Radiocontrast was first described to cause nephrotoxicity in the 1960s.^1,2 Contrast-induced nephropathy (CIN), now termed contrast-induced acute kidney injury (CI-AKI), is likely to increase in frequency over the next 10 to 15 years. This rise is largely due to increasing use of radiocontrast studies in patients who are older, sicker, or have attendant comorbidities such as diabetes mellitus, renal failure, cardiac failure, and volume depletion.³ CI-AKI is currently described as the third most common cause of hospital acquired renal failure, accounting for approximately 11% of cases.⁴ The incidence of CI-AKI reported in the literature has ranged between 1% and 45%, largely depending on the comorbidities of the study population, the clinical scenario in which the contrast is given, and the parameters used to define CI-AKI.⁵ With more than a million radiocontrast procedures performed annually in the United States, the incidence of CI-AKI is approximately 150,000 cases per year. At least 1% of these episodes require dialysis therapy (in half of patients, it will be permanent) with prolongation of hospital stay to an average of 17 days, with an additional cost of approximately $32 million annually. For episodes that do not require dialysis, the average prolongation of the hospital stay is 2 days (at $500 per day), and this translates to an added cost of $148 million annually.^6,7 The incidence and costs are higher in critically ill patients, who have associated comorbidities such as hypotension, hypovolemia, diabetes, and congestive heart failure.

This chapter will first examine the important renal complications of contrast media. This will be followed by an evaluation of laboratory investigations that provide insights into the pathogenesis of this disorder. The last section deals with 2 important clinical issues: (1) the use of low-osmolality radiocontrast agents specifically to reduce the incidence of CI-AKI and (2) adjunctive methods currently used to prevent the development of CI-AKI.

The obesity pandemic is a central driver of the dysmetabolic syndrome, hypertension, and diabetes. It is thus anticipated that there will soon occur a secondary epidemic of combined chronic kidney disease (CKD) and cardiovascular disease (CVD).⁸ Among patients with diabetes for 25 years or more, the prevalence of diabetic nephropathy in type 1 and type 2 diabetes is 57% and 48%, respectively. Approximately half of all cases of end-stage renal disease (ESRD) are due to diabetic nephropathy, with most of these cases driven by obesity-related type 2 diabetes and hypertension.⁹ With the graying of America and cardiovascular care shifting toward the elderly, the imperative thus exists to understand the relationship between decreasing levels of renal function as a major adverse prognostic factor in cardiac patients. AKI after contrast exposure as the most proximal renal event is predictable and highlights an opportunity for preventive measures outlined later in this chapter.

The overall prevalence of CI-AKI, defined as a transient rise in serum creatinine (Cr) ≥0.3 mg/dL above the baseline, occurs in approximately 7% of patients undergoing percutaneous coronary intervention (PCI) (Fig. 19-1).¹⁰ Fortunately, rates of CI-AKI leading to dialysis are quite low (0.5%-2.0%). However, the occurrence of CI-AKI is associated with catastrophic outcomes, including a 36% in-hospital mortality rate and a 2-year survival of only 19%.¹⁰ Transient rises in Cr are directly related to longer intensive care unit and hospital ward stays (3 and 4 additional days, respectively) after cardiac bypass surgery.¹¹ Recently, it has been shown that even transient elevations in Cr translate to differences in adjusted long-term outcomes including mortality, ESRD, and all-cause hospitalization after diagnostic catheterization or PCI (Fig. 19-2).^12,13 In addition to a heavy degree of confounding by older age, diabetes, and other factors, a secondary explanation is that when renal function declines, the associated abnormal vascular pathobiology accelerates, and hence, the progression of other diseases, including CVD, accelerates.

The limitations of our understanding of the epidemiology of CI-AKI should be emphasized. The literature has been impacted by inconsistent definitions of AKI based on temporal changes in the serum Cr level. This variation makes comparison of different populations and studies challenging. Earlier studies, including some that established risk prediction models for AKI in the context of cardiac procedures, used an increase in serum Cr of >0.5 mg/dL or a relative 1.5- to 3-fold increase (coupled with assessment of urine output) as the definition of CI-AKI. These criteria established in 2004 by the Acute Dialysis Quality Initiative are referred to as the RIFLE criteria (risk, injury, failure, loss, ESRD).¹⁴ The RIFLE definition correlates with progression to CKD and mortality. In 2007, these definitions were further modified by the Acute Kidney Injury Network (AKIN).^15,16 The AKIN criteria included a more sensitive definition of acute Cr change, using a relative increase of >0.3 mg/dL. Although this latter definition may identify more cases of AKI, the differential impact on outcome prediction versus the RIFLE criteria remains modest at best. Lastly, the Kidney Disease Improving Global Outcomes (KDIGO) criteria combined elements of both RIFLE and AKIN but kept the 0.3 mg/dL cutoff for AKI.¹⁷

More problematic for the study of CI-AKI is the reliance on the serum Cr as the biomarker of renal damage. Increases in serum Cr, regardless of the definitions used, require serial measures and are temporally delayed from the acute injury. Serum Cr also provides no information as to the anatomic location or mechanism of injury. In this regard, novel biomarkers of glomerular and tubular injury offer promise as more sensitive and specific measures of AKI. Most relevant in the context of contrast administration are serum cystatin C, which provides a sensitive approximation of glomerular function, and urinary tubular markers such as neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (LFABP), and kidney injury molecule-1 (KIM-1). Beyond the scope of this discussion are additional numerous molecules and signaling markers that are actively being investigated as alternatives to the serum Cr for the detection of CI-AKI.¹⁸

Mild, transient decreases in glomerular filtration rate (GFR) occur after contrast administration in almost all patients and are usually subclinical.¹⁹ There is a brief increase in renal blood flow followed by prolonged vasoconstriction within the kidneys after contrast exposure. The development of clinically significant CI-AKI can be predicted based on the presence or absence of specific risk factors (Table 19-1). A multivariable analysis of prospective trials has shown that baseline renal impairment, diabetes mellitus, congestive heart failure, and higher doses of contrast media increase the risk of CI-AKI.^20,21 Other risk factors include reduced effective arterial volume (eg, due to dehydration, nephrosis, cirrhosis) or concurrent use of potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory agents and aminoglycosides. Multiple myeloma has been suggested as a potential risk factor for CI-AKI, but a large retrospective study failed to demonstrate an increased risk in these patients.²² Of all these risk factors, preexisting renal impairment appears to be the single most important; patients with diabetes mellitus and renal impairment, however, have a substantially higher risk of CI-AKI than patients with renal impairment alone.^23,24

A growing population of individuals at risk for CI-AKI are those with symptomatic peripheral arterial disease (PAD). PAD impacts 8 to 12 million Americans and is a rising epidemic, driven by the aging of the population and increasing rates of diabetes. Management of symptomatic PAD, spanning the spectrum from claudication to critical limb ischemia, has evolved in the past decade to an endovascular first approach. Within the context of peripheral angiography, the specific risk factors for CI-AKI remain poorly defined. Extrapolating from the coronary experience, concerns related to total contrast volume, atheroembolism, and volume status remain key components of risk assessment and prevention. Pooled data would suggest the incidence of CI-AKI is approximately 10% to 15%.²⁵

The vast majority of patients who develop CI-AKI are asymptomatic, contributing to the lack of universal awareness of this complication. CI-AKI manifests usually as a decrease in GFR without hematuria and is typically nonoliguric. Nonoliguric AKI is generally more common in patients initially having a lower serum Cr prior to receiving contrast. In oliguric AKI, the time course of the oliguria and the rise in serum Cr depend on the preprocedure baseline serum Cr. Patients with normal renal function or mild renal functional impairment prior to receiving radiocontrast agents usually have oliguria lasting 2 to 5 days, with recovery to baseline renal function by day 7. Dialysis is infrequently required.^24,26 Some degree of residual renal impairment has been reported in as many as 30% of those affected by CI-AKI.²⁴ Other comorbidities such as sustained hypotension, hypovolemia, atheroembolism, and the concurrent use of nephrotoxic medications can also contribute to CI-AKI after coronary angiography and intervention. The occurrence of CI-AKI usually prolongs the hospital stay.²⁷ Finally, mortality is increased in patients who develop CI-AKI. In a retrospective study, Levy et al²⁸ compared the outcomes of hospitalized patients with CI-AKI to a control group of patients matched for age, baseline serum Cr, and type of diagnostic procedure who did not develop CI-AKI. The mortality in the CI-AKI group was 34% compared with 7% in the control group (P < .001; odds ratio, 5.5), even after controlling for baseline factors and in-hospital comorbidities.²⁸

The antidiabetic agent metformin may lead to the development of lactic acidosis in the setting of CI-AKI. This complication is rare and occurs only if the contrast administration results in significant renal failure and the patient continues to take metformin. In a recent review of this subject, no conclusive evidence was found to indicate that the use of contrast precipitated metformin-induced lactic acidosis in patients with serum Cr <1.5 mg/dL or 130 μmol/L at baseline. The complication was almost always observed in non–insulin-dependent diabetic patients with decreased renal function before injection of contrast media. Thus, while there is no justification to discontinue metformin before the day of the contrast-requiring procedure, it is recommended that patients not take this drug for 48 hours or so after contrast administration and resume taking the drug only if there are no signs of nephrotoxicity. This is especially true for patients in high-risk subgroups, described earlier.²⁹

CI-AKI usually develops within 24 to 72 hours following a radiocontrast study. In 2012, the KDIGO guidelines defined CI-AKI as a rise in serum Cr of ≥0.3 mg/dL within 48 hours of contrast exposure or a rise in serum Cr ≥1.5 times the baseline within a week of exposure or urine volume <0.5 mL/kg/h for a 6-hour period after contrast administration.²⁹ Because the urine output is commonly influenced by intravenous fluids and diuretics, most patients are diagnosed with CI-AKI based on the serum Cr. One interesting feature of oliguric CI-AKI is the presence of a low fractional excretion of sodium during the initial stages, despite the absence of clinical evidence of volume depletion.³⁰ The urinalysis microscopic exam demonstrates renal tubular epithelial cell casts or coarsely granular brown casts, but may occasionally be negative. Even in the absence of a rise in serum Cr, radiocontrast agents may still alter the urinary sediment, showing epithelial cells, epithelial cell casts, granular or muddy brown coarsely granular casts, and occasional crystals. Hence, routine urinalysis is not particularly specific and is not recommended after contrast procedures.^31,32 A persistent nephrogram 24 to 48 hours after the contrast study has been reported to be a sensitive indicator of the presence of renal failure (83% of patients with renal failure had a positive nephrogram) with high specificity (93% of patients without renal failure lacked the persistent nephrogram).³³ The persistent nephrogram has been related to an abnormal and persistent intrarenal vasoconstriction after contrast exposure.^33-35

There are 3 core elements that are intertwined in the pathophysiology of CI-AKI: (1) direct toxicity of iodinated contrast to nephrons; (2) micro-showers of atheroemboli to the kidneys; and (3) contrast- and atheroemboli-induced intrarenal vasoconstriction.³⁴ Direct toxicity to nephrons with iodinated contrast has been demonstrated and appears to be related to the osmolality of the contrast.³⁵ Hence, low ionic or nonionic and low-osmolar or iso-osmolar contrast agents have been shown to be less nephrotoxic in vitro. Micro-showers of cholesterol emboli are thought to occur in up to 50% of percutaneous interventions where a guiding catheter is passed through the aorta.³⁶ Most of these showers are clinically silent. However, in approximately 1% of high-risk cases, an acute cholesterol emboli syndrome can develop manifested by AKI, mesenteric ischemia, decreased microcirculation to the extremities, and in some cases, embolic stroke. Because AKI occurs after coronary artery bypass surgery with nearly the same risk predictors as in patients undergoing contrast procedures, it is thought that atheroembolism may be a common pathogenic feature of both causes of renal failure.³⁶ Finally, intrarenal vasoconstriction as a pathologic vascular response to contrast media and (perhaps) to cholesterol emboli is a third mechanism leading to hypoxic/ischemic injury to the kidney.³⁷ Hypoxia triggers activation of the renal sympathetic nervous system and results in a reduction in renal blood flow, especially in the outer medulla (Fig. 19-3).^37,38 It is important to note that animal studies do not demonstrate agreement regarding the direct vasoconstrictive and/or vasodilatory effects of contrast on the kidney.^39,40 In humans with vascular disease, endothelial dysfunction, and glomerular injury, it is believed that contrast and the multifactorial insult of renal hypoxia provokes a vasoconstrictive response and, hence, mediates in part an ischemic injury. The most important predictor of CI-AKI is underlying renal dysfunction. The “remnant nephron” theory postulates that after sufficient chronic kidney damage has occurred and the estimated GFR (eGFR) is reduced to <60 mL/min/1.73 m², the remaining nephrons must pick up the remaining filtration load, have increased oxygen demands, and are thus more susceptible to ischemic and oxidative injury.

It is important to distinguish CI-AKI from cholesterol emboli syndrome (CES) or atheroembolic renal disease. The incidence of CES following coronary angiography has been reported to be 1.4% in a recent study.⁴¹ Scolari et al⁴² retrospectively reported that 15 of 16,223 vascular procedures were complicated with CES, which had an incidence of 0.09%. In contrast, an autopsy study reported that the overall prevalence of CES was 25% to 30% of patients after cardiac catheterization.⁴³ Ramirez et al⁴⁴ noted cholesterol emboli at autopsy in 30% of patients who died within 6 months after undergoing aortography and 25.5% of patients who died within 6 months after undergoing coronary angiography. In contrast, the incidence of cholesterol embolism was 4.3% in age-matched controls who had not undergone a previous invasive vascular procedure. The cholesterol emboli in the control group may have resulted from spontaneous erosion of atheromatous plaques or from previous anticoagulant or thrombolytic therapy.⁴⁴

In patients with CES occurring after angiographic and vascular surgical procedures, the interval from the inciting event to the onset of renal symptoms may vary greatly. Some patients have immediate clinical features, but in others, the onset can be more insidious, with a delay of weeks or months between the precipitating event and clinical features. In 17 patients who developed atheroembolization after an arteriographic procedure, Frock et al⁴⁵ found the mean interval between the inciting event and diagnosis of atheroembolic renal disease to be 5.3 weeks. Contrast media–associated nephrotoxicity immediately follows the radiographic study. There is an increase in Cr level a few days after the procedure (usually within 72 hours); peak Cr level elevation occurs approximately 1 week after exposure and returns to baseline within 10 to 14 days.⁴⁶ Conversely, atheroembolic renal damage frequently has a delayed onset (days to weeks) and a protracted course; the outcome is often poor, resulting in progressive renal failure requiring dialysis. When a fulminant disease develops rapidly after angiography, the concomitant cutaneous, neurologic, and gastrointestinal complications usually accompany renal atheroembolic disease.^47-49 The recent development of transcatheter aortic valve replacement, which is performed in patients with high levels of comorbidities including CKD, has brought interest to the combination of embolic and chemotoxic injury with this procedure. During predilation of the aortic valve or balloon aortic valvuloplasty, it is possible that showers of cholesterol, calcium hydroxyapatite, and fibrotic material are received into the renal arterial bed. This, in addition to higher contrast volumes than in diagnostic angiography or PCI, is believed to be part of the explanation for the high rates of more severe cases of CI-AKI. A systematic review found 13 studies with more than 1900 patients reporting rates of CI-AKI defined by the Valve Academic Research Consortium (VARC) criteria, which correspond to the KDIGO definition presented previously, that ranged from 8.3% to 57% of the patients.⁵⁰ The following factors were associated with CI-AKI: blood transfusion; transapical access; higher preoperative Cr concentration; peripheral vascular disease; hypertension; and procedural bleeding events. Not unexpectedly, the 30-day mortality rate in patients with CI-AKI ranged from 13.3% to 44.4% and was 2-6-fold higher than in patients without CI-AKI. Interestingly, the amount of contrast agent used (typically >200 mL) was not associated with the occurrence of CI-AKI in most, but not all, studies.

Renal protection for CKD patients at risk (eGFR <60 mL/min/1.73 m²) can be thought of in 3 separate spheres: (1) long-term cardiorenal protection, (2) removal of renal toxins, and (3) prevention measures carried out before contrast exposure. Long-term cardiorenal protection involves 2 important concepts. The first concept is blood pressure control in CKD to a target of approximately 125/75 mm Hg.¹² The second concept is to use an agent that blocks the renin-angiotensin system, such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), but not both used together. Of note, either agent will cause a chronic rise in Cr >25% above the baseline in approximately 10% of cardiovascular patients.⁵¹ Even with an increase in Cr, the benefits of ACEI/ARB agents with respect to a reduction in new cases of ESRD, CHF, or cardiovascular death appear compelling.^52-58 It has been sufficiently shown that these benefits extend to nondiabetics and to African Americans with CKD.^57,58

Removal of toxins largely refers to the discontinuation of nonsteroidal anti-inflammatory agents, aminoglycosides, and cyclosporin. These agents all complicate contrast procedures and increase the risk of CI-AKI. Prevention measures done prior to contrast exposure include volume expansion, approaches to reduce the direct cellular toxicity of the contrast, and measures to reduce the intrarenal vasoconstriction, which occurs uniquely in CKD patients when exposed to iodinated contrast.⁵⁹