Contrast-induced acute kidney injury following PCI


Correspondence to: Dr Derek J. Hausenloy, The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK. Tel.: +44 20 3447 9894; fax: +44 20 3447 9505; e-mail:



Coronary revascularization using percutaneous coronary intervention (PCI) is one of the major treatments for patients with stable coronary artery disease, with approximately 1.5 million patients undergoing PCI in the United States and Europe every year. An important neglected complication of PCI is contrast-induced acute kidney injury (CI-AKI).


In this article, we review the definition, pathogenesis and management of CI-AKI and highlight potential therapeutic options for preventing CI-AKI in post-PCI patients.


CI-AKI is an important but underdiagnosed complication of PCI that is associated with increased in-hospital morbidity and mortality. Patients with pre-existing renal impairment and diabetes are particularly susceptible to this complication post-PCI. Optimization of the patients' circulating volume remains the mainstay for preventing CI-AKI, although the best strategy for achieving this is still controversial.


Following PCI, CI-AKI is an overlooked complication which is associated with significant morbidity and mortality. In this article, we review the pathophysiology of CI-AKI in patients undergoing PCI and discuss the potential therapeutic options for preventing it.


Coronary heart disease is one of the leading causes of death worldwide and remains a substantial contributor to morbidity, mortality and healthcare expenditure. The treatment of choice for many patients with stable coronary artery disease (CAD) is revascularization using percutaneous coronary intervention (PCI). Advances in PCI technology have resulted in increasing numbers of patients undergoing coronary revascularization via this approach. In Europe, 1·5 million people had PCI in 2010, and it is estimated that 1·5 million patients undergo PCI in the United States every year [1]. Complications related to the PCI procedure are still common and impact significantly on patient outcomes, even after successful revascularization. PCI is increasingly undertaken in patients with multiple comorbidities or in the context of acute illness or circulatory instability, and these factors have increased the risk of adverse events post-PCI.

Contrast-induced acute kidney injury (CI-AKI) is a prevalent but underdiagnosed complication of PCI that is associated with increased in-hospital morbidity and mortality [2-5]. The importance of this complication is being increasingly recognized. Several recent North American and European epidemiological studies have shown that the incidence of acute kidney injury (AKI) is increasing at an alarming rate [6]. Contrast-induced acute kidney injury (CI-AKI) has been reported to be the third most common cause of hospital-acquired renal failure [7, 8]. The incidence of acute renal insufficiency after PCI ranges from 2·0% in those patients with normal baseline renal function to as high as 20–30% in those patients with a baseline creatinine > 176 μM (or 2·0 mg/dL) prior to PCI [5, 9]. Nash et al. [7] reported that 11% of hospital-acquired renal insufficiency cases are due to contrast media, with coronary angiograms and PCI being the leading cause. The incidence of acute renal failure requiring dialysis following PCI, however, is fortunately rare and is < 1% [10].

Patients with pre-existing renal insufficiency, diabetes mellitus, congestive cardiac failure or advanced age are particularly susceptible to developing CI-AKI post-PCI. Baseline renal dysfunction is indeed the greatest risk factor with dehydration potentiating the risk [11]. In these high-risk patients, the incidence of CI-AKI has been estimated to range from 20 to 50% depending on the study and criteria used to diagnose AKI [12-14]. Even a mildly increased serum creatinine post-PCI is a predictor of worse clinical outcome. A serum creatinine level of only 115 μM (or 1·3 mg/dL), which in most patients indicates a reduction in renal function of about 50%, is associated with a twofold increase in total mortality and a 10% reduction in cumulative survival over 3 years [15]. There is increasing recognition that CI-AKI can have serious short-term and long-term consequences such as in-hospital death, long-term mortality, progression of chronic kidney disease and increased healthcare expenditure [5, 9, 16-20].

Definition of CI-AKI

CI-AKI is an impairment of renal function resulting from the administration of contrast media (CM) in the absence of an alternative aetiology [21]. CI-AKI is defined as either an absolute increase in serum creatinine (Cr) concentration of 44·2 μM (or 0·5 mg/dL) or a 25% relative increase in Cr from baseline [22, 23]. Recently, the Contrast-Induced Nephropathy Consensus Panel has recommended using a relative increase in Cr to define CI-AKI [24].

CI-AKI typically manifests within 3 days of contrast media administration, peaks within 3–5 days and resolves within 10–21 days [25]. In some instances, sustained or permanent renal injury occurs resulting in some cases with dialysis. To monitor for CI-AKI, it is recommended that serum creatinine measurements be continued for more than 48 h after exposure to contrast media [26, 27].

The effect of contrast osmolality

Currently, none of the available contrast medias are without risk in terms of cell toxicity and nephrotoxicity [28, 29]. The cytotoxicity of CM may depend on the presence of iodine, which is known to be toxic to human cells and bacteria [30].

Contrast nephrotoxicity and the risk of developing CI-AKI are related to the osmolality of the contrast media. This reflects the total particle concentration of the solution (the number of molecules dissolved in a specific volume) [31]. The osmolality of a particular CM appears to correlate with the iodine toxicity at a given concentration. It is widely accepted that contrasts with a high osmolality are associated with the greatest risk of developing CI-AKI. As a consequence, the osmolality of available contrast media has been gradually decreasing to physiological levels over the last 40 years. In the 1950s, only high-osmolar contrast media (e.g. diatrizoate) with osmolality five to eight times that of plasma were available. In the 1990s, isosmolar contrast media (e.g. iodixanol) were developed and are now widely in use [32].

Pathophysiology of CI-AKI

The pathophysiology of CI-AKI is still ill-defined and poorly understood. Implicated mechanisms include changes in the renal circulation leading to ischaemic and hypoxic damage to the renal medulla and the production of oxygen free radicals inducing tubular epithelial damage [33]. Hemodynamic instability with reduced effective arterial volume during the procedure, microemboli to the kidney and concomitant drug toxicity are other important factors that may be responsible for CI-AKI following PCI [34].

Renal medullary hypoxia is pivotal to the pathophysiology of CI-AKI [35-37]. The medulla, especially its outer part, is vulnerable to hypoxia due to high requirement of oxygen in Henle's thick ascending limb where sodium is reabsorbed [30].

Experimental findings indicate that contrast media in the medulla affect the balance between oxygen delivery and oxygen consumption [30]. Administration of contrast media rapidly induces a renal vasoconstrictive response and subsequent reduced blood perfusion. This has been ascribed to a number of different mediators, such as the renin–angiotensin system, changes in the intracellular calcium concentration of smooth muscle cells, adenosine and endothelin [38, 39]. In addition to the effect on renal perfusion, direct toxic effects of contrast media on tubular epithelium have also been described [40]. Increased natriuresis, secondary to either tubular damage or the intrinsic osmotic activity of these agents, may occur [41]. The attendant increases in osmotic load and viscosity associated with high osmolarity contrast may also increase hypoxia in the renal medulla [42]. Furthermore, low- and iso-osmolar contrast media have a higher viscosity, a physical property that may also play a role in the pathogenesis of CI-AKI.

Risk factors for developing CI-AKI post-PCI

Pre-existing chronic kidney disease (CKD) is the most important risk factor for developing CI-AKI post-PCI. CKD also predisposes to coronary artery disease and its complications such as microembolization during PCI [43]. Diabetes mellitus has been identified as another important risk factor. In patients with diabetes mellitus and CKD, the incidence of CI-AKI increases an additional twofold and can reach as much as 33% [12, 44]. There is no definitive evidence that CI-AKI correlates with the duration of diabetes or suboptimal glycaemic control, but tight glycaemic control should be achieved before contrast media exposure [45, 46].

The incidence of CI-AKI is also significantly higher in patients with several other comorbidities, including congestive heart failure, hypotension, hypertension, preprocedure shock, recent myocardial infarction (MI) and female gender (see Table 1) [47, 48]. Advanced age has emerged as a potential risk factor in CI-AKI. The apparently increased prevalence of CI-AKI in elderly patients is likely to be multifactorial in origin and may be attributable to the presence of large or small vessel renal atherosclerosis, underestimation of background CKD in this group, impaired cardiovascular performance (and hence renal oxygen delivery) and reduced regenerative capacity of the renal parenchyma in the face of acute injury. There remain, however, some controversy regarding the role of advanced age in CI-AKI and some claim that this is not an independent risk factor [5, 45].

Table 1. Predisposing factors for CI-AKI
Pre-existing renal failure
Acute myocardial infarction
Diabetes mellitus
Congestive cardiac failure
Female gender
Concomitant medication such as NSAIDs
Contrast media dose

The incidence of CI-AKI may also be increased by concomitant use of nephrotoxic agents such as nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors, which are used in more than 60% of patients referred for imaging procedures [49]. These drugs reduce renal circulatory adaptive responses. Other agents including amphotericin, cyclosporine-A, FK-506, anaesthetics and diuretics may increase the likelihood of developing CI-AKI [49-51].

The risk of CI-AKI increases if the PCI is undertaken in the context of reduced effective circulatory volume. This may be due to hypovolaemia (including overdiuresis), liver failure or cardiac failure. Sepsis, hypercalcaemia and rhabdomyolysis are further risk factors for developing CI-AKI [38].

The risk of CI-AKI is significantly higher among patients with acute MI undergoing PCI than among stable CHD patients undergoing elective PCI [52]. The most likely contributing factors for CI-AKI in this context are impaired systemic perfusion caused by left ventricular dysfunction, the need for the administration of large volumes of contrast medium and the lack of sufficient time to perform renal prophylactic therapies prior to contrast medium exposure.

The diagnosis of CI-AKI

Currently, the diagnosis of CI-AKI is dependent on determining the changes in serum Cr. However, in CI-AKI, serum Cr values do not rise immediately after the contrast insult. Such rises are dependent not only on a GFR reduction, which may be immediate, but also on the systemic accumulation of Cr produced by skeletal muscle. An estimated GFR is commonly derived from serum Cr measurements to determine whether CKD is present, and of what severity, but is unhelpful in assessing an acute decline in GFR unless the Cr is in steady state. Although there are clear limitations in the effectiveness of using serum Cr for the rapid detection of contrast-mediated renal injury, rises in serum Cr in hospitalized patients have been strongly associated with outcomes, including length of stay, mortality and healthcare expenditure. There is, however, growing interest in the use of more novel biomarkers that might provide a more rapid diagnosis of CI-AKI, particularly if their use might influence pre-emptive measures or subsequent monitoring.

The syndrome of AKI, formerly known as acute renal failure, has previously lacked a clear definition or a system of stratifying severity. The RIFLE (Risk, Injury, Failure, Loss and End-Stage Kidney Disease) [53] and AKIN (Acute Kidney Injury Network) [54]. AKI classification systems have sought to remedy this through the introduction of diagnostic criteria and severity staging for AKI. More recently, the KDIGO (Kidney Disease Improving Global Outcomes) consortium published a further adaption of these systems, which seeks to harmonize AKI diagnostic criteria and reach international consensus (see Table 2) [55].

Table 2. Staging of AKI [55]
StageSerum creatinineUrine output
1A rise of > 26·5 μM OR 1·50–2 times baseline< 0·5 mL/kg/h for 6–12 h
2A rise of 2·0–2·9 times baseline< 0·5 mL/kg/h for ≥ 12 h
33·0 times baseline OR creatinine > 353·6 μM OR Initiation of renal replacement therapy OR In patients < 18 years, decrease in eGFR to < 35 mL/min per 1·73 m2<0·3 mL/kg/h for ≥ 24 h OR Anuria for ≥ 12 h

Emerging biomarkers for early detection of AKI

The substantial lag time between renal injury and the consequent rise in serum Cr has disadvantages. Interventions to mitigate or reverse renal injury may be substantially delayed, while prognostic staging, and the planning of care, is dependent on serum Cr measurements extending to several days, which do present logistical difficulties. The emergence of novel biomarkers offers an opportunity to diagnose AKI at an earlier stage, which can differentiate between structural and functional AKI, and predict the outcome of established AKI [56]. The most promising renal biomarkers include plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), clusterin, cystatin C and interleukin-18 (IL-18) [57-59]. In a recent meta-analysis, it was confirmed that NGAL is a valuable renal biomarker in all settings of AKI investigated [60]. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, IL-18, NGAL, KIM-1 and clusterin are biomarkers for tubular reabsorption function [57]. The measurement of urinary calprotectin may be able to differentiate between pre-renal and intrinsic AKI [61]. The role of biomarkers in the early detection and staging of CI-AKI is the subject of ongoing clinical research.

Preventing CI-AKI post-PCI

It is important that patients undergoing PCI have an appropriate risk assessment for PCI-AKI. Precautionary measures before, during and after the use of contrast media that reduce the incidence of CI-AKI, such as discontinuation of nephrotoxic medications, and the use of appropriate volumes and types of contrast media, should be considered in all patients with renal insufficiency or with other risk factors for CI-AKI. Low-osmolar nonionic contrast is the contrast of choice for all patients at high risk of post-PCI renal insufficiency.

Contrast load will be minimized if the coronary intervention is performed by a skilful operator. Where available, biplane angiography is preferable to monoplane angiography as the contrast dose will be significantly reduced [62].

Hydration with normal saline

Pre-PCI hydration remains the most effective approach to preventing CI-AKI [11, 25, 63, 64]. In 2002, Muller et al. [65] published a randomized trial in 1620 patients comparing normal saline to 0·45% saline and demonstrated a reduction in the incidence of CI-AKI from 2·0% to 0·7%. The benefits of plasma volume expansion have been attributed to suppression of the renin–angiotensin–aldosterone system, down-regulation of tubulo-glomerular feedback, dilution of the contrast media, prevention of renal cortical vasoconstriction and avoidance of tubular obstruction [63].

Sodium bicarbonate

One of the mechanisms hypothesized to be responsible for CI-AKI development is the production of oxidative stress with the intrarenal accumulation of reactive oxygen species. Alkalinization of tubular fluid has been shown to diminish the production of reactive oxygen species [33, 66]. This has led to the investigation of sodium bicarbonate as a CI-AKI prophylactic therapy. Despite the fact that pretreatment with sodium bicarbonate is more protective than with sodium chloride in animal models of acute ischaemic renal failure [67], the results of studies in humans have been conflicting [68-71].

To evaluate the available controversial data and to assess the effectiveness of normal saline vs. sodium bicarbonate infusion, a few meta-analyses of randomized controlled trials have been performed. Some of these meta-analyses suggest a significant benefit with the use of NaHCO3-based hydration in the prevention of CI-AKI [72-74]. However, a couple of meta-analyses have failed to find any benefit in hydration with sodium bicarbonate [71, 75]. Whether sodium bicarbonate is beneficial and superior to normal saline remains a subject of debate.

N-Acetylcysteine and CI-AKI

The antioxidant N-acetylcysteine (NAC) has been suggested as a therapy to attenuate the risk of developing CI-AKI by scavenging oxygen free radicals generated as a result of renal tubular toxic damage. However, there has been ongoing debate over whether NAC is effective in preventing CI-AKI. The current literature suggests that its role as an adjunct to saline hydration in patients with mild to moderate renal insufficiency is limited. In the largest randomized study thus far assessing the efficacy of NAC for preventing CI-AKI, intravenous NAC (500 mg) did not provide renal protection in patients with impaired renal function compared with placebo [76]. One recent prospective randomized controlled trial that enrolled 320 patients also failed to prove the benefit of NAC in this setting [64]. Another study has shown that NAC may possibly reduce the incidence of CI-AKI in patients undergoing primary PCI for acute MI; however, the in-hospital mortality and morbidity were not significantly different between the two groups [77]. There may be a role for this agent where complete hydration is not possible (e.g. emergency coronary angiography or symptomatic congestive heart failure), or in patients with more severe renal dysfunction (serum Cr > 2·5 mg/dL) [78], however, this requires further investigation.


Angiotensin-converting enzyme inhibitors (ACE-Is) are widely used in patients who might require coronary angioplasty. The renin–angiotensin system (RAS) has been implicated in the pathogenesis of CI-AKI, and this can be inhibited by using ACE inhibitors [79, 80]. The available data on the use of ACE-I with associated risks of CI-AKI are sparse and conflicting. Some reports have proposed the use of ACE-I to protect the kidneys from the effects of CI-AKI [79, 81], while other reports have implicated ACE-I to be nephrotoxic and exacerbate renal failure in patients with CI-AKI, especially for patients with pre-existing renal impairment [82, 83]. They suggest omitting the drug for 24 h prior to a coronary angiogram [84]. However, using a large prospectively collected database of 7230 patients undergoing a coronary intervention, ACEIs were found retrospectively to decrease the risk of contrast nephropathy by 39% in patients with GFR< 60 mL/min/1·73 m2 [27]. Based on multiple studies, it is a common practice in most of UK hospitals to continue ACE-Is in patients with mild to moderate renal insufficiency who are undergoing PCI.

Statins and CI-AKI

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are widely given for the primary and secondary prevention of CAD. They have pleiotropic effects, which include improved endothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, anti-inflammatory properties and stabilization of atherosclerotic plaque [85]. In addition, they are widely deployed in cholesterol lowering for the primary and secondary prevention of cardiovascular disease. Statins have been reported to reduce the risk of cardiovascular events and the development of diabetes [85]. Recently, they have also been shown to reduce cardiovascular events in patients with CKD, and their use in patients with CKD is widespread.

Reports have demonstrated that pretreatment with statins prevented CI-AKI after PCI. From recent publications, pravastatin (10 mg/day), among several statins, reduced the rates of renal dysfunction in patients with cardiovascular disease and chronic kidney disease [86, 87]. Although the preventive mechanism of CI-AKI by pravastatin treatment remains unknown, it is probably mediated via the pleiotropic actions listed above rather than lipid-lowering effects. Moreover, pravastatin may be more beneficial for renal protection than other statins, because of its water-soluble structure. Standard doses (10–20 mg/day) of pravastatin without any adverse effect on organs (insulin secretion from the pancreatic β cells, sugar uptake by fat cells or muscles) are reported to be effective in preventing CAD [88, 89].

Remote ischaemic preconditioning (RIPC)

Novel treatment strategies are required to prevent CI-AKI in patients undergoing PCI. In this respect, the safe and low-cost therapeutic intervention of remote ischaemic preconditioning (RIPC) is a potential strategy for preventing CI-AKI. RIPC refers to a powerful endogenous protective phenomenon whereby brief episodes of nonlethal ischaemia and reperfusion to one organ confer protection against a sustained lethal episode of ischaemia and reperfusion in another organ [90]. Recent proof-of-concept clinical studies have shown that RIPC using transient ischaemia and reperfusion of the lower limb can preserve kidney function in patients undergoing elective endovascular [91], open surgical repair of an abdominal aortic aneurysm [92] and coronary artery bypass graft surgery [93]. It has been recently demonstrated in a proof-of-concept clinical study that RIPC could reduce the incidence of CI-AKI in PCI patients [94]. Large randomized controlled trials are now required to confirm the efficacy of RIPC in CI-AKI and investigate whether clinical outcomes can be improved.


CI-AKI is an important, underdiagnosed complication of PCI that is associated with prolonged hospital admission, significant morbidity and mortality. The increasing use of PCI, and its deployment during acute illness or in patients with high comorbidity, is likely to result in increasing prevalence of CI-AKI after PCI. Patients with pre-existing renal dysfunction, diabetes, congestive cardiac failure are most at risk. Risk assessment and the institution of preventive therapy such as preventing dehydration are essential. Prompt diagnosis and management can minimize the adverse effects of CI-AKI. The development of novel biomarkers such as NGAL is promising and may enable more rapid detection of CI-AKI. This, in turn, may offer earlier opportunities for mitigating renal injury and for assessing prognosis. Further study is required to discover novel therapeutic strategies for protecting renal function against CI-AKI in patients undergoing PCI, so we can improve clinical outcomes in patients with CAD.


This work was supported by the British Heart Foundation grant number FS/06/023. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.


The Hatter Cardiovascular Institute, University College London, London, UK (S. Tehrani, D. M. Yellon, D. J. Hausenloy); Centre for Nephrology, UCL Medical School, Division of Medicine, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK (C. Laing).