Pharmacology of Contrast-Induced Nephropathy

Imaging is commonly used in hospitals and outpatient settings to diagnose and treat disease and injury. Providers should understand the contrast agents used, the roles of contrast agents, possible adverse events, and treatment of patients with contrast-induced reactions, particularly nephropathies.Contrast-induced nephropathy (CIN) is an acute renal injury occurring after exposure to contrast media. Contrast agents are most often used to enhance imaging, particularly computed tomography and magnetic resonance imaging, or in procedures such as cardiac catheterization.1 Contrast-induced nephropathy occurs within 48 hours of exposure to intravenous or intra-arterial iodinated contrast material. This exposure results in an acute kidney injury, defined as an increase in serum creatinine by 50% or more or by 0.3 mg/dL or more, with the peak typically seen approximately 12 hours after exposure.2 Contrast-induced nephropathy is the third most common cause of acute renal failure in hospitalized patients. Other causes of acute kidney injury, including disease states, drug exposures, and toxin exposures, should be ruled out.3Certain patients may be at higher risk than others of developing CIN. Factors that put patients at risk of CIN include impaired baseline renal function, defined as an estimated glomerular filtration rate between 45 and 60 mL/min, and diabetes mellitus.2,4 Other patient factors that may play a role in CIN include advanced age, heart failure, anemia, and hypotension. Patients who develop acute renal failure after receipt of intravenous or intra-arterial contrast material may have up to a 20% increased risk of mortality.3 Additionally, CIN can be associated with increased length of hospital stay, requirement for renal replacement therapy, and increased health care cost. Therefore, every patient should be screened for risk factors for developing CIN and clinically assessed for the appropriateness of contrast agent use.Of the various types of contrast media, iodinated agents are the most commonly used.5 Iodinated contrast media allow for enhanced imaging of various anatomical features that may otherwise be difficult to see with radiological imaging. Iodinated contrast media are categorized as ionic or nonionic and as monomers or dimers (Table 1). Compared with ionic agents, nonionic iodinated contrast agents tend to have lower incidences of allergic reaction, pain on injection, nausea, vomiting, tissue necrosis related to extravasation, and nephrotoxicity.5Several qualities of iodinated contrast agents make them commonly used imaging agents. Iodine is absorbed into tissues. When electromagnetic radiation comes in contact with iodine, the iodine absorbs the energy of the x-ray beam, so a shadow appears on the image receptor because the radiation is not reflected back at the detector.5 Iodinated contrast agents largely reside in the intravascular space and have the highest concentration in areas of high perfusion, such as the kidneys, liver, and brain. These agents inherently have low protein binding. Elimination half-life is 90 to 120 minutes but can be delayed up to weeks in patients with compromised renal function.Gadolinium chelates are a common type of contrast medium used primarily in magnetic resonance imaging. Although gadolinium chelates have some properties (such as osmolality) similar to those of iodinated contrast agents, they do not seem to be a significant cause of CIN in patients with normal renal function. Gadolinium-based products may contribute to nephrotoxicity in patients with preexisting renal dysfunction. However, because the association between gadolinium-based agents and nephrotoxicity remains somewhat controversial and gadolinium chelates are considered safer than iodinated contrast agents, this review focuses only on CIN caused by iodinated contrast agents.7Contrast-induced nephropathy occurs via 2 main mechanisms: renal ischemia and direct cytotoxic activity.5 Contrast agents cause renal vasoconstriction by increasing the release of endothelin and adenosine from renal cells. These agents also increase the production and release of reactive oxygen species, which can lead to direct cytotoxic effects on renal tubular cells. Combined with a decrease in nitric oxide production, these mechanisms propagate ischemia and nephropathy within the kidneys. Direct cytotoxicity is mediated by osmotic necrosis or vacuolization, which signals apoptosis within renal cells with the uptake of iodinated contrast agents.5Although shellfish allergies are commonly noted in patients, an allergy to shellfish does not immediately put a patient at risk for an allergy to iodinated contrast material or increase the risk of developing CIN. Shellfish allergies have been linked to tropomyosins, compounds that do not contain iodine. Iodine is not typically considered an allergen. Allergic reactions may be more likely in patients who have a high propensity of developing allergies to anything. Contrast agent allergies are proposed to occur through nonspecific binding to allergen binding sites on immunoglobulin E proteins of mast cells and basophils. The reaction is more likely to occur in patients with high circulating concentrations of immunoglobulin E and mast cells at the time of contrast agent administration.8Contrast-induced nephropathy is thought to occur in up to 14% of patients who receive iodinated contrast material.1,9 However, a study evaluating a low-osmolar agent (iohexol) and an iso-osmolar agent (iodixanol) showed that the incidence of CIN may be as low as 4%, with a higher incidence in patients with preexisting renal dysfunction.4 Additionally, 2 studies comparing patients who received intravenous or intra-arterial contrast material with those who did not found incidences of acute kidney injury (AKI) of 6% to 11%. However, the rates of AKI did not differ between the groups, even among patients with preexisting renal dysfunction.9,10 These studies are limited by their retrospective study design, inability to control for the types or amounts of contrast material administered, and other patient-specific factors, but they call into question whether the true incidence of CIN is lower than previously reported.Prevention is especially important in CIN, and many studies have investigated the role of pharmacotherapy in CIN prevention. Pre-medication with steroids and antihistamines is often used to prevent anaphylactic reactions in patients with known or suspected allergies, but premedication likely has limited utility in preventing other adverse reactions, such as CIN. Strategies that have been studied specifically for the prevention of CIN are summarized in Table 2.Hydration is thought to prevent CIN by expanding intravascular volume to counteract vasoconstriction and other hemodynamic effects caused by iodinated contrast media. Large randomized controlled trials evaluating the effect of hydration on the incidence of CIN are lacking, but numerous small studies have evaluated different hydration strategies. Two studies have evaluated the use of intravenous saline to prevent CIN following percutaneous coronary intervention in patients with myocardial infarction. Both studies found a reduced risk of CIN in patients who received intravenous saline during and for 12 to 24 hours after percutaneous coronary intervention. However, patients who did not receive hydration were more likely to have hypotension, which may have contributed to the development of AKI.11,12Another study of patients who received contrast media for cardiac catheterization compared oral and intravenous hydration and found a lower incidence of CIN in patients who received intravenous hydration.3 In a randomized controlled trial comparing an aggressive fluid administration protocol (targeted to maintain a higher left ventricular end-diastolic pressure) with a standard rate of intravenous saline administration in high-risk patients undergoing percutaneous coronary intervention, investigators found a lower incidence of CIN in the group receiving aggressive fluid administration.13 Hydration protocols vary widely in the studies that have been conducted, and the optimal volume and timing of intravenous isotonic saline administration are yet to be determined. Examples of intravenous hydration regimens are listed in Table 2.14Research has also compared the effect of hydration using isotonic (0.9%) and hypotonic (0.45%) saline. Isotonic saline was found to be superior to hypotonic saline in a randomized controlled trial, with less CIN occurring in patients who received isotonic saline.15 This effect is thought to be due to the ability of isotonic saline to create a more profound intravascular volume expansion than hypotonic saline. Overall, intravenous hydration with 0.9% saline is recommended for prevention of CIN in patients receiving iodinated contrast agents unless the fluid volume is contraindicated on the basis of patient-specific characteristics.Hydration with fluid containing sodium bicarbonate may provide an additional benefit over saline by alkalinizing the urine to decrease free radical injury, thereby minimizing the renal tubular damage caused by iodinated contrast material. This theory has been tested in a variety of studies producing somewhat conflicting results, with some small studies showing a benefit and others showing no difference between sodium bicarbonate and saline. One of the first studies to examine sodium bicarbonate for CIN prevention compared it with isotonic saline and found a significant decrease in the rate of CIN (1.7% vs 13.6%).16 This study was a single-center trial and the results have not been consistently replicated, with one retrospective study even showing an increase in CIN with sodium bicarbonate administration.17The largest study to date evaluating sodium bicarbonate for CIN prevention included almost 5000 patients at high risk for CIN. Patients were randomized to receive either isotonic (0.9%) saline or a 1.26% sodium bicarbonate infusion before and after receiving iodinated contrast material. No difference between the 2 groups was seen in the composite primary outcome (death, need for dialysis, and persistent increase in serum creatinine of 50% or more at 90 days) or in any of the secondary outcomes.14 Although the data are conflicting, sodium bicarbonate is generally not considered to have a benefit over other methods of hydration in the prevention of CIN.Historically it was believed that CIN could be prevented through the prophylactic use of N-acetylcysteine. N-acetylcysteine (a reactive oxygen scavenger) was thought to prevent CIN by minimizing the effects of reactive oxygen species formed in the kidney after exposure to iodinated contrast agents, although clinically this does not seem to be the case.5 The use of N-acetylcysteine to prevent CIN was largely disproved in a prospective randomized controlled trial in which the researchers gave oral N-acetylcysteine or placebo to patients in vulnerable populations before and after iodinated contrast agent exposure. The investigators found no differences between the 2 groups in mortality or need for dialysis within 30 days of exposure.18 Weisbord and colleagues14 compared oral N-acetylcysteine with placebo for the prevention of CIN in high-risk patients undergoing angiography. Their study found no difference in the primary composite outcome (death, need for dialysis, and persistent increase in serum creatinine of 50% or more at 90 days) or secondary outcomes with N-acetylcysteine administration.14 The use of N-acetylcysteine is not considered beneficial for the prevention of CIN but is generally considered safe. Providers who use N-acetylcysteine should note the risk of anaphylaxis with this medication and take appropriate precautions.Ascorbic acid has been used to prevent CIN because it has been shown to act as an antioxidant by scavenging oxygen free radicals. Ascorbic acid also has been used to ameliorate renal damage in other disease states, such as damage caused by cisplatin or aminoglycosides. A small double-blind randomized controlled trial showed a possible benefit of administering 5 g of oral ascorbic acid (3 g before and 2 g after contrast agent administration) over placebo. Twenty percent of patients in the placebo group and 9% of patients in the ascorbic acid group developed CIN.19 However, more recent studies have failed to show this benefit, particularly when fluid administration is considered.20 A study by Albabtain and colleagues20 evaluated the combination of N-acetylcysteine and ascorbic acid versus intravenous saline administration alone and found that intravenous saline alone was as beneficial as N-acetylcysteine plus ascorbic acid.20 Although the mechanism of ascorbic acid in CIN prevention is promising, no large randomized controlled trial has confirmed this benefit, and the routine use of ascorbic acid is not recommended.An additional prevention strategy for CIN is to increase or preserve renal perfusion to optimize removal of administered contrast material. Vasodilators have been used to optimize renal blood flow. Fenoldopam is a dopamine D1 receptor agonist that produces systemic, peripheral, and renal arterial vasodilatation. It has therefore been hypothesized that fenoldopam would be beneficial as a prophylactic agent for CIN. However, in a study by Stone and colleagues,21 patients experienced hypotension as a significant adverse effect of this therapy. Fenoldopam was also not beneficial in preventing CIN regardless of patients’ diabetes status, baseline renal function, N-acetylcysteine use, hydration status, or amount of contrast agent received. This finding may add evidence to the theory that CIN is caused by direct tubular necrosis and not by decreased blood flow. Low-dose dopamine has been considered renal protective up to a dose of 2 μg/kg per minute through a dilatory effect on the renal vasculature. Another study of dopamine found no benefit for CIN and possible harm in patients after cardiac intervention.22 Overall, the use of vasodilators for CIN prevention is not promising, and vasodilators are not recommended to prevent or treat CIN at this time.Diuretics have been used in an attempt to minimize CIN. Diuretic use balances hydration in conjunction with diuresis to minimize fluid overload. In theory, with increased fluid in the renal tubules, loop diuretics such as furosemide help dilute the contrast material to which the tissue is exposed and thus minimize damage.23 However, diuretics may lower overall fluid volume, leading to further assault to renal tissue.23 Initial studies of diuretic use along with hydration found deleterious effects and a higher incidence of CIN. Weinstein and colleagues24 randomized patients to receive intravenous fluid plus furosemide (mean dose, 110 mg) or intravenous fluid alone and found a higher incidence of CIN in patients receiving the diuretic.More recent studies have presented data with varying results. The MYTHOS (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy [CIN] Prevention) study prospectively evaluated patients with chronic kidney disease undergoing cardiac procedures requiring contrast agent administration.23 The 2 patient groups received either continuous infusion of sodium chloride solution (standard hydration) or a bolus of normal saline plus furosemide (0.5 mg/kg, maximum of 50 mg) before contrast material administration. The investigators found a significant reduction of CIN incidence (4.6% vs 18%) in the furosemide group compared with the standard-hydration group. Similar results were seen in the PROTECT-TAVI (Prophylactic Effect of Furosemide-Induced Diuresis With Matched Isotonic Intravenous Hydration in Transcatheter Aortic Valve Implantation) trial, in which patients undergoing transaortic valve replacement were randomized to receive either hydration alone or hydration plus furosemide.25 The investigators found a higher incidence of AKI but no difference in the number of patients requiring dialysis in the hydration-only group. Further study is needed to delineate the patient population that may benefit from the use of diuretics to prevent CIN. Therefore, diuretics are not recommended for routine use at this time.Many medications given to patients who receive iodinated contrast media for imaging or angiography procedures can potentially cause nephrotoxicity. These medications are especially common in hospitalized patients. Examples include nonsteroidal anti-inflammatory drugs, antibiotics such as vancomycin and aminoglycosides, immunosuppressive medications such as cyclosporine and tacrolimus, and loop diuretics. The risk of CIN related to the concomitant use of potentially nephrotoxic medications has not been elucidated in clinical studies. However, it is recommended that these medications be withheld or minimized if possible before and after the patient receives iodinated contrast material to minimize the potential for additive risk to the kidneys. It may be particularly prudent to avoid medications that cause renal vasoconstriction and therefore decreased blood flow to the kidneys, such as nonsteroidal anti-inflammatory drugs, in the 24 to 48 hours before and after contrast agent administration.A single session of intermittent hemodialysis has been shown to decrease the serum concentration of iodinated contrast material by 40% to 80%.26 This modality is typically reserved for patients whose kidney function will probably not recover on its own and those with morbid situations such as fluid overload, acid-base abnormalities, or critical electrolyte disturbances.2,27 Many practitioners use this strategy in patients who are currently receiving dialysis and require imaging with contrast agents by administering hemodialysis after imaging to minimize any further damage from CIN.Contrast-induced nephropathy is usually identified within 48 hours of receipt of iodinated contrast material. The serum creatinine level typically peaks within 5 days of receipt of contrast material, and CIN usually starts to resolve 3 to 7 days after the injury. Other causes of AKI should be ruled out and/or treated before implicating contrast media. There are currently no specific treatment recommendations for CIN other than supportive care. If CIN occurs, nephrotoxic medications should be avoided. Renal function should be monitored and renal replacement therapy should be initiated if necessary. Renal replacement therapy has been observationally reported to be necessary in 0.7% to 7% of cases of CIN.28 Patients with CIN have increased hospital costs, increased in-hospital mortality, and increased mortality up to year 5 after injury.28Contrast-induced nephropathy is an undesirable consequence of using iodinated contrast agents, which are often critical to patient care. In patients with normal renal function and without other risk factors, the risk of CIN is low. These patients are unlikely to need aggressive preventive measures, although volume depletion and nephrotoxic medications should be avoided. Patient-specific risk factors should be evaluated before using iodinated contrast agents. Preventive measures should be used for patients with significant risk factors. According to currently available research, the most well-supported preventive measure is the use of intravenous hydration with 0.9% saline. Other modalities of prevention have not consistently been shown to have significant benefit in counteracting the development of CIN and should not be used routinely to prevent CIN.