INTRODUCTION

Acute kidney injury (AKI) may develop after administration of iodinated contrast material. AKI that is related to iodinated contrast material has historically been called contrast-induced nephropathy (CIN) or contrast-induced AKI (CI-AKI). However, nephrology and radiology communities have also adopted the term “contrast-associated AKI (CA-AKI),” because it is not possible to exclude other causes of AKI in many clinical and most research settings. CA-AKI is a generally reversible form of AKI, although its development may be associated with adverse outcomes .

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TERMINOLOGY

Acute kidney injury (AKI) that occurs shortly after administration of iodinated contrast may or may not be causally related to contrast material:

• “Contrast-associated AKI (CA-AKI)” or, synonymously, “postcontrast AKI” are broad terms that refer to AKI occurring shortly after administration of iodinated contrast and that may or may not be directly caused by the contrast material. The term CA-AKI applies to situations in which a detailed clinical evaluation for other potential AKI etiologies has not been performed or in which other causes of AKI cannot be reasonably excluded. CA-AKI should also be used to refer to increases in creatinine (or decreases in estimated glomerular filtration rate [eGFR]) after contrast exposure in research studies.
• “Contrast-induced AKI (CI-AKI),” previously called “contrast-induced nephropathy (CIN),” is a specific term that refers to the subset of postcontrast AKI that is judged to be causally linked to contrast material administration. In an individual patient, the presence of a causal link between contrast exposure and AKI can only be judged after a thorough clinical evaluation for other potential causes of AKI. If after such an evaluation, no other causes (other than contrast exposure) are identified, then it is appropriate in these instances to use the term CI-AKI. Although some experts contend that, even after a thorough clinical evaluation fails to reveal an alternative etiology, it is not possible to establish causality. However, this is also the case for other causes of AKI, such as sepsis-induced acute tubular necrosis (ATN), or ATN caused by an alternative nephrotoxic agent.

Intravascular iodinated contrast media have been considered nephrotoxic based in large part upon animal experiments, uncontrolled human studies, and anecdotal observations. (See ‘Pathogenesis’ below.)

However, because many of these older reports lacked comparable control groups that did not receive contrast material, their applicability to our understanding of CI-AKI is unclear. Large propensity-matched controlled studies have since suggested that many cases of AKI following contrast administration may in fact be related to coincident nephrotoxic exposures (eg, hypovolemia, cardiac dysfunction, infection) present at the time that contrast material was administered .

As a result of these larger studies, multiple authorities in the radiology and nephrology communities adopted alternate terms (CA-AKI or postcontrast AKI) to refer to any AKI that occurs shortly after administration of iodinated contrast material. Such terms are agnostic to cause and include both CI-AKI as well as coincidental AKI. Since coincident AKI is so common, true CI-AKI cannot be diagnosed accurately in the context of a clinical research study, even when conducted with a control arm not exposed to contrast material .

Thus, the term “CI-AKI” (or “CIN”) should be reserved for AKI that can be causally linked to contrast material administration. If other potential etiologies have not been excluded or if other potential etiologies are identified, then AKI occurring shortly after contrast exposure should be referred to as “CA-AKI” or “postcontrast AKI.”

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PATHOGENESIS

The best data related to the nephrotoxicity of contrast media come from animal models. Studies show evidence of acute tubular necrosis (ATN), but the mechanism by which ATN occurs is not well understood . The two major theories are that ATN is caused by renal vasoconstriction resulting in medullary hypoxia, possibly mediated by effects of viscosity and by alterations in nitric oxide, endothelin, and/or adenosine, and also as a direct result of the cytotoxic effects of the contrast agents on tubular cells. Tubular cell injury may be exacerbated by renal vasoconstriction, and these two theories are not mutually exclusive.

Compared with other types of ATN (such as ischemic), contrast-induced acute kidney injury (CI-AKI) is usually characterized by relatively rapid recovery of kidney function (see ‘Clinical features’ below). If ATN contributes to CI-AKI, it is not clear why recovery occurs relatively quickly (ie, within a few days) compared with a longer duration (ie, one to three weeks), as with ATN due to other causes. One likely possibility is that the degree of tubular necrosis is much less severe than seen in other settings. It is also possible that the decline in glomerular filtration rate (GFR) is due to functional changes in tubule epithelial cells rather than necrosis. This phenomenon may be at least in part due to redistribution of membrane transport proteins from the basolateral to the luminal membrane .

In addition, it is possible that prerenal factors or intratubular obstruction contribute to the pathogenesis. This possibility is suggested by the observation that the fractional sodium excretion (FENa) may be <1 percent in patients with CI-AKI, which is characteristic of prerenal physiology.

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CLINICAL FEATURES

The major clinical manifestations of contrast-induced acute kidney injury (CI-AKI) include:

• Early, mild increase in serum creatinine – An increase in serum creatinine that is generally observed within 24 to 48 hours after the iodinated contrast exposure and that is usually mild. The serum creatinine typically starts to decline toward baseline within three to seven days of the exposure to contrast.
• Nonoliguria – Because the AKI is typically mild, most patients are nonoliguric. Oliguria (if it occurs) develops immediately after the procedure. Oliguria and more significant elevations in creatinine can be seen with severe AKI or when CI-AKI develops in patients with moderate to severe chronic kidney disease (CKD) at baseline.
• Urinary sediment consistent with acute tubular necrosis – The urinary sediment may show classic findings of acute tubular necrosis (ATN), including muddy brown granular and epithelial cell casts and free renal tubular epithelial cells (picture 1 and picture 2). However, the absence of these urinary findings does not exclude the possibility of CA-AKI.

Other manifestations of reduced glomerular filtration rate (GFR) may be present, including hyperkalemia, acidosis, and hyperphosphatemia.

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EVALUATION

Patients who have suspected contrast-induced acute kidney injury (CI-AKI) should undergo a focused history and physical examination (to elucidate other possible causes of AKI) and have a urinalysis with microscopic examination of the urinary sediment (to identify findings consistent with a diagnosis of CI-AKI or findings that suggest an alternative etiology). Oliguria and severe AKI are less common findings in CI-AKI. Thus, patients with oliguria and patients with severe AKI (who may require kidney replacement therapy) should undergo a more extensive evaluation for alternate etiologies of AKI.

Although an ultrasound is often obtained among hospitalized patients with AKI, we generally do not obtain an ultrasound initially among patients whose presentation is characteristic of CI-AKI. However, we do obtain an ultrasound to exclude other causes of AKI among patients with risk factors for urinary tract obstruction who do not follow a classic clinical course of CI-AKI or if the diagnosis of CA-AKI is questionable (eg, oliguria, severe AKI). (See “Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting”.)

The urinalysis provides important diagnostic information by excluding other causes of AKI. However, it does not provide a conclusive, positive diagnosis of CI-AKI. As noted above, the classic findings of CI-AKI, including muddy brown granular and epithelial cell casts and free renal tubular epithelial cells, are not present in all patients diagnosed with CI-AKI and are not specific for CI-AKI. (See ‘Clinical features’ above and “Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults”, section on ‘Urinalysis’ and “Urinalysis in the diagnosis of kidney disease”, section on ‘Examination of the urine sediment’.)

However, the absence of other findings, such as white blood cells (WBCs), WBC casts, dysmorphic red blood cells (RBCs), and RBC casts, is useful to exclude interstitial nephritis and glomerular diseases as causes of AKI. Conversely, the presence of WBCs, WBC casts, dysmorphic RBCs, or RBC casts suggests causes of AKI other than acute tubular necrosis (ATN), such as interstitial nephritis or glomerular lesions. Such patients often require a kidney biopsy.

Protein excretion in patients with CI-AKI is typically absent or mild (unless the patient had proteinuric chronic kidney disease [CKD] at baseline). However, the presence of albuminuria (detected by a qualitative dipstick or by an albumin-to-creatinine ratio) does not exclude CI-AKI, even if albuminuria was not previously present; the reasons for this are as follows:

• Many of the commonly used iodinated radiocontrast agents induce false-positive results when either a dipstick or sulfosalicylic acid is used to detect proteinuria. How this occurs is not clear, but protein excretion may be overestimated by as much as 1.5 to 2 g/L. Thus, the dipstick may be positive for albuminuria within the first 24 hours of contrast administration, even if albumin excretion is truly normal.
• An albumin-to-creatinine ratio may reveal moderately or severely increased albuminuria in the acute phase of AKI (regardless of the cause) due to a low urine creatinine combined with impaired tubular reabsorption of albumin.

There are no characteristic radiographic features of contrast nephropathy. As in other causes of AKI, a prolonged nephrogram may be seen among patients with CI-AKI who undergo a noncontrast-enhanced computed tomography (CT) scan.

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DIAGNOSIS

Contrast-induced acute kidney injury (CI-AKI) is a clinical diagnosis. A clinical diagnosis of CI-AKI is made based upon the following features:

• The characteristic rise in serum creatinine concentration beginning within the first 24 to 48 hours after contrast exposure.
• In the judgment of the clinician, reasonable exclusion of other causes of AKI.

As noted above, exclusion of other causes of AKI requires a routine evaluation of AKI with careful history and physical, urinalysis, and other pertinent laboratory studies; kidney ultrasound and kidney biopsy may be needed, if appropriate. (See ‘Evaluation’ above and “Evaluation of acute kidney injury among hospitalized adult patients”.)

Even if other causes of AKI are identified, it is still possible that iodinated contrast exposure may have contributed to kidney injury.

A kidney biopsy is generally not helpful for the diagnosis of CI-AKI, since the lesions of ATN are focal and nonspecific and because CI-AKI is generally short lived. However, as with the ultrasound, a biopsy may rarely be required to exclude other causes of AKI among patients who do not follow a classic clinical course or in whom the diagnosis of contrast nephropathy is uncertain.

Differential diagnosis — The differential diagnosis includes, but is not limited to, renal atheroemboli (in setting of intra-arterial contrast administration), ischemic acute tubular necrosis (ATN), acute interstitial nephritis, and prerenal changes caused by the addition of or dose adjustments in diuretics and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the postcontrast period. (See “Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults” and “Clinical manifestations and diagnosis of acute interstitial nephritis”.)

Among patients who develop AKI after angiography, CI-AKI must be distinguished from renal atheroemboli. Renal atheroemboli are generally characterized by one or more of the following:

• The presence of other embolic lesions (such as digital ischemia of the toes) or livedo reticularis.
• Transient eosinophilia and hypocomplementemia, although these findings are not observed in all patients with renal atheroemboli
• Delayed onset of kidney function decline, often days to weeks after angiography (whereas contrast-associated AKI [CA-AKI] develops within 48 hours of angiography)
• Protracted course with frequently little or no recovery of kidney function

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MANAGEMENT

The management of patients with contrast-associated acute kidney injury (CA-AKI) is supportive and includes elimination and avoidance of other potential kidney insults, hemodynamic and electrolyte assessment and management, appropriate dose adjustment of medications for the reduction in glomerular filtration rate (GFR), and, among those with severely decreased kidney function, monitoring for uremic signs and symptoms. An overview of the management of AKI is presented separately. (See “Overview of the management of acute kidney injury (AKI) in adults”.)

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NATURAL HISTORY AND PROGNOSIS

As noted above, patients with contrast-induced acute kidney injury (CI-AKI) usually have a mild reduction in glomerular filtration rate (GFR). In the majority of cases, the kidney function starts to improve within three to seven days, and the patient returns to, or close to, baseline estimated GFR (eGFR) [8,39]. In one study that included 21 patients with CI-AKI, 12 (57 percent) returned to baseline kidney function, and four additional patients (19 percent) had a partial recovery within five to seven days [39]. Five patients (24 percent) had persistent kidney dysfunction at the time of discharge.

Dialysis is rarely required for CI-AKI. In one study of over 1800 consecutive patients who underwent percutaneous interventions, the incidence of AKI that was severe enough to require dialysis was <1 percent [2]. The risk may be higher among patients with severe, underlying chronic kidney disease (CKD) [2,8,43]. The indications for dialysis are the same in patients with CI-AKI as in other forms of AKI. (See “Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose”.)

The serum creatinine concentration is insensitive to modest reductions in GFR; residual kidney dysfunction may therefore persist, even if the creatinine has returned to baseline. Patients with underlying CKD have the highest risk of developing persistent kidney injury following an episode of AKI, and AKI in such patients increases the risk of CKD progression. This issue is discussed separately. (See “Kidney and patient outcomes after acute kidney injury in adults”, section on ‘Degree of recovery’.)

The development of contrast-associated AKI (CA-AKI) is associated with adverse short- and long-term outcomes. The 30-day, one-year, and five-year mortality risks are higher among patients who develop CA-AKI [44-47]. In one analysis of 9512 patients identified from randomized trials, the 30-day mortality rate was approximately 5 percent among patients who developed AKI following percutaneous coronary intervention compared with <1 percent among those who did not [45]. Postcontrast AKI is also associated with greater rate of cardiovascular events, heart failure, and requirement for acute and maintenance dialysis [48,49].

However, it is possible that the association of CA-AKI with these adverse consequences is due to underlying comorbidities that contribute to both the AKI and to such outcomes [50].

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SUMMARY AND RECOMMENDATIONS

• Acute kidney injury (AKI) that occurs shortly after administration of iodinated contrast may or may not be causally related to contrast material. “Contrast-associated AKI (CA-AKI)” is a broad term that refers to AKI occurring shortly after administration of iodinated contrast and that may or may not be directly caused by the contrast material. “Contrast-induced AKI (CI-AKI),” previously called “contrast-induced nephropathy (CIN),” is a specific term that refers to the subset of CA-AKI that is judged, after a thorough clinical evaluation, to be causally linked to contrast material administration. The term CA-AKI applies to situations in which a detailed clinical evaluation for other potential AKI etiologies has not been performed or in which other causes of AKI cannot be reasonably excluded. CA-AKI should also be used to refer to increases in creatinine (or decreases in estimated glomerular filtration rate [eGFR]) after contrast exposure in research studies. (See ‘Terminology’ above.)
• The major clinical manifestations of CI-AKI include (see ‘Clinical features’ above):
  • An increase in serum creatinine that is generally observed within 24 to 48 hours after the iodinated contrast exposure and that is usually mild.
  • Most patients are nonoliguric. Oliguria may develop in patients with severe AKI and in patients with moderate to severe chronic kidney disease (CKD) at baseline.
  • The urinary sediment usually, but not always, shows classic findings of acute tubular necrosis (ATN), including muddy brown granular and epithelial cell casts and free renal tubular epithelial cells (picture 1 and picture 2).
• Patients with suspected CI-AKI should undergo a focused history and physical exam and have a microscopic examination of the urinary sediment to identify findings that suggest an alternative etiology. Patients with oliguria and patients with severe AKI (who may require kidney replacement therapy) may be more likely to have an alternate etiology of AKI. A kidney ultrasound is not typically required, although it may be obtained to exclude other causes of AKI among patients with risk factors for urinary tract obstruction who do not follow a classic clinical course of CI-AKI, or if the diagnosis of CI-AKI is questionable (eg, oliguria, severe AKI). Protein excretion in patients with CI-AKI is typically absent or mild (unless the patient had proteinuric CKD at baseline). However, the presence of albuminuria (detected by a qualitative dipstick or by an albumin-to-creatinine ratio) does not exclude CI-AKI. (See ‘Evaluation’ above.)
• CI-AKI is a clinical diagnosis. A clinical diagnosis of CI-AKI is made based upon the following features (see ‘Diagnosis’ above):
  • The characteristic rise in serum creatinine concentration beginning within the first 24 to 48 hours after contrast exposure
  • In the judgment of the clinician, reasonable exclusion of other causes of AKI

A kidney biopsy is generally not helpful for the diagnosis of CI-AKI, since the lesions of ATN are focal and nonspecific and because CI-AKI is generally short lived. However, as with the ultrasound, a biopsy may rarely be required to exclude other causes of AKI among patients who do not follow a classic clinical course or in whom the diagnosis of CI-AKI is uncertain.

• The differential diagnosis includes, but is not limited to, renal atheroemboli (in setting of intra-arterial contrast administration), ischemic ATN, acute interstitial nephritis, and prerenal changes caused by the addition of or dose adjustments in diuretics and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the postcontrast period. (See ‘Differential diagnosis’ above.)
• As with most other etiologies of AKI, the management of patients with CI-AKI is supportive and includes elimination and avoidance of other potential kidney insults, hemodynamic and electrolyte assessment and management, appropriate dose adjustment of medications for the reduction in GFR, and, among those with severely decreased kidney function, monitoring for uremic signs and symptoms. An overview of the management of AKI is presented separately. (See ‘Management’ above and “Overview of the management of acute kidney injury (AKI) in adults”.)
• Patients with CI-AKI usually have a mild reduction in GFR that, in the majority of cases, starts to improve within three to seven days. Most patients return to, or close to, their baseline estimated GFR. Dialysis is rarely required for CI-AKI. (See ‘Natural history and prognosis’ above.)