure to an ICA has not been shown to reduce the risk of the subsequent development of nephropathy in patients with preexisting renal insufficiency.76 However, Marenzi et al77 showed that hemofiltration use before, during, and after the administration of ICAs in patients with severe renal dysfunction may show promise for reducing the incidence of contrast-induced nephropathy and in-hospital adverse events. Therefore, additional studies will be required to determine the utility of hemodialysis or hemofiltration as a preventive measure against contrast-induced nephropathy in at-risk patients.
In patients who develop contrast-induced nephropathy, the treatment is similar to the methods for prevention. Adequate hydration remains the mainstay of therapy with additional protective measures, such as avoiding other nephrotoxic drugs and possibly instituting hemodialysis, can be considered. Early consultation with a nephrologist might prove helpful. Fortunately, in most circumstances, contrast-induced nephropathy follows a benign course and often spontaneously resolves.
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