Contrast-induced nephropathy: Basic concepts, pathophysiological implications and prevention strategies☆
Introduction
Contrast-induced nephropathy (CIN) is reversible acute renal failure observed after administration of iodinated contrast media (CM) during angiographic or other medical procedures such as urography. The expected increase of serum creatinine (sCr) generally appears within 48 h after CM exposure, reaching a peak within the following 5 days. Increased morbidity, hospital stay and mortality is often associated with CIN (Golshahi et al., 2014, Rewa and Bagshaw, 2014). CIN has a considerable prevalence that reaches 15% in high-risk patients (see below; Section 6. Risk factors of CIN), whereas in ordinary patients the incidence does not exceed 1% (Rancic, 2016).
CM are non-reabsorbable solutes of high-, low- or isoosmolality, which act as osmotic diuretics, reducing electrolyte re-absorption along the nephron and thereby causing an increase in urine output (Solomon, 2014). Iodinated CM can be ionic or non-ionic, depending on their solubility in water. First generation CM have really high osmolalities (around 1000–2500 mOsm/kg) compared to plasma (290 mOsm/kg), due to the fact that osmolality, molar concentration and ionic strength are directly proportional quantities (Pannu, Wiebe, Tonelli, & Alberta Kidney Disease, 2006). The second generation CM were mainly characterised by lower solution osmolality of around 400–800 mOsm/kg, through formation of ionic dimers (ioxaglate) or non-ionic monomers (iopromide, iopamidol, iohexol, ioversol) (Pannu et al., 2006). The final step in evolution was the development of isoosmolar CM, such as iodixanol and iotrolan, which are non-ionic dimeric compounds. Pure low-osmolar CM solutions are actually hypo-osmolar. Therefore, in order to reach plasma osmolality electrolytes are added (Jost et al., 2011).
The osmotic properties of CM could account for numerous hemodynamic alterations, including vasodilatation, increases in circulating blood volume and peripheral blood flow, and decreases in systemic resistance (hypotension) (McClennan, 1990). Hemodilution effects result from extravascular water shifts into the bloodstream that contribute to some of the hemodynamic perturbations associated with high-osmolar CM administration. Red blood cell changes (crenation and rigidity) and endothelial damage directly at the injection site accompanied by release of vasoactive substances, such as serotonin, histamine, prostaglandins, fibrinolysins, kallikreins, leukotrienes, bradykinin etc., may lead to hemodynamically altered microcirculation or other physiologic changes that may cause side effects. Some hemodynamic effects can be related to osmolality and to a lesser degree to the chemotoxic properties of the CM. These include negative inotropic effects and decrease in myocardial contractility after intra-cardiac injections. Decreased cardiac output and increased pulmonary artery pressure may occur along with plasma volume changes noted previously. Effects on the cardiac conduction system may result in abnormal electrocardiogram patterns, some of which may be clinically significant depending on the underlying cardiovascular status.
Reduction of osmolality in modern CM has ameliorated their safety profile (Caiazza, Russo, Sabbatini, & Russo, 2014) at the expense of increased viscosity (Jost et al., 2011). Viscosity strongly depends on iodine concentration of the solution, increasing exponentially (Seeliger et al., 2007) and strongly influences renal side-effects. CM with higher viscosity increase urine viscosity leading to higher tubular pressure that causes low urine flow rate and clearance, which in their turn prolong bioavailability, leading to a more pronounced tubular injury (Seeliger et al., 2010, Ueda et al., 1993). High osmolality could actually reduce exposure through osmotic diuresis and in vitro dilution (Lenhard et al., 2012). Animal studies have shown that during administration of high viscosity isoosmolar CM, osmotic diuresis is missing and the dwelling time of CM in the urinary tubules and thus their bioavailability is higher (Jost, Pietsch, Lengsfeld, Hutter, & Sieber, 2010) (Fig. 1).
To mitigate this effect, current practice mandates a) right choice of the agent, b) heating of low-osmolar/isoosmolar CM before use because viscosity is inversely proportional to temperature and c) aggressive hydration around the time of exposure to dilute the agents and decrease their viscosity (Dorval et al., 2013). Most medical centres no longer use intravascular, high-osmolar CM to avoid various adverse effects associated with their use (ACR Committee on Drugs and Contrast Media, 2016). A meta-analysis showed that in patients with underlying renal insufficiency, nephrotoxicity of CM with low-osmolality is lower compared to high-osmolar CM (Barrett & Carlisle, 1993). It is not clear yet whether intravenous low-osmolar or isoosmolar CM (iodixanol) are less detrimental regarding CIN (Dong et al., 2012, McCullough and Brown, 2011). According to the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery guidelines (Authors/Task Force members, 2014), for patients with moderate-to-severe chronic kidney disease undergoing coronary angiography or multi-detector computed tomography, CM volume should be minimized and isoosmolar should be considered over low-osmolar agents at the recommended dose for both of them < 350 mL or < 4 mL/kg or total contrast volume/glomerular filtration rate (GFR) < 3.4. According to the American College of Radiology guidelines (ACR Committee on Drugs and Contrast Media, 2016), extrinsic warming to human body temperature (37 °C) of iodinated CM could minimize complications and improve vascular opacification in certain applications, such as high-rate (> 5 mL/s) intravenous low-osmolar CM power injections; viscous iodinated agent injections (e.g., iopamidol 370); and direct arterial injections using small catheters (≤ 5 Fr). According to the American College of Radiology and the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines, intravenous volume expansion with isotonic fluids prior to CM administration could prevent the risk of CIN (see below) (ACR Committee on Drugs and Contrast Media, 2016, Authors/Task Force members, 2014) (Table 1).
Section snippets
Objective and methods of the review
The literature was screened up to November 2016 to select publications focusing on the topic “contrast-induced nephropathy” with due emphasis given to relevant reviews summarizing developments during the past five years. Medline, Science Citation Index, and the Cochrane Library were searched, using the following key words: N-acetylcysteine (NAC); antioxidants; ascorbic acid; CM; fluid therapy; nephropathy; nitric oxide; oxidative stress; ROS; and sildenafil citrate either in the title,
Terminology
CIN describes a sudden deterioration in kidney function occurring within 48 h after intravascular administration of iodinated CM, which is due to the CM. On the other hand, post-contrast acute kidney injury (AKI) describes a sudden deterioration in kidney function occurring within 48 h after intravascular administration of iodinated CM regardless of the cause (Baumgarten and Ellis, 2008, Davenport et al., 2014, Davenport et al., 2013, Katzberg and Newhouse, 2010, McDonald et al., 2013, McDonald
Incidence of CIN
CIN is generally considered a reversible form of acute renal failure that begins soon after iodinated CM administration during angiographic or other procedures such as urography and it is recognized as an increase of sCr level that generally appears in the first 48 h after exposure to the CM and reaches a peak within the next 5 days (Wi et al., 2011). CIN is associated with increased morbidity, hospital stay and mortality (Golshahi et al., 2014, Rewa and Bagshaw, 2014). There are no standard
Pathophysiology of CIN
The exact pathophysiology of CIN is obscure (ACR Committee on Drugs and Contrast Media, 2016) and several factors may be implicated, including renal ischemia, particularly in the medulla, reactive oxygen species (ROS) formation, reduction of nitric oxide production, and tubular epithelial and vascular endothelial injury (Andreucci et al., 2014a, Scoditti et al., 2013) (Fig. 2). Iodinated CM may exert their nephrotoxic effects in several ways. Hemodynamic alterations resulting in renal medullary
Risk factors of CIN
Multiple risk factors for CIN have been proposed, including among others diabetes mellitus; dehydration; cardiovascular disease; diuretic use; multiple myeloma; hypertension; hyperuricemia; and multiple iodinated CM doses within a short time (< 24 h); female gender; advanced age; the amount and type of the contrast medium as well as the type of the intervention for which CM is used (Abujudeh et al., 2009, ACR Committee on Drugs and Contrast Media, 2016, Davenport et al., 2013, Heyman et al., 2013
Prevention strategies for CIN
All patients receiving CM should be evaluated for the risk of CIN and high-risk patients should be considered for prevention strategies supported by clinical evidence. Because CIN is a potentially preventable clinical condition, an increased knowledge of CIN should increase the likelihood of reducing the risk of its occurrence. In patients without risk factors, the incidence of CIN appears to be minor (< 1%) but in high-risk patients the incidence seems to be high (up to 15%) (Rancic, 2016).
Conclusions
The exact pathophysiology of CIN remains obscure. Consequences of CIN can be devastating, especially in the vulnerable subgroups of the general population. However, the need for contrast-based medical examinations and interventions is constantly increasing. All patients should be evaluated for CIN risk and an individualized risk-benefit strategy prepared. Intravenous volume expansion using isotonic fluids prior to CM administration is the intervention proven most effective. The value of using
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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