Contrast-Induced Nephropathy

Updated: Feb 14, 2017
  • Author: Renu Bansal, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Practice Essentials

Contrast-induced nephropathy (CIN) is defined as the impairment of renal function—measured as either a 25% increase in serum creatinine (SCr) from baseline or a 0.5 mg/dL (44 µmol/L) increase in absolute SCr value—within 48-72 hours of intravenous contrast administration. (See Etiology.)

For renal insufficiency (RI) to be attributable to contrast administration, it should be acute, usually occurring within 2-3 days (although it has been suggested that RI up to 7 days post–contrast administration be considered CIN); it should also not be attributable to any other identifiable cause of renal failure. A temporal link is thus implied. [1] Following contrast exposure, SCr levels peak between 2 and 5 days and usually return to normal in 14 days. (See Presentation and Workup.)

Complications

CIN is one of the leading causes of hospital-acquired acute kidney injury. It is associated with a significantly higher risk of in-hospital and 1-year mortality, even in patients who do not need dialysis.

Nonrenal complications of CIN include the following:

  • Procedural cardiac complications (eg, Q-wave MI, coronary artery bypass graft [CABG], hypotension, shock)
  • Vascular complications (eg, femoral bleeding, hematoma, pseudoaneurysm, stroke)
  • Systemic complications (eg, acute respiratory distress syndrome [ARDS], pulmonary embolism)

There is a complicated relationship between CIN, comorbidity, and mortality. Most patients who develop CIN do not die from renal failure. Death, if it does occur, is more commonly from either a preexisting nonrenal complication or a procedural complication.

Concerns

Many physicians who refer patients for contrast procedures and some who perform the procedure themselves are not fully informed about the risk of CIN. A survey found that less than half of referring physicians were aware of potential risk factors, including diabetes mellitus. (See DDx.)

A lack of consensus exists regarding the definition and treatment of CIN. Studies differ in regard to the marker used for renal function (SCr versus estimated glomerular filtration rate [eGFR]), the day of initial measurement and remeasurement of the marker, and the percentage increase used to define CIN. This makes it difficult to compare studies, especially in terms of the efficacy of various treatment modalities. (See Treatment and Medication.) [2]

The reported incidence of CIN might be an underestimation. SCr levels normally rise by day 3 of contrast administration. Most patients do not remain hospitalized for so long and there is no specific protocol to order outpatient SCr levels 3-5 days after the procedure.

Other renal function markers

The use of SCr as a marker of renal function has its limitations. Indicators such as the eGFR and cystatin C are increasingly considered to be more reliable and accurate reflectors of existing renal function. [3, 4]

The eGFR can be calculated using the Modification of Diet in Renal Disease (MDRD) formula or the Cockroft-Gault formula. The Cockroft-Gault formula calculates eGFR using age, sex, and body weight, which are factors that, independent of GFR, influence SCr. The MDRD equation also includes blood urea nitrogen (BUN) and serum albumin.

The eGFR works best at low creatinine values. SCr and GFR share a curvilinear relationship. At lower SCr values, doubling SCr is associated with a corresponding 50% decrease in GFR. However, in elderly patients with chronic kidney disease (CKD) who have high SCr values at baseline, a 25% rise in SCr is actually indicative of a relatively modest reduction in GFR. Nonetheless, even a 25% increase in SCr in this situation has been shown to have great impact, especially in terms of inhospital and 1-year mortality. [5]

Serum cystatin C is a serum protein that is secreted by nucleated cells. It is freely filtered by the glomerulus and has been found to be an accurate marker of GFR. Compared with SCr, cystatin C changes much earlier after contrast administration and is not subject to confounding factors, such age, sex, and muscle mass, that influence SCr values independent of the underlying GFR. Cystatin C is increasingly being used as a marker of renal function in cardiac surgical patients.

Patient education

Patients with risk factors for CIN should be educated about the necessity of follow-up care with their physicians with a postprocedure SCr estimation, especially if the initial procedure was done on an outpatient basis.

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Etiology

Contrast media (CM) act on distinct anatomic sites within the kidney and exert adverse effects via multiple mechanisms. They cause a direct cytotoxic effect on the renal proximal tubular cells, enhance cellular damage by reactive oxygen species, and increase resistance to renal blood flow. They also exacerbate renal vasoconstriction, particularly in the deeper portions of the outer medulla. This is especially important in patients with CKD, because their preexisting abnormal vascular pathobiology is made worse by the effects of CM. [6, 7]

Renal (particularly medullary) microcirculation depends on a complex interplay of neural, hormonal, paracrine and autocrine influences. Of note are the vasodilator nitric oxide (NO) and the vasoconstrictors vasopressin, adenosine (when it acts via the high affinity A1 receptors), angiotensin II, and endothelins. Prostaglandins cause a redistribution of blood flow to the juxtamedullary cortex and, therefore, are protective.

NO, in particular, seems to be very important, with antiplatelet, vasodilatory, insulin sensitizing, anti-inflammatory, and antioxidant properties. It has been suggested that plasma levels of asymmetrical dimethylarginine (ADMA), which is an endogenous inhibitor of all NO synthase isoforms, can be used as a marker of CIN, especially in patients with unfavorable outcomes.

CM-mediated vasoconstriction is the result of a direct action of CM on vascular smooth muscle and from metabolites such as adenosine and endothelin. Additionally, the osmotic property of CM, especially in the tubular lumen, decreases water reabsorption, leading to a buildup of interstitial pressure. This, along with the increased salt and water load to the distal tubules, reduces GFR and causes local compression of the vasa recta. All of this contributes to worsening medullary hypoxemia and renal vasoconstriction in patients who are already volume depleted.

Finally, CM also increase resistance to blood flow by increasing blood viscosity and by decreasing red cell deformability. This intravascular sludging generates local ischemia and causes activation of reactive oxygen species that result in tubular damage at a cellular level.

Comparison of contrast-agent nephropathy potential

The ability of different classes of CM to cause CIN is influenced by their osmolality, ionicity (the ability of the contrast media to dissociate in water), and molecular structure. Each of these characteristics, in turn, influences their behavior in body fluid and their potential to cause adverse effects. (See Table 1, below.) [8]

Agents are classified as high, low, or iso-osmolar, depending on their osmolality in relation to blood. Low-osmolarity contrast media (LOCM) is actually a misnomer, since these agents have osmolalities of 600-900 mOsm/kg and so are 2-3 times more hyperosmolar than blood. High-osmolarity contrast media (HOCM) are 5-7 times more hyperosmolar than blood, with osmolalities greater than 1500 mOsm/kg.

Molecular structure of CM refers to the number of benzene rings. Most CM that were developed in the 1990s are dimers with 2 benzene rings. Dimeric CM, while nonionic and with low osmolarity, have high viscosity, which may influence renal tubular blood flow.

The ratio of iodine to dissolved particles describes an important relationship between opacification and osmotoxicity of the contrast agent. The higher ratios are more desirable. High-osmolar agents have a ratio of 1.5, low-osmolar agents have a ratio of 3, and iso-osmolar agents have the highest ratio, 6.

While the safety of LOCM over HOCM in terms of CIN seems intuitive, clinical evidence of it came from a meta-analysis by Barrett and Carlisle. [9] They showed the benefit of using LOCM over HOCM mostly in high-risk patients. The Iohexol Cooperative Study was a large, prospective, randomized, double-blinded, multicenter trial that compared the risk of developing CIN in patients receiving the low-osmolarity agent iohexol versus the high-osmolarity agent diatrizoate. While the HOCM group was 3.3 times more likely to develop CIN compared with the LOCM group, this was seen only in patients with preexisting CKD (baseline SCr greater than or equal to 1.5 mg/dL). In addition to CKD; diabetes mellitus, male sex, and contrast volume were found to be independent risk factors.

Even within the LOCM category, the risk is not the same for all agents. High-risk patients have a higher likelihood of developing CIN if they receive iohexol than if they receive another agent (ie, iopamidol) in the same class.

A comparison of two iso-osmolar LOCM (iohexol and iodixanol) in the Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media (NEPHRIC study), arguably the most definitive study in this category to date, found that the odds of developing CIN in high-risk patients were almost 9 times greater for the study's iohexol group than for the iodixanol group. The incidence of CIN was 3% in the iodixanol group versus 26% in the iohexol group. [10] However, these results were not duplicated in some subsequent studies.

When iodixanol was used, the Rapid Protocol for the Prevention of Contrast-Induced Renal Dysfunction (RAPPID) trial found a 21% incidence of CIN, [11] and the Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty (CONTRAST) trial found a 33% incidence of CIN. [12] Finally, the Renal Toxicity Evaluation and Comparison Between Visipaque (Iodixanol) and Hexabrix (Ioxaglate) in Patients With Renal Insufficiency Undergoing Coronary Angiography (RECOVER) trial compared the iso-osmolar contrast medium iodixanol to the low-osmolarity agent ioxaglate and found a significantly lower incidence of CIN with iodixanol than with ioxaglate (7.9% vs 17%, respectively). [13]

Thus, although the data are by no means uniform, they seem to suggest that the iso-osmolar contrast agent iodixanol may be associated with smaller increases in SCr and lower rates of CIN when compared with other LOCM, especially in patients with CKD and in those with CKD and diabetes mellitus. [14]

Risk factors

Risk factors for CIN can be divided into patient-related, procedure-related, and contrast-related factors (although the risk factors for CIN are still being identified and remain poorly understood). Patient-related risk factors are as follows:

  • Age
  • CKD
  • Diabetes mellitus
  • Hypertension
  • Metabolic syndrome
  • Anemia
  • Multiple myeloma
  • Hypoalbuminemia
  • Renal transplant
  • Hypovolemia and decreased effective circulating volumes - As evidenced by congestive heart failure (CHF), an ejection fraction (EF) of less than 40%, hypotension, and intra-aortic balloon counterpulsation (IABP) use

Procedure-related risk factors are as follows:

  • Urgent versus elective
  • Arterial versus venous
  • Diagnostic versus therapeutic

Contrast-related risk factors are as follows:

  • Volume of contrast
  • Contrast characteristics, including osmolarity, ionicity, molecular structure, and viscosity

The single most important patient-related risk factor is preexisting CKD, even more so than diabetes mellitus. [15] Patients with CKD in the setting of diabetes mellitus have a 4-fold increase in the risk of CIN compared with patients without diabetes mellitus or preexisting CKD.

Table: Physiochemical Properties of Contrast Media

Although the data are by no means uniform, they seem to suggest that the iso-osmolar contrast agent iodixanol may be associated with smaller increases in SCr and lower rates of CIN when compared with low-osmolar agents, especially in patients with CKD and in those with CKD and diabetes mellitus. [14] Guidelines from the American Heart Association (AHA)/American College of Cardiology (ACC) for the management of acute coronary syndromes patients with CKD recommend the use of IOCM (class I level of evidence).

Table 1. Physiochemical Properties of Contrast Media [16] (Open Table in a new window)

Class of Contrast Agent Type of Contrast Agent Iodine Dose



(mg/mL)



Iodine/Particle Ratio Viscosity



(cPs at 37°C)



Osmolality



(mOsm/kg H2 O)



Molecular Weight (Da)
High-osmolar monomers



(ionic)



Diatrizoate (Renografin)



Ioxithalamate (Telebrix)



370



350



1.5



1.5



2.3



2.5



1870



2130



636



643



Low-osmolar dimers



(ionic)



Ioxaglate (Hexabrix) 320 3 7.5 600 1270
Low-osmolar monomers



(nonionic)



Iohexol (Omnipaque)



Iopamidol (Isovue)



Iomeprol (Iomeron)



Ioversol (Optiray)



Iopromide (Ultravist)



Iopentol (Imagopaque)



350



370



400



350



370



350



3



3



3



3



3



3



10.4



9.4



12.6



9



10



12



780



790



620



790



770



810



821



777



778



807



791



835



Iso-osmolar dimers



(nonionic)



Iodixanol (Visipaque)



Iotrolan (Isovist)



320



320



6



6



11.8



8.5



290



290



1550



1620



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Epidemiology

Occurrence in the United States

CIN is the third leading cause of hospital-acquired acute kidney injury. Decreased renal perfusion and surgery (or in some studies, nephrotoxic medications) are the number one and number two causes, respectively.

An analysis of 15 prospective and retrospective studies from 1976-1996 report an incidence of CIN of 3.1-31%. The number varies depending on the definition used for CIN; the contrast agent characteristics, including the type, amount, duration, and route of administration; preexisting risk factors; and length of follow-up (including the day of measurement of postcontrast serum creatinine).

In patients without risk factors, the incidence may be as low as 2%. With the introduction of risk factors, like diabetes, the number rises to 9%, with incidences being as high as 90% in diabetics with CKD. Therefore, the number and the type of preexisting risk factors directly influence the incidence of renal insufficiency. It is also procedure dependant, with 14.5% overall in patients undergoing coronary interventions compared to 1.6-2.3% for diagnostic intervention, as reported in literature. [17]

Race- and age-related demographics

While African Americans with diabetic nephropathy have a faster acceleration of end-stage renal disease (ESRD), independent of other variables, race has not been found to be a risk factor for CIN.

The incidence of CIN in patients older than age 60 years has been variously reported as 8-16%. It has also been shown that in patients with acute MI who have undergone coronary intervention, an age of 75 years or older is an independent risk factor for CIN.

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Prognosis

CIN is normally a transient process, with renal function reverting to normal within 7-14 days of contrast administration. Less than one-third of patients develop some degree of residual renal impairment.

Dialysis is required in less than 1% of patients, with a slightly higher incidence in patients with underlying renal impairment (3.1%) and in those undergoing primary PCI for myocardial infarction (MI) (3%). However, in patients with diabetes and severe renal failure, the rate of dialysis can be as high as 12%.

Of the CIN patients who need dialysis, 18% end up requiring it permanently. However, many of these patients will have had advanced renal insufficiency and concomitant diabetic nephropathy and will have been destined for dialysis regardless of the episode of CIN.

A growing body of knowledge indicates that acute kidney injury after contrast medium can be a harbinger of CKD or ESRD. In one observational study, the population studied appeared representative of the general population undergoing angiography and the rate of acute kidney ingury was consonant with other studies. The finding that persistent kidney damage can occur after contrast-induced acute kidney injury highlights the potential for acceleration of the progression of kidney injury in individuals with pre-existing CKD. [18]

Mortality

Patients who require dialysis have a considerably worse mortality rate, with reported rates of 35.7% inhospital mortality (compared with 7.1% in the nondialysis group) and a 2-year survival rate of only 19%.

CIN by itself may be an independent mortality risk factor. Following invasive cardiology procedures, patients with normal baseline renal function who develop CIN have reduced survival compared with patients with baseline chronic CKD who do not develop CIN.

In one study of the effect of CIN on long-term mortality after percutaneous coronary intervention in patients with or without CKD, CIN was found to be significantly correlated with long-term mortality in the entire cohort (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.62 to 2.29, P < 0.0001) and in patients with CKD (HR 2.62, 95% CI 1.91 to 3.57, P <0.0001) but not in patients without CKD (HR 1.23, 95% CI 0.47 to 2.62, P = 0.6). The rate of CIN in patients with CKD was 11% and 2% in patients without CKD. [19]

Gadolinium-based agents

Gadolinium-based CM (used for magnetic resonance imaging [MRI]), when compared with iodine-based CM, have a similar, if not worse, adverse effect profile in patients with moderate CKD and eGFR of less than 30 mL/min. Their use has been implicated in the development of nephrogenic systemic fibrosis, a chronic debilitating condition with no cure.

A review of 3 series and 4 case reports suggested that the risk of renal insufficiency with gadolinium is similar to that of iodinated radiocontrast dye. The reported incidence varies from 4% in stage 3 CKD to 20% in stage 4 CKD. It may even be worse, as suggested by some investigators. A study of 57 patients found that acute renal failure was seen in 28% of patients in the gadolinium group, compared with 6.5% of patients in the iodinated CM group, despite prophylactic saline and N-acetylcysteine (NAC). [20]

The risk factor profile with gadolinium-based CM is similar to that for iodinated CM; the incidence of acute renal failure is higher in patients with any of the following:

  • Older age
  • Lower baseline creatinine clearance
  • Diabetic nephropathy
  • Anemia
  • Hypoalbuminemia

Risk stratification scoring systems

CIN is the result of a complex interplay of many of the above risk factors. The presence of 2 or more risk factors is additive, and the likelihood of CIN rises sharply as the number of risk factors increases. Researchers have tried to objectively quantify and predict the contribution of each risk factor to the ultimate outcome of CIN.

Risk stratification scoring systems have been devised to calculate an individual patient’s risk of developing CIN. This has mostly been done in patients undergoing percutaneous coronary intervention (PCI), especially those with preexisting risk factors. Mehran et al developed a scoring system based on points awarded to each of the following multivariate predictors [21] :

  • Hypotension = 5 points
  • Intra-aortic balloon pump (IABP) use = 5 points
  • CHF = 5 points
  • SCr of greater than 1.5 mg/dL = 4 points
  • Age greater than 75 years = 4 points
  • Anemia = 3 points
  • Diabetes mellitus = 3 points
  • Contrast volume = 1 point for each 100 mL used

Risk categories by total calculated score, CIN rates, and requirements for dialysis were as follows:

  • Low risk (score of ≤5): CIN rate 7.5%, dialysis in 0.04%
  • Moderate risk (score of 6-10): CIN rate 14%, dialysis in 0.12%
  • High risk (score of 11-15): CIN rate 26.1%, dialysis in 1.09%,
  • Very high risk (score of ≥16): CIN rate 57.3%, dialysis in 12.6%

Bartholomew et al worked to create another scoring system and took into consideration 8 variables, including creatinine clearance of less than 60 mL/min, IABP use, urgent coronary procedure, diabetes mellitus, CHF, hypertension, peripheral vascular disease (PVD), and volume of contrast used. [22]

Lin et al validated a simpler scoring system for predicting the risk of CIN in patients undergoing emergent percutaneous coronary intervention (PCI). [23] The system consists of the following risk factors, each of which is assigned 1 point:

  • Age >75 years
  • Baseline SCr >1.5 mg/dL
  • Hypotension
  • IABP use

Risk categories by scores and CIN incidence were as follows:

  • Low risk: 0 points; incidence 1.0%
  • Moderate risk: 1-2 points; incidence 13.4%
  • High risk: ≥3 points; incidence 90.0%
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