Contrast-Induced Acute Kidney Injury and the Role of Chronic Kidney Disease in Percutaneous Coronary Intervention

Introduction

Contrast-induced acute kidney injury (CI-AKI) is commonly defined as the occurrence of acute renal impairment within 48 to 72 hours after administration of iodinated contrast media (CM) in the absence of other causes for acute kidney injury (AKI). Although the advent of new generation contrast agents has resulted in a decreased incidence of CI-AKI, it remains a concern especially in patients undergoing cardiac catheterization. The increasing volume of percutaneous coronary intervention (PCI) procedures, particularly in the elderly, also contributes to an increased number of patients at risk for CI-AKI. However, risk factors for AKI in general are common and overlap with risk factors for CI-AKI, especially in the elderly. Therefore, differentiating true CI-AKI from AKI due to other causes is challenging, and recent reports suggest that the incidence of CI-AKI may have been overestimated. Data on the prevalence, risk factors, and risk assessment for CI-AKI in patients undergoing cardiovascular procedures including cardiac catheterization, PCI, and transcatheter aortic valve replacement (TAVR) are reviewed in this chapter. Furthermore, we will discuss the role of chronic kidney disease (CKD) as a condition that is rapidly increasing worldwide and is known to be one of the most important predictors of CI-AKI. Special considerations are described for patients on dialysis or who have undergone renal transplantation. Pharmacologic and nonpharmacologic strategies to prevent CI-AKI are discussed.

Definition of Contrast-Induced Acute Kidney Injury

Varying terminology to describe CI-AKI has been used throughout the literature (e.g., contrast-induced nephropathy [CIN], contrast nephropathy, contrast-associated AKI). Several definitions of CI-AKI have also been proposed. Most commonly, CI-AKI is defined as an absolute serum creatinine (sCr) increase of ≥0.5 mg/dL (44 μmol/L) or a ≥25% relative increase in sCr from baseline within 48 to 72 hours of CM exposure.

Because many risk factors, preventive measures, and the prognosis of contrast-induced deterioration of renal function are similar to other forms of AKI, the Kidney Disease Improving Global outcomes (KDIGO) working group proposed a standardized definition with graded criteria for all forms of AKI. The term CI-AKI was introduced to describe patients with AKI secondary to CM exposure. The following criteria were developed and refer to its mildest stage: an increase in sCr ≥0.3 mg/dL (≥26.5 μmol/L) within 48 hours; or an increase in sCr ≥1.5 times the baseline value within 7 days; or a urine volume less than 0.5 mL/kg/h for 6 hours. Of note, this definition reflects functional assessment and considers urine output, combining elements from definitions previously proposed by the Acute Kidney Injury Network (AKIN) and the Risk, Injury, Failure, Loss, and End-stage (RIFLE) criteria defined by the Acute Dialysis Quality Initiative (ADQI). The severity of AKI is staged by the increase of sCr, reduction in urine output, and the need for renal replacement therapy ( Fig. 6.1 ). Importantly, these criteria do not specify a time frame for the deterioration of kidney function after CM exposure. Most CI-AKI cases occur early after CM exposure but in a minority of patients the peak increase of sCr may occur as many as 5 days after the application of CM. The 2012 KDIGO practice guidelines strongly recommend to first rule out causes other than CM (e.g., drug toxicity, compromised hemodynamics) in patients who develop deterioration in kidney function after administration of CM. The American College of Radiology Manual on Contrast Media uses an alternative approach and differentiates between post-contrast AKI (PC-AKI) and CIN. PC-AKI may be due to any nephrotoxic cause including contrast application, whereas CIN is defined as a sudden deterioration in renal function that is specifically caused by the intravascular administration of iodinated CM. Hence, CIN or CI-AKI, respectively, are considered sub-entities of PC-AKI.

Pathophysiology

The pathophysiology of CI-AKI is complex, and the underlying mechanisms are not yet fully understood. Animal or laboratory studies suggest that CM is directly nephrotoxic to the tubular epithelium causing redistribution of membrane proteins, reduction of extracellular Ca ²⁺ , DNA fragmentation, disruption of intercellular junctions, reduced cell proliferation, apoptosis, and altered mitochondrial function. CM administration also indirectly promotes renal ischemic injury secondary to an imbalance between vasodilatory and vasoconstrictive mediators resulting in a decline in regional blood flow. These effects, together with reactive oxygen species (ROS) formation, result in oxidative damage and cellular injury. The hemodynamic effects of CM are greatest in the renal medulla, which is characterized by generally low blood flow to preserve osmotic gradients and enhance urinary concentration. CKD plays a central role in the pathophysiology of CI-AKI because it is associated with fewer functional nephrons, which may increase the susceptibility for CM-induced toxicity.

Epidemiology and Risk Factors for Contrast-Induced Acute Kidney Injury

The incidence of CI-AKI is highly dependent on the patient population studied and the diagnostic criteria used. Therefore, reported rates of CI-AKI among patients undergoing PCI vary significantly and range between less than 3% in patients with normal kidney function and up to 40% in patients with CKD. Overall, the development of low-osmolar (mostly nonionic) iodinated contrast agents has resulted in a decrease of CI-AKI. Compared to earlier generation high-osmolar ionic CM, the newer agents are associated with reduced rates of CI-AKI and a decreased risk of other adverse effects.

The volume of CM administered has also been shown to impact the risk of CI-AKI. High volumes of CM (>350 mL or >4 mL/kg) or previous administration of CM within 72 hours significantly increases the risk of CI-AKI. However, even lower CM volumes (<100 mL) can place vulnerable patients at risk. In this context, a CM volume to creatinine clearance ratio of greater than 3.7 is a significant and independent predictor of an early abnormal increase in sCr after PCI.

The risk associated with CM is further confounded by other factors including concomitant medications, patient characteristics, and procedural details. Table 6.1 provides a summary of medications with a potential impact on the risk for CI-AKI. While some drugs may increase the risk of CI-AKI due to their influence on renal hemodynamics (e.g., nonsteroidal antiinflammatory drugs and angiotensin-converting enzyme inhibitors), others may cause direct tubular toxicity (e.g., diuretics and certain antibiotics).

Among patient-related factors, baseline renal function is the most powerful predictor of CI-AKI. An analysis of 985,737 patients undergoing PCI from the National Cardiovascular Data Registry (NCDR) demonstrated that the risk of CI-AKI increased with declining baseline estimated glomerular filtration rate (eGFR). Tsai et al. reported a 7.8% incidence of CI-AKI in patients with an eGFR ≥60 mL/min/1.73 m ² , 13.6% in patients with an eGFR of 45 to 60 mL/min/1.73 m ² , 23.1% in patients with an eGFR of 30 to 45 mL/min/1.73 m ² , and 36.9% in patients with an eGFR less than 30 mL/min/1.73 m ² . Other patient-related risk factors that influence the risk of CI-AKI include age, diabetes, and anemia.

Diagnostic cardiac catheterization and PCI, respectively, are the leading procedural causes of CI-AKI. Patients receiving primary PCI for acute myocardial infarction (MI), especially in the setting of hemodynamic instability, are at the highest risk, followed by patients undergoing elective PCI and diagnostic cardiac catheterization. These differences in risk may be attributed to insufficient time for preventive measures in MI patients undergoing urgent PCI, or the higher contrast load used for coronary interventions compared to diagnostic procedures. Patients presenting in an acute clinical setting may also have a higher risk profile compared to patients undergoing a diagnostic study. In patients with acute MI and hypotension or cardiogenic shock, hypoperfusion of the kidneys may directly lead to renal hypoxia and AKI, or it may increase the susceptibility for CI-AKI. Overall, these findings underscore the complex and multifactorial etiology of CI-AKI and the challenge of identifying true CI-AKI.

Other forms of AKI after PCI may be misinterpreted as CI-AKI. Catheter manipulation may result in the release of atheroemboli from the aorta into the renal circulation, leading to AKI. Authors of the recently published Acute Kidney Injury After Radial or Femoral Access for Invasive Acute Coronary Syndrome Management (AKI-MATRIX) trial hypothesized that a reduction of atheroemboli to the renal circulation may have been one of the contributing factors that led to the reduction of AKI associated with radial compared to femoral access. The lower rate of AKI after PCI associated with a radial versus femoral approach was recently confirmed by data from a retrospective single-center cohort study of 2937 patients.

Predicting the Risk of Contrast-Induced Acute Kidney Injury