Contrast-Induced Nephropathy

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 chronic kidney disease (CKD), because their preexisting abnormal vascular pathobiology is made worse by the effects of CM. ^{[10, 11]}

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 increases resistance to blood flow by increasing blood viscosity and by decreasing red cell deformability. The resulting intravascular sludging generates local ischemia and causes activation of reactive oxygen species that cause 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. ^[12] See Table 1, below.

Table 1. Physiochemical Properties of Contrast Media ^[13] (Open Table in a new window)

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 that showed the benefit of using LOCM over HOCM, mostly in high-risk patients. ^[14] 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 of 1.5 mg/dL or higher). In addition to CKD, other independent risk factors were diabetes mellitus, male sex, and higher contrast volume.

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. ^[15] 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, ^[16] and the Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty (CONTRAST) trial found a 33% incidence of CIN. ^[17] 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). ^[18]

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. ^[19]  

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
• Kidney transplant
• Hypovolemia and decreased effective circulating volumes - As evidenced by chronic 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. ^[20] 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.

Occurrence in the United States

CIN is the third leading cause of hospital-acquired AKI. Decreased renal perfusion causing either prenal injury or acute tubular necrosis is the commonest cause ^[21] .

Despite numerous studies, the actual incidence of contrast induced nephropathy is not clear. The number varies, depending on the following:

• The definition used for CIN
• The contrast agent characteristics, including the type, amount, duration, and route of administration
• Preexisting risk factors
• 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%. In those with risk factors, such as diabetes, the rate rises to 9%, and to as high as 90% in patients with diabetic nephropathy. Therefore, the number and the type of preexisting risk factors directly influence the incidence of renal insufficiency. Incidence rates are also procedure dependent, with reports in the literature ranging from 1.6-2.3% for diagnostic interventions to 14.5% overall in patients undergoing coronary intervention. ^[22]

Although the risk for CIN with CT scans has been a long-standing concern, a retrospective study by Hinson et al of 17,934 emergency department visits from 2009 to 2014 found that IV contrast was not associated with an increased frequency of AKI. Whether patients underwent contrast-enhanced, unenhanced, or no CT, there were no significant differences in the incidence of AKI, dialysis, or mortality, regardless of baseline renal function. ^[7]

The main strengths of this study were the large number of patients and the use of two controls. However, this was a single-center study and it excluded patients with serum creatinine levels >4.0 mg/dL as well as those with renal transplants.

In another study, of 13,126 patients who underwent percutaneous vascular interventions, the incidence of CIN was noted to be 3%. Of the 400 patients who developed CIN, 26 (6.5%) required dialysis. ^[23]

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 60 years has been variously reported as 8%-16%. It has also been shown that in patients with acute myocardial infarction (MI) who undergo coronary intervention, age of 75 years or older is an independent risk factor for CIN.

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 percutaneous coronary intervention (PCI) for 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 have advanced renal insufficiency and concomitant diabetic nephropathy and would have progressed to needing dialysis regardless of the episode of CIN.

A growing body of knowledge indicates that AKI after contrast medium exposure can be a harbinger of CKD or ESRD. In one observational study that included 3986 patients who underwent coronary angiography, 12.1% of patients experienced contrast-induced AKI, and of those, 18.6% suffered persistent renal damage. ^[24] The population studied appeared representative of the general population undergoing angiography and the rate of AKI was consonant with other studies. The finding that persistent kidney damage can occur after contrast-induced AKI highlights the potential for acceleration of the progression of kidney injury in individuals with preexisting CKD.

Mortality

Patients who require dialysis have a considerably worse prognosis, with a reported rate 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. ^[25]

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, but may even be worse, as suggested by some investigators. In a study of 57 patients, 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). ^[26]

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 quantify 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 ^[27] :

• Hypotension = 5 points
• Intra-aortic balloon pump (IABP) use = 5 points
• CHF = 5 points
• SCr >1.5 mg/dL = 4 points
• Age >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 the following 8 variables ^[28] :

• Creatinine clearance < 60 mL/min
• IABP use
• Urgent coronary procedure
• Diabetes mellitus
• CHF
• Hypertension
• Peripheral vascular disease
• Volume of contrast used

Lin et al validated a simpler scoring system for predicting the risk of CIN in patients undergoing emergent percutaneous coronary intervention (PCI). ^[29] 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%