2 2 deﬁnitions ([Cr] ≥0.5 mg/dL, ≥25%) consistently pre- dicted adverse events after PCI [15]. Therefore, a complete deﬁnition for CIN encompasses absolute (≥0.5 mg/dL) and relative increase (≥25%) in serum creatinine at 48–72 hours after exposure to a contrast agent compared to baseline serum creatinine values, when alternative explanations for renal impairment have been excluded [9]. 3. Incidence of CIN Based on these deﬁnitions, the overall incidence of CIN in the general population has been estimated to lie between 1%–6% [16]. The ﬁgure is higher when CIN follows PCI. In their retrospective analysis of the Mayo Clinic PCI registry comprising of 7586 patients, Rihal et al. found the incidence for general population undergoing PCI to be 3.3% and dialysis was needed in 0.3% [17]. However, incidence of CIN rises up to 20% or more in selected patient subsets, especially in patients with underlying cardiovascular disease [9]. 4. Pathogenesis of CIN Although the pathogenesis of CIN is not well understood, there is increasing evidence that it occurs as a combination of direct toxicity to the renal tubular epithelium, oxidative stress, ischemic injury, and renal tubular obstruction [18– 20]. Also, increased intratubular pressure secondary to contrast-induced diuresis and increased perivascular hydro- static pressure may lead to medullary hypoxia through lower medullary blood ﬂow [21]. Renal ischemia may be the result of an imbalance between vasoactive substances (Adenosine and Endothelin) and vasodilators (NO and Prostaglandins) [19]. Signiﬁcant urine volume is needed to clear the high osmotic load of the contrast medium. Exposure to this high osmotic load results in characteristic histopathological changes of osmotic nephrosis, a morphological pattern with vacuolization and swelling of the renal proximal tubular cells [22]. In a study, this ﬁnding was seen in almost a quarter (22%) of patients undergoing renal biopsy within 10 days of contrast exposure [23]. 5. Risk Factors of CIN The risk factors of CIN have been extensively studied in the past and can be classiﬁed into modiﬁable and nonmodiﬁable risk factors. These have also been subdivided into “patient related” and procedure related and are tabulated in Table 1. 5.1. Age. The elderly remain at a higher risk of CIN after PCI, although the reason has not been elucidated yet. It is believed to be multifactorial, including age-related reduction in glomerular ﬁltration rate (GFR), tubular function, as well as more diﬃcult vascular access requiring greater amount of contrast, presence of multivessel disease, and comorbids. A few studies have found age older than 70 years to be an independent predictor of CIN in multivariate analysis [24– 26]. Cardiology Research and Practice 5.2. Pre-existing Renal Disease. Baseline elevated serum creatinine was found to be an independent predictor of CIN in numerous studies. Increase in baseline Cr level to 1.2 mg/dL or higher resulted in an exponential increase in the risk of nephrotoxicity [27]. Risk of developing CIN after undergoing PCI rises with lowering GFR [28]. 5.3. Diabetes Mellitus. Many studies have found Diabetes Mellitus (DM) as an independent risk factor for CIN in studies [17, 26, 29]. This risk is also independent of preexisting renal dysfunction [26, 30]. The incidence of CIN in diabetics varies from 5.7% to 29.4% [30, 31]. Given an increasing prevalence of DM in the general population and a higher risk of vascular disease among this group, diabetic patients represent a major fraction of patients requiring radiological procedures with use of contrast including PCI. Toprak et al. showed that in patients with preexisting renal insuﬃciency, Diabetes Mellitus independently increased the risk of development of CIN and need for dialysis as opposed to pre-DM and Normal Fasting states [32], while Berns showed that the incidence of CIN in diabetics was higher if Cr > 4.0 compared to Cr between 2.0 and 4.0 mg/dL. Clearly, there is a synergistic eﬀect of diabetes and pre existing renal insuﬃciency [33]. 5.4. Cardiac Risk Factors. Congestive Heart Failure, Anterior MI, Cardiogenic Shock, and Use of Intra-aortic Balloon Pump have all been associated with increased risk of CIN after PCI, mainly because they all lead to Reduced Renal Perfusion [17, 26, 34, 35]. 5.5. Volume of Contrast. Volume of contrast remains the primary modiﬁable risk factor. Increasing complexity of coronary intervention invariably has led to higher volumes used per procedure and this overall augments the risk of CIN. Many studies have documented a clear correlation between volume of contrast and risk of CIN [24, 36–38]. There is also an association of CIN with closely placed procedures which ultimately translates into an increased amount of contrast used cumulatively [36]. McCullough et al. showed that the risk of CIN is minimal in patients receiving less than 100 mL of contrast media during procedures, or the volume of contrast used is <5 mL/kg/Serum Cr [29]. However, whether incidence of CIN is dose related or not has also been studied. In their study of 118 patients with Cr >1.3 and pre existent renal disease, Mekan et al. found that the contrast-induced reduction in renal function was not signiﬁcantly higher with a higher volume of contrast (>100 mL) [39]. On the other hand, Kane et al. demonstrated a signiﬁcant rise in incidence of CIN with increase of volume of contrast [38]. The ratio of the volume of contrast media to the creatinine clearance (V/CrCl) has been correlated with the area under the curve of contrast media concentration over time. With that concept, Laskey et al. showed that a V/CrCl ratio >3.7 was a signiﬁcant and independent predictor of an early abnormal increase in serum creatinine after PCI in an unselected population of 3,179 patients [40].