Introduction

Among ST segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) worsening of renal function resulting in acute kidney injury (AKI) is a frequent complication, known to be associated with adverse outcomes [1–4]. The worsening of renal function throughout the hospitalization period in STEMI patients is multifactorial, though the most important reason is considered contrast-induced AKI, related mainly to the amount and type of contrast material and to preprocedural renal function [5–7]. A growing amount of data now suggests that AKI, in this clinical scenario, has a complex and multifactorial pathogenesis which goes beyond the administration of contrast volume during catheterization. These factors include an adverse hemodynamic state resulting in reduced renal perfusion, other metabolic factors such as drugs administered (especially blockers of the renin-angiotensin axis) as well as the occurrence in parallel of sepsis, bleeding, atheroembolic disease and acute hyperglycemia [8–10] (Fig. 1). In the present review we describe the various factors associated with AKI in this specific patient population, including new novel theories. We hope that this will aid physicians in a better awareness of those at risk for this complication, enabling the implementation of both primary and secondary preventive measures.

Fig. 1
figure 1

Pathophysiology of acute kidney injury in acute myocardial infarction with permission from Oxford University Press (#3654161388880)

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Contrast-induced nephropathy

Contrast-induced acute kidney injury (CI-AKI) is a prevalent and deleterious complication of coronary angiography. CI-AKI has been reported to be the third most common cause of hospital-acquired renal failure [11]. The risk of CI-AKI is directly associated with increasing contrast media volume [6]. The incidence of CI-AKI ranges from 2 % in patients with normal baseline renal function to as high as 20–30 % in patients with a baseline creatinine >2.0 mg/dl [12]. Even after adjusting for baseline renal function and comorbidities, in-hospital mortality is about fivefold higher in patients with CI-AKI, and 1-year and 5-year mortality rates are about fourfold higher [13]. The average amount of contrast volume used in primary PCI has been reported to be higher than in elective PCI [14]. In addition, the contrast volume/estimated glomerular filtration rate (eGFR) ratio was recently shown to predict AKI among patients undergoing primary PCI [15, 16].

Time to reperfusion

Recent data suggest an association between longer time to reperfusion and CI-AKI in patients undergoing primary PCI [17]. Time to coronary reperfusion is a powerful prognostic marker in STEMI patients [18, 19] and major efforts are devoted to minimizing the total ischemic duration in order to improve survival following STEMI [20]. The sudden myocardial insult in STEMI often results in an acute reduction of cardiac output. This early hemodynamic deterioration may theoretically lead to reduced renal perfusion and consequently to kidney injury. Bradycardia or tachycardia in the acute STEMI setting can have similar hemodynamic effects. Short renal hypoperfusion is often associated with a prerenal failure, defined as a reversible loss of renal function without structural damage [21]. A more profound and prolonged hypoperfusion primarily affects the function and structure of tubular epithelial cells and, in severe cases, this is characterized by epithelial cell ischemia and necrosis. Nevertheless, ischemia-related injury does not exclusively lead to alterations of epithelial cell function and structure but also causes interstitial inflammation and interstitial microvasculopathy [22–24]. In contrast to prerenal injury, these alterations can result in irreversible loss or delayed restoration of renal function, and may increase susceptibility to CI-AKI. In addition, longer symptom duration prior to hospital admission is associated with higher admission C-reactive protein and lower hemoglobin levels in STEMI patients [25], both demonstrated to be associated with increased risk for AKI in STEMI patients. It appears that, in addition to the well-known fact that “time is myocardium” among STEMI patients, one might also say that “time is kidney”.

Cardiac pump function and hemodynamics

Among the eight different risk factors included in the current most widely applied score to estimate the risk of CI-AKI [26], three (hypotension, congestive heart failure, and intra-aortic balloon pump) are directly related to cardiac pump function and to acute hemodynamic deterioration. This score was also validated recently among STEMI patients undergoing primary PCI [27]. A report by Marenzi et al. demonstrated that among STEMI patients undergoing PCI, age, anterior infarct location, contrast agent volume, time to reperfusion >6 h, and use of intraaortic balloon were independent predictors of CI-AKI. These factors were used to build a specific score which demonstrated a graded increase in CI-AKI incidence as well as in-hospital mortality as the risk score increased [28]. Both scores (Mehran’s and Marenzi’s) have been recently assessed in a HORIZONS-AMI sub-study of STEMI patients undergoing primary PCI, where CI-AKI was shown to be associated with adverse short- and long-term outcomes [14]. Similarly, in a recent study published by our group, STEMI patients developing AKI were more likely to be at a critical state and to sustain significant arrhythmias and congestive heart failure episodes in addition to lower left ventricular ejection fraction [29]. We also demonstrated that every 1 % reduction in left ventricular ejection fraction was associated with a 10 % increase in the risk AKI [30]. Following the resumption of coronary flow and the improvement of left ventricular function as well as the resolution of arrhythmias, hemodynamic impairment often resolves although renal function may still remain impaired or lag behind in recovery.

Inflammatory and metabolic markers

Several metabolic markers have been postulated to play a role in the development of AKI in STEMI patients.

C-reactive protein

The ischemic injury and myocardial necrosis following a STEMI incite an acute inflammatory response. Among the various pro-inflammatory cytokines, high sensitive C-reactive protein (hs-CRP) has emerged as a powerful and independent predictor of heart failure and long-term mortality [31]. Elevated periprocedural hs-CRP was shown to be associated with an increased risk for AKI in non-MI patients undergoing PCI [32]. A recent study demonstrated that among STEMI patients, admission hs-CRP level is an independent risk factor for AKI [33]. There is convincing evidence that the elevation of the serum hs-CRP level in STEMI patients may not be just an epiphenomenon, but rather may directly contribute to the inflammatory state. hs-CRP can directly activate the clotting system [34], and mediate enhanced expression of adhesion molecules, reduced nitric oxide production and impairment of antioxidant defenses [35] resulting in endothelial dysfunction. Endothelial dysfunction and decreased activity of renal vasodilators has been regarded as an important contributor to AKI development [36]. Thus, it is possible that elevated peri-PCI hs-CRP levels are not only a marker for AKI, but may also make kidneys more vulnerable to contrast-induced damage.

Admission glucose

Hyperglycemia is common in patients with STEMI, even in the absence of a history of diabetes mellitus (DM), and has been identified as a major independent predictor of both in-hospital congestive heart failure and mortality in STEMI [37, 38]. Recent evidence demonstrated that acute hyperglycemia was also associated with increased risk for contrast-induced nephropathy following primary PCI [10, 39, 40]. Hyperglycemia may represent an epiphenomenon of the stress response, mediated by cortisol and catecholamines whose release is elicited by the hemodynamic compromise or myocardial damage. Hyperglycemia may, however, exert a direct negative impact on renal function. The outer medullary region is particularly susceptible to ischemic injury because of its high metabolic activity and low prevailing oxygen tension [41]. The partial oxygen pressure of the outer medulla in the kidney is very low during normal function. Contrast media aggravates hypoxic injury to this region by increasing renal vascular resistance [42]. Hyperglycemia may lead to increased production of oxygen free radicals with increased oxidative stress and suppressed flow-mediated vasodilatation, inducing medullary hypoxia and ischemia, thus exacerbating the deleterious effect of contrast material [43, 44]. Furthermore, acute hyperglycemia may induce osmotic diuresis, resulting in volume depletion and increasing the risk for pre-renal azotemia and contrast toxicity. Patients with hyperglycemia also exhibit more metabolic abnormalities in the background that can lead to higher inflammatory biomarkers [44].

Admission anemia

Previous studies have shown that anemia increases the risk of CI-AKI in various patient populations [45–47]. Contrast media could increase oxygen affinity of hemoglobin, so oxygen delivery to the peripheral tissues might be impaired [42]. Local renal hypoxia can therefore be aggravated among patients with low hemoglobin levels after exposure to contrast media; hence, the combination of contrast-induced vasoconstriction and anemia may decrease oxygen delivery, sufficiently to cause renal medullary hypoxia. The presence of anemia in the acute STEMI setting can thus further aggravate the ischemic insult to the kidney, resulting in greater susceptibility to AKI [48].

Hyperuricemia

Previous studies have shown that elevated uric acid levels increase the risk of AKI in patients undergoing cardiac surgery [49, 50] and non-emergent PCI [51]. Elevated serum uric acid levels were also associated with increased short- and long-term mortality among myocardial infarction patients [52–55]. A report by Park et al. demonstrated that, among patients undergoing PCI, patients with AKI had higher uric acid levels, and that uric acid was independently associated with the risk for AKI [51]. Hyperuricemia inhibits the nitric oxide system in the kidneys and increases endothelin-1 concentrations, resulting in loss of renal blood flow autoregulation, renal vasoconstriction and reduced medullary blood flow [56]. Hyperuricemia has also been shown to stimulate the expression of C-reactive protein and induces the infiltration of inflammatory cells into the renal parenchyma with resultant tissue injury [57]. Elevated uric acid levels may thus reduce renal perfusion, exacerbating ischemia/reperfusion injury, further aggravating the ischemic insult to the kidney, with the result of greater susceptibility to AKI.

Bleeding complications

Anemia is known to be an independent predictor of CI-AKI [45, 46] being one of the main variables of the Mehran contrast-induced nephropathy risk score [26]. However, few previous studies or risk score models have accounted for periprocedural bleeding as a risk factor for the development of CI-AKI. A recent report demonstrated that, among patients undergoing PCI, those who experienced periprocedural bleeding had a higher likelihood of developing CI-AKI, and CI-AKI incidence correlated closely with bleeding severity [58]. It also appears that the transradial approach is also associated with a lower rate of occurrence of both acute and chronic renal dysfunction following PCI, when compared to the transfemoral approach, a fact which could be attributed at least in part, to the lower bleeding risk associated with the radial puncture [58, 59].

Conclusion

Among STEMI patients undergoing primary PCI, AKI is complex and should not be assumed to be solely due to contrast media. Hemodynamic abnormalities representing a special type of acute cardio-renal syndrome and various metabolic factors should be considered when evaluating the risk for this complication.