European Society of Cardiology (ESC) curriculum section and guidelines referenced 2.4 Invasive imaging: cardiac catheterisation and angiography. ESC: updated contrast-induced nephropathy (CIN) prevention guidelines 2014. European Society of Urogenital Radiology: updated contrast media safety committee guidelines 2011. Learning objectives Define CIN and recognise this as a common and serious complication in susceptible patients receiving intravascular contrast media. Understand the possible pathological mechanisms underlying CIN. Describe the clinical and periprocedural risk factors for CIN and perform a risk assessment for patients receiving contrast media. Appreciate the established strategies used to prevent CIN and be aware of novel therapies. Recognise the onset of CIN and manage this complication appropriately. Introduction Contrast-induced nephropathy (CIN), also known as contrast-induced acute kidney injury, is an iatrogenic renal injury that follows intravascular administration of radio-opaque contrast media (CM) in susceptible individuals. CIN was first described during the 1950s in case reports of fatal acute renal failure that had occurred following intravenous pyelography in patients with renal disease arising from multiple myeloma.1 2 Despite technological advances, CIN remains responsible for a third of all hospital-acquired acute kidney injury (AKI)3 4 and affects between 1% and 2% of the general population and up to 50% of high-risk subgroups following coronary angiography (CA) or percutaneous coronary intervention (PCI).5 The proliferation of imaging methods and interventional procedures involving administration of intravascular CM in both non-cardiac modalities (eg, vascular CT angiography and interventional vascular angiography) and in established (eg, CA and PCI) and emerging cardiac modalities (eg, CT coronary angiography (CTCA) and transcatheter aortic valve implantation (TAVI)) has significantly increased the number of patients exposed to CM and thus the number at risk of CIN. The widespread adoption of primary PCI for the treatment of acute myocardial infarction (AMI), despite significantly improving cardiovascular outcomes, has increased the incidence of CIN due to the inherent difficulties in rapidly assessing CIN risk, instigating prophylactic measures, attendant haemodynamic compromise and higher contrast volumes, all known risk factors for the development of CIN.6 Despite several therapeutic approaches, the rising age and incidence of comorbidity within the broad cohort of cardiac patients receiving CM has ensured that the prevention of CIN remains a significant clinical challenge.7 As will be discussed in the following sections, the estimated risk of an individual developing CIN can be calculated using known pre-existent clinical and periprocedural factors, which are consistent with the proposed pathological mechanisms of CIN. Pre-existent stage III chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) 25% baseline at 3/12) 18.6% vs 0.9% (p=0.0001)Maioli et al,28 n=1490 Haemodialysis 0.7% McCullough et al 25 7% Gruberg et al 27 CIN, contrast-induced nephropathy; CM, contrast media; eGFR, estimated glomerular filtration rate. However, it is important to recognise that a direct causal relationship between CIN and mortality has not been established in these observational studies. The onset of CIN is more likely to occur in the presence of severe cardiac injury or disease, which alone conveys a poor prognosis. As such CIN may be a marker of adverse cardiovascular outcomes rather than an independent risk factor. A recent meta-analysis by James et al,29 reviewed 39 observational studies that investigated cardiovascular outcomes in those with CIN and demonstrated an increased risk of mortality, cardiovascular events, renal failure and prolonged hospitalisation. However, it was found that baseline clinical characteristics that simultaneously predispose to both CIN and mortality were strong confounders, especially so in unadjusted studies. Even with appropriate adjustment for comorbidity, the authors recommend that any firm conclusions about causality should be interpreted with caution. Nonetheless, a number of plausible pathological mechanisms exist that might explain a direct link between CIN and major adverse cardiac events (MACE). In the short term these include acute volume overload, electrolyte disturbance, uraemia or haemodialysis (HD) in cases of severe CIN. Longer term MACE in those who suffer persistent renal injuries may be increased secondary to the cardiovascular risk associated with progressive CKD and its many pathological manifestations, including accelerated atherosclerosis, vascular calcification and left ventricular (LV) hypertrophy.30 However, it is less conceivable how minor or transient changes in kidney function might increase MACE risk. In order to demonstrate a definite causal link between CIN and MACE, large randomised controlled trials (RCTs) are needed to demonstrate that effective CIN prevention strategies are also able to reduce short-term and long-term MACE, specifically using therapies that offer no additional cardiovascular risk reduction benefits. Given the similarities that exist between renal and cardiovascular disease and their respective treatments, this is unlikely to be feasible. In view of the many complex confounders associated with MACE, CIN clinical trials that focus exclusively on clinically important renal outcomes, such as persistent worsening of renal function, new onset proteinuria and progression to end-stage renal failure (ESRF), may to some degree circumvent any spurious relationship that is seen with MACE correlates. Despite the lack of evidence supporting any direct causality effect on MACE, the onset of CIN following cardiac procedures remains an ominous event which should prompt additional clinical vigilance and early intervention. Proposed mechanisms underlying CIN Intravascular CM are concentrated tri-iodinated benzene compounds that are radio-opaque as a result of their associated iodine moieties. All CM agents are cytotoxic and this may be compounded by the ionic strength, osmolality or viscosity of each specific agent.31 Ionic ‘hyper-osmolar’ solutions were the first to be used; however, these agents were found to be highly nephrotoxic and are now rarely administered.32 As such safer agents, including non-ionic ‘low-osmolar’ (LOCM) or ‘iso-osmolar’ (IOCM) solutions were developed. These formulations are significantly more viscous than blood plasma, with viscosity inversely related to osmolality33 (table 3). These two physicochemical properties of CM are thought to be implicated in the pathogenesis of CIN in addition to direct vasoactive and cytotoxic effects.34 Table 3 Comparison of CM agents by osmolality and viscosity Blood plasma Iso-osmolareg, Visipaque Low-osmolareg, Omnipaque High-osmolareg, Hypaque Osmolality 290 mosmol/L 290 mosmol/L 890 mosmol/L 2100 mosmol/L Viscosity 3–4 mPa s 8.8 mPa s 6.8 m mPa s 4.1 mPa s CIN risk N/A Low Low High CIN, contrast-induced nephropathy; CM, contrast media. The kidney is particularly vulnerable to ischaemic injury as it is subjected to high metabolic and osmotic stress and it is supplied by an intricate microvascular circulation susceptible to local and systemic hypoperfusion. This is most evident in the outer medullary region of the kidney where oxygen requirements are high due to active sodium resorption in the ascending loop of Henle and the partial pressure of oxygen is low at approximately 20 mmHg.35 This relative ischaemia is related to the delicate blood supply provided for by the descending vasa recta (DVR), which is a long and narrow diameter vessel with high vascular resistance, and which may be further compounded by arteriovenous shunting.36 Patients with CKD are at an additional risk of renal ischaemia due to the increased metabolic demands placed on a reduced nephron bed which is often coupled with a compromised microvascular and macrovascular circulation.37 Although understanding of the complex pathogenesis of CIN is incomplete, the primary model identifies ischaemia in the vulnerable outer medullary region of the kidney as being pivotal.36 Following intravascular administration of CM, a prolonged period of renal vasoconstriction occurs due to an imbalance of local vasoactive mediators, such as nitrous oxide,38 adenosine, endothelin,39 prostaglandin and reactive oxygen species (ROS)40 which are released by the vascular endothelium in direct response to CM cytotoxicity. The resulting ischaemic tissue releases further noxious vasoactive mediators including ROS, thus prolonging the duration of vasoconstriction. The increased viscosity of the admixture of CM and blood plasma within the DVR results in a further reduction in medullary blood flow41 and the hyperosmolality of CM in plasma has been shown to cause red cell distortion and aggregation which may also contribute to reduced perfusion due to capillary obstruction.42 As CM is filtered and concentrated within the tubules, the resulting increase in viscosity causes tubular obstruction which, coupled with ROS release, induces an acute tubular injury.43 Thus, the combination of cytotoxicity, vasoconstriction and viscosity present a potent combination for the induction of medullary ischaemia/reperfusion injury (figure 1). Figure 1 Pathophysiological mechanism underlying CIN is shown. CIN, contrast-induced nephropathy; NO, nitric oxide, ROS, reactive oxygen species. Adapted from Seeliger et al.89 The risk of CIN is increased in elderly patients and those with diabetes or CKD, which may be due to the presence of endothelial dysfunction and an exaggerated vasoconstrictive response to CM.44 Equally, patients with poor pre-renal perfusion, such as those with congestive cardiac failure (CCF), renovascular disease or intravascular volume depletion, are also at increased risk of CIN due to the deleterious effect of renal vasoconstriction coupled with low preload. As observed in clinical studies, the presence of anaemia and thus reduced oxygen carrying capacity of blood would be expected to worsen ischaemia in the outer medullary region of the kidney.45 Risk factors and risk assessment In order to reduce the chance of CIN occurrence it is important to review the risk factors and indications for CM administration prior to any CM procedure. Most CIN risk factors can be assessed from the clinical history, physical examination and common laboratory investigations. Further risk factors may become apparent periprocedurally. Pre-existent CKD is probably the most important pre-procedural risk factor for CIN. The European Society of Urogenital Radiology Consensus Working Panel46 in 1999 stated that CIN risk becomes clinically significant when baseline SCr concentration is ≥1.3 mg/dL (≥115 mmol/L) in men and ≥1.0 mg/dL (≥88.4 mmol/L) in women. These figures approximate to an eGFR 350 mL or >4 mL/kg) and previous CM exposure within 72 h8 are directly related to the development of CIN. A specific method for quantifying the maximum safe volume of contrast has been proposed by Laskey et al 52 who demonstrated that a ratio of the volume of contrast media to creatinine clearance (V/CrCl) greater than 3.7:1 correlates strongly with the risk of developing CIN in patients with moderate CKD undergoing CA. In addition, the presence of periprocedural haemodynamic instability requiring the use of inotropic agents or intra-arterial balloon pump9 therapy is particularly high-risk feature. A number of these risk factors have been integrated into a well-known post-procedure risk scoring system and validated in a large cohort study by Mehran et al 9 (table 4). Table 4 The Mehran risk score for the prediction of CIN9 Mehran score periprocedural CIN risk factor Score Hypotension (SBP 1 h of inotropic support) 5 Intra-arterial balloon pump therapy 5 Chronic heart failure, (NYHA III/IV or recent pulmonary oedema) 5 Age >75 years 4 Diabetes mellitus 3 Anaemia (male: HCT 16 CIN risk Low 7.5% Moderate 14% High 26.1% Very high 57.3% Dialysis risk 0.04% 0.12% 1.09% 12.6% CIN, contrast-induced nephropathy; HCT, haematocrit; NYHA, New York Heart Failure Association; SBP, systolic blood pressure. A similar scoring system has also been proposed by Tziakas et al 53 who found that pre-existing renal disease, metformin use, history of previous PCI, peripheral arterial disease and ≥300 mL of contrast volume were also independent predictors of CIN. A limitation of these scoring systems is that calculation is only possible after CM has been administered. However, it is clinically desirable to be able to predict the risk of CIN before the patient is exposed to CM allowing appropriate precautionary measures to be taken. Such a pre-procedural CIN risk score has been proposed by Maioli et al,8 following validation in a prospective cohort study (table 5). Table 5 A pre-procedural risk score for CIN (adapted from Maioli et al 8) Pre-procedural risk factor Score Prior CM exposure within 72 h 3 Left ventricular ejection fraction baseline SCr 2 Baseline SCr >1.5 mg/dL 2 Diabetes mellitus 2 Creatinine clearance (eGFR) 73 years 1 Score 0–3 4–6 7–8 >9 CIN risk Low 1.1% Moderate 7.5% High 22.3% Very high 52.1% CIN, contrast-induced nephropathy; CM, contrast media; eGFR, estimated glomerular filtration rate; SCr, serum creatinine. A number of other novel CIN risk factors have been identified, including pre-procedure glucose levels54 55 and low-density lipoprotein cholesterol;56 however, these have yet to be integrated into risk scoring systems. It may be possible to use commonly used cardiovascular risk scoring methods to approximate CIN risk, for example, a Global Registry of Acute Coronary Events score of >140 in patients with AMI having normal baseline renal function has been shown to predict risk of CIN in a small cohort study.57 A novel fluid status assessment method using Bio-Impedance Vector Analysis has also been demonstrated to independently predict CIN58 in a small clinical trial; however, it has not yet been translated into a CIN risk scoring system or guided volume repletion strategy. Established preventative measures In 2014, the European Society of Cardiology published updated guidelines on CIN59 prevention which provides a framework for the use of the following evidence-based strategies (figure 2 and table 6). For all patients referred for CM procedures, a CIN risk assessment should be performed which includes baseline measurement of SCr and calculation of eGFR using a suitable formula, for example, Modification of Diet in Renal Disease or Chronic Kidney Disease–Epidemiology. If patients are identified as being at risk of CIN, particularly if eGFR is 300 mL/h then perform CM procedure. Continue matched fluid replacement for 4 h post procedure IIb A In severe CKD, prophylactic haemofiltration prior to complex PCI may be considered Fluid replacement rate 1 L/h without negative loss, 0.9% sodium chloride intravenous hydration for 24 h post procedure IIb B N-acetyl-cysteine instead of intravenous hydration is not recommended III A Infusion of 8.4% sodium bicarbonate instead of 0.9% sodium chloride is not recommended III A In severe CKD prophylactic renal replacement therapy is not routinely recommended III B CIN, contrast-induced nephropathy; CKD, chronic kidney disease; CM, contrast medium; IOCM, iso-osmolar contrast medium; LOCM, low-osmolar contrast medium; LV, left ventricular; PCI, percutaneous coronary intervention; V/CrCl, volume of contrast media to creatinine clearance. Adapted from Windecker et al.59 Figure 2 Algorithm for the prevention of CIN is shown. AKI, acute kidney injury; BP, blood pressure; CHF, chronic heart failure; CIN, contrast-induced nephropathy; eGFR, estimated glomerular filtration rate; IOCM, iso-osmolar contrast medium; LOCM, low-osmolar contrast medium; MI, myocardial infarction; NaCl, sodium chloride; NaHCO3 −, sodium bicarbonate; Scr, serum creatinine; V/CrCl, volume of contrast media to creatinine clearance. Patients should be advised to stop all non-essential nephrotoxic medications (table 7) for 24 h prior to and for 48 h following the CM procedure pending SCr measurement. It is also recommended that patients receiving intra-arterial CM with an eGFR of 300 mL/h) using balanced intravenous isotonic saline (0.9%) delivery and intravenous furosemide infusion (0.25 mg/kg). The REMEDIAL II study83 demonstrated superiority of the RENALGUARD system plus oral NAC in preventing CIN (11%, 16/146) against a control group receiving sodium bicarbonate (1.26%) regimen plus oral NAC (20.5%, 30/146; OR 0.47; 95% CI 0.24 to 0.92). As such these novel therapies hold promise for higher risk patients especially those who are physiologically unable to tolerate large intravenous fluid volumes. In order to minimise CM load, novel automated contrast injection devices have been developed which decrease the volume of CM used and which have been shown to reduce the incidence of CIN.84 It has been proposed that rapid removal of CM from the blood pool may have benefit in preventing CIN; although prophylactic HD has not been shown attenuate the incidence of CIN,85 some benefit has been observed with both pre-procedural and post-procedural86 haemofiltration (HF) and simultaneous HF,87 which may be partially explained through optimisation of periprocedural intravascular volumes. However, HF is a resource-intensive therapy that should be reserved for very-high-risk patients, such as for those with pre-dialysis ESRF88 or those with severe CKD undergoing complex PCI. Direct extraction of CM in coronary venous blood, captured using a coronary sinus catheter, is an interesting experimental intervention89 which has yet to be proven in clinical trials. Summary and conclusion CIN represents a significant clinical and health economic problem that may be under-recognised through limitations in the currently available biomarkers. Although often a transient injury, CIN may progress to significant persistent renal impairment, ESRF and adverse cardiovascular outcomes. There are a number of recognised risk factors, although the prediction of CIN, particularly prior to contrast administration, remains challenging. Current interventions are largely centred on the avoidance of dehydration, the withdrawal of nephrotoxic agents and minimisation of contrast load, which has limited efficacy in preventing CIN in vulnerable patients. The unmet clinical need in CIN therefore resides in accurate prediction, effective intervention and rapid detection to prevent adverse cardiorenal outcomes. Each of these areas, particularly predictive risk scoring systems, innovative pharmacological and mechanical interventions and novel biomarkers are currently the subject of intensive research and development that may lead to the future development effective strategies to mitigate the risk of CIN. You can get CPD/CME credits for Education in Heart Education in Heart articles are accredited by both the UK Royal College of Physicians (London) and the European Board for Accreditation in Cardiology—you need to answer the accompanying multiple choice questions (MCQs). 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