Contrast-induced acute kidney injury

Clinical Queries: Nephrology 0101 (2012) 34–41

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Clinical Queries: Nephrology January–March 2012, Vol. 1/Issue 1

j o u r n a l h o m e p a g e : h t t p : / / w w w. e l s e v i e r. c o m / l o c a t e / c q n

ISSN No.: 2211-9477

Contrast-induced acute kidney injury Anupama Kaul* *Assistant Professor, Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rabareilli Road, Lucknow.

a r t i c l e

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Article history: Received 9 November 2011 Accepted 16 November 2011

Keywords: Acute kidney injury Contrast-induced nephropathy N-acetylcysteine

a b s t r a c t

Contrast-induced nephropathy (CIN) is described as a sudden deterioration of renal function i.e. an increase in serum creatinine (SCr) > 25% or an absolute rise of 0.5 mg/dL over a baseline in SCr within 48 hours of intravascular contrast administration in the absence of an alternative cause in absence of any other cause. The CIN has been reported as third most common cause of acute kidney injury in hospitalized patients. The exact mechanism of nephrotoxicity due to contrast agents is not yet clear yet it is presumed to be interplay renal vasoconstriction resulting in medullary hypoxemia and the direct cytotoxic effects of contrast agents on renal tubular cells. Diabetes, multiple myeloma, and advanced age are some of the modifiable factors while contrast volume, shock, hypotension, and congestive heart failure are a few non-modifiable risk factors for its occurance. Use of an imperfect marker of kidney function (SCr) may result in a false sense of safety, as only the ‘tip of the iceberg’ is being exposed by such measurements. Use of intravenous normal saline, sodium bicarbonate infusion and N-acetylcysteine are relatively cost-effective and safe, in reducing the risk of CIN, and may considered in patients undergoing procedures with intravascular contrast. Copyright © 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.

Contrast-induced nephropathy (CIN) is commonly described as a sudden deterioration of renal function after intravenous (IV) or ­intra-arterial (IA) administration of iodinated contrast media in ­absence of any other cause.1 As the interventions requiring usage of contrast media for therapeutic or diagnostic use is increasing, CIN has been reported as third most common cause of acute kidney ­injury in hospitalized patients with increasing risk to morbidity and mortality.2 According to Marenzi et al hospitalized patients who ­received contrast media and who acquired CIN had significantly higher mortality rate (31% vs 6%) than patients who did not acquire CIN.3 Presently for clinical practice, CIN is defined as an increase in serum creatinine (SCr) > 25% or an absolute rise of 0.5 mg/dL over a baseline in SCr within 48 hours of intravascular contrast administration in the absence of an alternative cause.4 Types of contrast agents Major risk to the usage of contrast agents is the increased incidence of contrast-induced renal failure. Following are the various types of contrast agents available: 1. High-osmolar (>1600 mOsm/L) ionic RCM (HOCM) were the first agents developed and are produced using the meglumine and sodium salts of diatrizoic acid.

*Corresponding author. E-mail address: [email protected] ISSN: 2211-9477 Copyright © 2012. Reed Elsevier India Pvt. Ltd. All rights reserved. doi: 10.1016/S2211-9477(11)70005-X

2. Low-osmolar (< 850 mOsm/L) RCM (LOCM), both ionic and non-ionic, its usage is on a rise in clinical practice as they have less systemic adverse effects. These agents are predominantly monomeric, non-ionic agents with the exception of the two dimers: ioxaglate (ionic) and iodixanol (non-ionic). Thirdgeneration iso-osmolar (< 300 mOsm) non-ionic agents, such as iodixanol and iotrolan, their nephrotoxic potential as compared with the low-osmolar contrast media is currently being investigated. The structural modification among the contrast agents has r­ esulted in reduction in the osmolarity to a near physiologic value, but at the price of a substantial increase in viscosity. The newer generation of low and iso-osmolar agents are considered safe, as compared with the high-osmolar radio contrast media. Unlike the ionic agents, they are minimally reabsorbed by the nephron,5,6 less cardiac effects (causing less depression of ventricular contractility and less reduction in coronary sinus calcium concentration), less effect on complement consumption, cause fewer hypersensitivity reactions,7 and have a less disruptive effect on the endothelial wall of blood vessels. Systemic effects, such as a feeling of warmth (especially after IV use), that depend on iodine content, osmolality, and sodium ion concentration are less frequent with these agents.5 Gadolinium has been considered to carry low or no risk of nephrotoxicity. However, there are some reports of reversible acute renal failure, particularly in patients with significant renal dysfunction. More importantly, the administration of gadolinium to patients with renal dysfunction has been associated with a severe fibrosing disorder called nephrogenic systemic fibrosis (NSF). There are emerging

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data from animal experiments, case reports, and small series that gadolinium-based contrast media can be associated with nephrotoxicity when given at high doses (greater than 0.3 mmol/kg) for use as a contrast agent in standard (non-MR) digital subtraction angiography.8–11 Some have claimed that the nephrotoxic profile of gadolinium is similar to that of diluted iodinated contrast media.9 Based upon this limited literature, it is difficult to be certain that gadolinium is completely free of important nephrotoxicity in high-risk azotemic ­patients.12,13 Furthermore gadolinium-based imaging should not be performed, if at all possible, in patients with an estimated glomerular filtration rate < 30 mL/min because of the risk of NSF. No data are available and there is no consensus opinion among experts regarding safety of gadolinium-based in patients with an ­estimated GFR of 30–60 mL/min who also have an increased risk of iodinated contrast nephropathy.

0.5 (CI, 0.36–0.68), while it is 0.75 (CI, 0.52–1.1) in patients without prior renal failure. All these suggest that HOCM is generally more nephrotoxic than LOCM and use of LOCM may be beneficial, particularly in patients with renal failure.20 The CIN Consensus Working Panel suggests that ‘for IA administration in high-risk patients with chronic ­kidney disease, particularly those with diabetes mellitus, non-ionic, isosmolar contrast is associated with the lowest risk of CIN’.19 Apart from osmolality, there has been few clinical evidence to support that iodine content, ionicity, and viscosity of contrast media contribute to their toxicity.19

Risk assessment

Hydration

There are various risk factors closely associated with increased ­occurrence of CIN. Table 1 summarizes the most commonly encountered modifiable and non-modifiable.

Pre-procedural clinical features associated with contrast-induced nephropathy Pre-existing renal insufficiency

Pre-existing renal insufficiency is the primary predisposing factor for CIN.14 The incidence of CIN was 5.3% in 3232 patients with normal renal function and 15.7% in 959 patients with baseline SCr concentration > 1.2 mg/dL (P < 0.001).1 In the Minnesota Registry of Interven­ tional Cardiac Procedures, CIN was diagnosed in 22% of patients with SCr concentration 2.0–2.9 mg/dL and in 30% of patients with SCr concentration > 3 mg/dL.15–21

Diabetes mellitus

The incidence of CIN varies from 5.7% to 29.4% in diabetic patients. However for those with preserved renal function and in the absence of other risk factors, the CIN incidence is usually comparable to that of a non-diabetic population.16,17

Old age and others

Old age has been regarded as an independent risk factor of CIN, particularly for those > 75 years old16 indicate that age, male gender, atherosclerotic disease, and low left ventricular ejection fraction should no longer be considered risk factors for CIN.18

Features of contrast media

Features of contrast media are: high-osmolar (HOCM, 600–800 mOsm/ kg H2O), low-osmolar (LOCM, 290 mOsm/kg H2O), and isosmolar (IOCM, around 2000 mOsm/kg H2O).19 However, great variations of ­osmolality may occur in different products with the same generic name. For example diatrizoate, generally regarded as HOCM, may be available as a product with an osmolality of 550 mOsm/kg H2O.19 In a meta-analysis of 25 trials, the pooled odds of CIN with LOCM is 0.61 (95% confidence interval [CI], 0.48–0.77) times that after HOCM. For ­patients with existing renal failure, this odds ratio is

Table 1 Pre-procedural clinical risk factors for contrast-induced nephropathy. Modifiable risk factors

Non-modifiable risk factors

Contrast volume Hydration Concomitant nephrotoxic agents Recent contrast administration Type of contrast

Diabetes, multiple myeloma Chronic kidney disease Shock/hypotension Advanced age (> 75 years) Congestive heart failure

Volume of contrast media

Multivariate analyses have established the correlation between higher dose of contrast and risk for CIN.22 The CIN Consensus Working Panel concludes that higher contrast volumes (> 100 mL) are associated with higher rates of CIN in patients at risk.19

Volume depletion and dehydration has been observed to be an ­(although now rare) important risk factor prior to the radiographic study. Current practice encourages volume expansion prior to most contrast requiring procedures. However conditions predisposing to effective volume depletion may still exist during contrast studies ­despite fluid administration like in patients with poor cardiac output, cirrhosis or hypoalbuminuria, or in critically ill patients with sepsis syndrome or shock. Various predictive algorithms generally including intraprocedural factors limiting their use prior to the procedure are being considered to estimate the risk for CIN but none of them have been validated. Mehran developed a risk score for predicting CIN that includes congestive heart failure, hypotension, age > 75 years, anemia, diabetes, RCM volume, and CKD defined as a SCr > 1.5 mg/dL or an eGFR of < 60 mL/min/1.7 m2.16 It was observed that the risk of CIN ­increases in a graded fashion as the eGFR decreases from < 60 mL/min/1.7 m2 to < 20/mL/min/1.7 m2.16 The Mehran risk score was calculated for each of three groups: no renal dysfunction (average score 5.9–2.8); transient renal dysfunction (average score 6.8–2.7); and persistent renal dysfunction (average score 6.3–2.8). Renal dysfunction was associated with increased risk for major cardiac events, in-hospital mortality, and new onset of dialysis dependent renal failure during hospitalization.13 Both transient and persistent renal dysfunctions were associated with a twofold–three-fold increased risk of reduced overall survival. The Dartmouth dynamic registry (DDR)23 found that renal dysfunction (0.5 mg/dL absolute increase in SCr) was associated with older age, female gender, increased comorbidities, severe coronary disease, baseline renal insufficiency, and urgent interventions. Pathophysiology of contrast-induced nephropathy The exact mechanism of nephrotoxicity due to contrast agents is not yet clear but is presumed to be interplay of various proposed mechanisms. Two major theories are renal vasoconstriction resulting in medullary hypoxemia (mediated by alterations in nitric oxide [NO], endothelin, or adenosine), and the direct cytotoxic effects of contrast agents on renal tubular cells by free oxygen radicals, increased oxygen consumption and increased intratubular pressure secondary to contrast-induced diuresis, increased urinary viscosity, and tubular obstruction, all resulting in renal medulla ischemia (Figure 1). These intrinsic causes act along with the harmful extrinsic (pre-renal) causes such as dehydration and decreased effective intravascular volume in occurrence of contrast-induced nephrotoxicity. The best data-related to the pathogenesis of contrast nephropathy come from animal models. It is been observed in lab animals that renal failure occurred on usage of radio contrast agent only when there was ­compromised systemic and renal circulation. Brezis and Rosen proposed that nephrotoxicity occurs when the medullary circulation is compromised due to disruption of the subtle balance between the

A. Kaul / Clinical Queries: Nephrology 0101 (2012) 34–41

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Renal vasoconstriction

Imbalance of renal vasodilators and vasoconstrictors

Increase in viscosity and reduction in medullary blood flow

Cytotoxic effects of CM

Medullary hypoxemia → Ischemia → Tubular necrosis

Generation of reactive oxygen species

Apoptosis of renal cells

Treatment: • NAC • Soidum bicarbonate

Treatment: • Hydration • NAC • Fenoldopam

Figure 1  Treatment algorithm for renal vasoconstriction and cytotoxic effects of contrast media. CM: contrast media, NAC: N-acetylcysteine.

high metabolic needs of the tubular segments of the renal medulla and their hypoxic environment.22 This balance is normally maintained by the interplay between vasodilator and vasoconstrictor ­influences, mediated by the activity of NO, prostaglandin, and ­endothelin systems within the medulla. After the injection of radiographic contrast media, there is a transient increase, followed by a more prolonged decrease, in renal blood flow.24–28 This change ­occurs due to disruption of the normal physiologic balance as a ­result of the delivery of a large hyperosmotic load to the juxtaglomerular apparatus,29 or it may be caused by systemic mediators such as atrial natri­ uretic peptide (ANP) and antidiuretic hormone. Endothelin-129,31,32 has been implicated as the most likely causative agent in a number of studies, but a clinical trial of an endothelin-receptor antagonist33 failed to show a protective effect. As intrarenal hypoxia sets in which is directly-related either to the hemodynamic changes or to the increased tubular energy expenditure due to osmotic stress.34,35 Due to compromised renal circulation for example, in patients with diabetes and renal failure (who are at highest risk of CIN, intrarenal hypoxia leads to impaired endothelium-derived vasorelaxation. It has been observed that these intratubular agents causes tubuloglomerular feedback and increase renal adenosine concentrations as a result of enhanced adenosine triphosphate hydrolysis, which ­enhances the renal hemodynamic effects of contrast media, resulting in local renal vasoconstriction.36 Blockage of vasodilatory prostaglandin production by indomethacin and sodium depletion have both been shown to increase the adenosine effect in the kidneys.37,38 Renal ischemia before contrast application increases the toxicity of prostaglandin blockade39 and enhances adenosine generation, leading to renal vasoconstriction.40 Both adenosine and contrast material show disparate effects regarding regional blood flow of the kidney with medullary vasodilation.27,41 Animal experimental models that revealed a nephroprotective effect of adenosine antagonism (using either theophylline or aminophylline) corroborate these findings.42–44 Reactive oxygen species (ROS) have also been implicated as a contributing factor and may be the cause of the vacuolization of epithelial cells in the proximal tubules.44–47 There is evidence that renal free-sradical production is increased after contrast administration,48,49 whereas infusion of superoxide dismutase and allopurinol, each of which should reduce free-radical content, have been reported to ameliorate contrast-induced hypo perfusion.50 Although lipid peroxidation and tubular oxidative damage could presumably lead to transient renal dysfunction, definitive experimental evidence confirming the role of renal oxidative damage in contrast nephropathy remains sparse.25,51

Clinical characteristics Contrast-induced renal failure begins within the first 12–24 hours after the contrast study which in majority of cases is non-oliguric.

Usually the decline in renal function is mild and transient, with r­ ecovery of renal function typically beginning within 3 to 5 days. However some patients have plasma creatinine values exceeding 5 mg/dL and occasionally requiring dialysis, persistent renal failure has been observed among those with pre-existing advanced underlying disease particularly in diabetes. From < 1% to 12% of patients have reportedly required dialysis, the wide range likely influenced by baseline kidney function and other co-morbidity. The in-hospital mortality in the patients requiring dialysis was significantly higher than in those without acute renal failure (36% vs 1%, respectively); 2-year survival in the group requiring dialysis was only 19%.

Interference with urinary protein measurement Many of the commonly used iodinated radio contrast agents induce false-positive results when either a dipstick or sulfosalicylic acid is used to detect proteinuria. How this occurrence is not clear, but protein excretion may be overestimated by as much as 1.5–2 g/L. Thus, the urine should not be tested for protein for at least 24 hours after a contrast study.

Diagnosis and differential diagnosis The diagnosis of radio CIN is based upon the characteristic rise in plasma creatinine concentration beginning with the first 12–24 hours. The differential diagnosis includes ischemic acute tubular necrosis, acute interstitial nephritis, and renal atheroemboli. The former two require additional insults such as sepsis or hypotension, or medication exposure. In patients having diffuse atherosclerosis undergoing angiography who develop acute kidney injury, renal atheroemboli should be an important and significant differential diagnosis of contrast nephropathy. These two can be differentiated by following distinguishing characteristics seen in atheroembolic phenomenon: ●●

●● ●●

●●

The presence of other embolic lesions (as on the toes) or livedo reticularis. Transient eosinophilia and hypocomplementemia. Onset of renal failure that may be delayed for days to weeks after the procedure. Protracted course with frequently little or no recovery of renal function.

Preventive strategies Preventive measures for CIN occurrence is aimed at strategies ­directed in reducing the kidney injury and adverse outcomes associated with such injuries. To date, there are no available data to



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show reduction in injury and relatively little data addressing the long-term adverse outcomes. Various strategies are carried out to minimize the risk.

Hydration Intravenous volume expansion is considered the standard strategy for prevention of contrast-induced acute kidney injury (CIAKI) in high-risk patients exposed to contrast, though there are no ran­ domized control trials to prove its efficacy and is almost universally accepted as an appropriate and safe measure to prevent CIN. Several studies have compared hydration protocols and their ­effectiveness in preventing CIN. It works on the principle that efforts in inducing adenosine production for vasoconstriction of the afferent arterioles reduces the workload and oxygen consumption of the renal medulla, thus normal saline prevents CIN more significantly than half saline because of higher sodium load, better volume ­expansion, and stronger inhibition of the renin-angiotensin pathway.52,53 This hypothesis is supported by studies showing detrimental effects of furosemide, an inhibitor of sodium reabsorption in the loop of Henle,54 and beneficial effects of captopril, an angiotensinconverting enzyme inhibitor.55

Sodium bicarbonate Sodium bicarbonate curbs CIN by increasing medullary pH and therefore decreasing the production of OH- from tissue ischemia.56 Randomized trial of 119 patients by Merten et al has suggested that the use of sodium bicarbonate hydration is superior to sodium chloride hydration.57 Rates of CIN were significantly lower in the sodium bicarbonate group (1.7%, n = 1) when compared with the sodium chloride group (13.6%, n = 8). This protocol used an infusion of 3 mL/kg/hr for 1 hour before and 1 mL/kg/hr for 6 hours after the procedure. Silva et al conducted a literature review as well as a small randomized study assessing the effectiveness of bicarbonate in preventing CIN, suggesting strong protective effect of ­sodium bicarbonate, the randomized study failed to show a significant difference in efficacy between 0.9% saline solution alone and a solution of 1.3% sodium ­bicarbonate.57 However, it should be noted that the randomized study consisted of a relatively small sample size (n = 27) and that no patients in either group developed CIN. The authors concluded that the small number of patients did not allow definite conclusions. Although additional studies are needed, these data suggest that a modified regimen with sodium bicarbonate may be effective in the high-risk patient. High-risk patients should be administered 0.9% saline by IV infusion at a rate of approximately 1 mL/kg/hr, adjusted appropriately for the patient’s current fluid status and cardiovascular condition. This treatment should be commenced 6–12 hours before the procedure and continued for up to 12–24 hours after the radiographic examination, if diuresis is appropriate. Although clinical studies have not shown uniformly that dehydration is a definite risk factor, iodinated contrast agents increase urine volume and osmolar clearance, and their effect on the kidney is prolonged by the decrease in both renal blood flow and GFR seen in dehydrated states.1 Pharmacologic agents to increase renal blood flow All attempts to reduce the incidence of CIAKI with systemic administration of vasodilators have failed in multicenter clinical trials. Reasons for such failure could be due to hypotensive effects of these agents resulting in exacerbation of the medullary vasoconstriction produced by the contrast medium and the use of vasoconstrictive antagonists that lacked specificity for the renal receptors within the medullary portion of kidney. Atrial natriuretic peptide, with or without saline, has been reported in reducing the ­incidence of CIN, possibly by antagonizing the

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secretion of renin, suppressing release of endothelin, and increasing GFR by dilating the afferent arterioles and constricting the efferent ones,58 while blocking tubular reabsorption of sodium and disrupting the tubuloglomerular feedback mechanism. However, neither did ANP prevent CIN in ­patients with SCr concentration N1.5 mg/dL59 nor did it improve the overall rate of dialysis-free survival in patients with acute tubular necrosis at a high-dose of 200 ng/kg/min intravenously for 24 hours.60 The possible reason could be that at high doses of ANP, hypotension results which is detrimental to compromised kidney.61 Kurnik et al studied 247 high-risk patients (renal impairment and diabetes mellitus in 50%) and showed the frequency of ­CIN to be higher in the anaritide group (23 < 25%) than in the placebo group (19%).59 Subgroup analysis showed no treatment benefit in patients with diabetes. Weisberg and Kurnik also found no additional protective benefit from treatment with ANP when compared with fluid hydration alone.62 Thus, ANP is no longer recommended for prophylaxis of CIN.

Calcium channel blockers The role of calcium as a mediator of CIN, thought to be related to its positive effect on hemodynamics and their cytoprotective influence on renal cells was first investigated by Neumayer et al.63 However, Solomon et al found no benefit from a single pre-procedural dose of calcium channel blocker in their series of 78 patients with chronic renal impairment undergoing angiography.22 Similarly, Khoury et al showed no statistically significant difference in renal function between the 42 treated patients and the 43 controls64; the authors thus concluded that prophylactic nifedipine is not clinically beneficial and should not be routinely administered for prophylaxis of contrast nephropathy. Despite the negative results in humans, Duan et al and Wang showed preventive role in renal ­injuries-induced by diatrizoate in rats.65,66 In presence of lack positive results in human trials, calcium channel blockers have failed to gain wide use as a prophylactic tool till date.

Adenosine antagonists Adenosine, a potent vasoconstrictive agent, has been implicated as a mediator in tubuloglomerular feedback, a mechanism that may have a role in the pathogenesis of contrast-induced nephrotoxicity. Acute renal failure in different animal models revealed a nephroprotective effect of adenosine antagonism.67–69 Theophylline, a non-specific adenosine receptor antagonist when given as an IV bolus of 2.5–5 mg/Kg of body weight before administration of contrast agent or orally for three consecutive days before contrast injection have shown the benefit in reducing the incidence of CIN (4% vs 16%; P = 0.046). These ­results have been consistent with a similar observation by Huber et al involving 78 patients in the ICU.62 There was no significant change in SCr levels or creatinine clearance among 64 patients with pre-existing chronic renal insufficiency (SCr levels > 1.5 mg/dL) when two groups (all patients received > 100 mL of iopromide, an LOCM, and IV hydration before computed tomography (CT) or peripheral angiography) were subsequently randomized to receive 840 mg of oral theophylline a day or a placebo as observed by Erley et al.70 The possible explanation could be due to the use of LOCM and hydration and that the addition of theophylline did not result in a further benefit. But, the authors suggested that adenosine antagonists may have a role to play in cases in which sufficient hydration may not be possible, such as in congestive cardiac failure, in which there is concomitant decrease in renal blood flow. Several studies have not been able to show no benefit of adenosine antagonism administered before a procedure.71–73 Lack of consensus in clinical studies coupled with potential side effects of theophylline and the narrow therapeutic index of this drug, adenosine antagonism cannot yet be recommended for routine prophylactic use in the current clinical setting.

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A. Kaul / Clinical Queries: Nephrology 0101 (2012) 34–41

Dopamine agonists Dopamine is a potent vasodilator of the renal arteries, its use by Hans et al in infusion of 2.5 mg/kg/min during and after angiographic procedures provide protection against contrast-mediated renal dysfunction although only a small improvement and that to not sustained beyond day.74 Fenoldopam is a selective dopamine D1 agonist, causing va­ sodilatation of both renal and systemic vessels is thought to be protective against contrast-mediated renal vasoconstriction and increase renal plasma flow (RPF). Kini et al showed a 4.7% risk of CIN as compared to hydration group alone where its incidence was 18.8%;75 however, IV administration may cause clinically significant hypotension (due to its systemic vasodilatory effects) limiting its widespread use.

Targeted renal therapy with fenoldopam Targeted renal therapy (TRT) refers to the delivery of therapeutic medications directly to the kidneys via the renal arteries. This intrarenal (IR) drug administration improves the therapeutic window by increasing intrarenal drug concentration and reducing systemic effects. The Benephit Infusion Catheter (Angiodynamics, Queensbury, NY) is a bifurcated infusion catheter that allows TRT during coronary or peripheral catheterization to reduce CIN risk in patients with renal insufficiency. Tierstein et al compared the effect of TRT vs IV fenoldopam and found that patients who received TRT had significantly higher RPF, GFR, and nadir systolic blood pressure than those who received IV fenoldopam. Allaqaband et al found no additional benefit of fenoldopam over hydration with saline in patients with chronic renal insufficiency (baseline creatinine levels > 1.6 mg/dL or creatinine clearance < 60 mL/min).76 A deleterious rather than a protective effect on renal function in patients with diabetes was the observation by Weisberg and Kurnik.62

Endothelin-receptor blockers Endothelin induces vasoconstriction through the activation of ­endothelin-A (ET-A) receptor and vasodilatation through endothelin-B (ET-B) receptor. Okldroyd et al suggested that bosentan, an orally active endothelin antagonist, attenuated the contrast-mediated reduction of renal function in the isolated perfused rat kidney and in a multiple-insult rat model with contrast-induced renal dysfunction.77 BQ123 selective ET-A receptor antagonist may prevent the contrast-induced decrease of oxygen tension in the outer medulla without enhancing the local blood flow by antagonizing the stimulation effect of ET-A receptor on Na+–K+–ATPase activity. A recent prospective multicenter randomized trial has shown that ­endothelin-receptor antagonists actually exacerbate radiographic contrast-induced nephrotoxicity. The vasoconstriction effects of endothelin may increase significantly in patients with chronic renal insufficiency. Wong et al studied 158 patients with chronic renal insufficiency (mean creatinine level, 2.7 ± 1 mg/dL) undergoing cardiac angiography who were randomized to receive a mixed endothelin A and B antagonist or a placebo.78 The mean SCr levels and the incidence of contrast nephrotoxicity was ­increased in the treated group (P = 0.002; incidence of 56% in the treated group vs 29% in the placebo group). This negative effect was apparent for patients with and without diabetes.79

Prostaglandins A study of 117 patients receiving three separate doses of prosta­ glandin E1 (alprostadil) or a placebo showed reduced incidence of CIN in the prostaglandin group; however, a higher dose caused hypotension and increased the risk of nephropathy.71

Koch et al80 in 130 patients with renal impairment (SCr levels ≥ 1.5 mg/dL) assessed the effectiveness and compatibility of prosta­ glandin E1 in preventing contrast-induced renal dysfunction (analyzed using three separate definitions of a rise in SCr levels, ≥ 0.5, ≥ 1.0, or ≥ 1.5 mg/dL, within 48 hours of contrast injection) at three different doses of 10 ng/kg/min, 20 ng/kg/min, and 40 ng/kg/min of IV infusion over 6 hours, starting 1 hour before contrast injection vs IV physiologic saline placebo.80 None of the four groups showed a significant change in creatinine clearance. Although these results are promising, the study had limitation in form of smaller number in each subgroup, that the trial did not strictly control hydration status, type of contrast agent used (86% had non-ionic and 11.5% had ionic contrast agents administered), mode of administration of contrast material, and volume of contrast material given (volumes ranged from 20 mL to 445 mL), serious adverse effects. Thus efficacy and safety in preventing renal dysfunction in patients with pre-existing impaired renal function needs large-scale trials with stricter controls. Thus therapies that have shown either to have no benefit or to cause harm include dopamine, mannitol, furosemide, atrial natri­ uretic peptide, mixed endothelin antagonists, and calcium channel blockers. Dopamine, mannitol, and furosemideca use increase in prerenal perfusion by promoting dehydration or renal artery constriction. Calcium channel blockers have not shown to be of any benefit.

Pharmacologic agents to reduce free oxygen radicles N-acetylcysteine

N-acetylcysteine (NAC) prevents contrast-induced activation of poly(ADP-ribose), a final substrate of caspase 3, NAC also scavenges ROS such as OH- and O2-, preserves NO that dilates medullary vasculature and reduces sodium reabsorption and oxygen consumption,63 tipping the balance against medullary vasoconstriction, hypoxia, and CIN. The renal protective effects of NAC may also be contributed to its vasodilatation properties evident by higher renal blood flow in dogs during endotoxin-induced shock with NAC infusion than those without. A non-randomized study suggested that NAC might improve renal function in patients with hepatorenal syndrome.81,82 Tepel et al observed an 2% incidence of CIN79 in the NAC group and 21% in the control group (P = 0.01) in a study of 83 patients ­undergoing CT with SCr concentration 2.4 ± 1.3 mg/dL. These patients were randomly assigned either to ­receive NAC (600 mg orally twice daily) and 0.45% saline intravenously, before and after administration of iopromide (LOCM), or to receive placebo and 0.45% saline.64 A series of studies, including meta-analyses have shown conflicting results. In a recent meta-analysis of 41 randomized trials, Kelly et al concluded that NAC stands out as the most effective agent for preventing CIN in patients with chronic renal insufficiency.83 The reported association of CIN with increased morbidity, mortality, and hospital stay might justify the use of NAC as a routine intervention for prophylaxis of CIN since NAC is readily available, inexpensive, and relatively safe.74 The generation of ROS is facilitated in an acid environment as might occur in the distal nephron. Administration of sodium bicarbonate or acetazolamide will alkalinize the urine and presumably slow down the generation of these toxic oxygen species. Multiple single center trials in these patients have also produced conflicting results but recent meta-analyses suggest a benefit particularly in patients of CIAKI.

Extracorporeal strategies to remove contrast from the body Preventive hemodialysis or hemofiltration

Removal of contrast media by hemodialysis after the procedure in patients with pre-existing renal failure has been shown to have no effect on CIN and is unwarranted as a routine practice.84,85 Vogt et al showed no beneficial effect of prophylactic hemodialysis as compared to saline hydration in removal of contrast efficiently.86 In fact these



A. Kaul / Clinical Queries: Nephrology 0101 (2012) 34–41

patients who underwent hemodialysis were more likely to have a decline in renal function and require additional hemodialysis. However, use of hemofiltration in prophylaxis of ­CIN by Marenzi et al showed less frequent rise of SCr among patients in the hemofiltration group than among control ­patients (5% vs 50%, P < 0.001).87 In addition, temporary renal replacement therapy was required in 25% of the control group and in only 3% in the hemofiltration group. Inhospital events (52% vs 9%) and mortality rates (14% vs 2%) and cumulative 1-year mortality figures (30% vs 10%) were all higher in the control group than in the hemofiltration group. Marenzi et al attributes most of the benefits to hemofiltration due to its associated hemodynamic stability, preserving the circulating blood volume and preventing renal ­hypoperfusion.76 In contrast, hemodialysis can induce hypovolemia and may consequently worsen renal ischemic injury, delayed recovery of renal function, and result in the need for prolonged treatment. Although these results are extremely encouraging, the widespread use of hemofiltration is limited by its relatively high cost. It could be an effective preventive strategy in high-risk group of ­patients (those with SCr levels > 4 mg/dL and undergoing multiple interventions requiring a larger volume of contrast agent than that used during simple diagnostic radiographic procedures. Although hemofiltration may prove useful in the coronary care setting, the relevance of hemofiltration as a prophylactic strategy in general radiology departments is questionable.

Differences between contrast agents in the incidence of contrast-induced acute kidney injury Contrast media, like other osmotic particles, increase the intraluminal pressure by drawing water into the renal tubular lumen. Ueda et al found that the hydrostatic pressures of the proximal and distal ­tubule rose for about 20 minutes after infusion of diatrizoate (HOCM), iohexol (LOCM), or ioxaglate (LOCM) in the rat kidneys, respectively.88,89 The raised interstitial pressure may compress the microcirculation of the vasa recta, resulting in medullary hypoxia and CIN.90 Administering LOCM prevents intra-renal injury. A meta-analysis of 39 trials compared HOCM with LOCM showing significant reduction in CIAKI. It was observed that patients with diabetes and SCr levels between 1.5 mg/dL and 3.5 mg/dL who underwent coronary or aorto­ femoral angiography with LOCM contrast had a significantly lesser incidence of CIAKI than the group that received HOCM contrast.91 However there are conflicting reports as to whether low-osmolar or iso-osmolar CM are more beneficial in preventing CIN. Aspelin et al, found lesser incidence of CIN to develop with iso-osmolar CM than low-osmolar CM (iohexol). Liss et al involving over 57,000 ­patients, showed that the risk for developing acute renal failure and dialysis was higher when patients received the iso-osmolariodixanol vs the low-osmolarmedia ioxaglate or iohexol.92

Pre-procedural preparation to avoid contrast-induced nephropathy Patients undergoing contrast studies should be assessed for the risk of developing AKI secondary to contrast agents. All patients should have a pre-procedure creatinine, and a GFR estimation should be calculated. 1. Diuretics should be withheld the day of the procedure to prevent dehydration. 2. Non-steroidal anti-inflammatory drugs (NSAIDs) should be discontinued, but aspirin and clopidogrel can be administered before the procedure. 3. Use of intravenous normal saline which is relatively costeffective and safe, volume supplementation reduces the risk of CIN, and should be considered in all patients undergoing procedures with intravascular contrast. The infusion rate and total volume of hydration should be reduced in ­patients with a history of CHF.

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4. Use of LOCM prevents intrarenal injury may help in preventing CIN. The total contrast volume should be closely monitored. 5. Sodium bicarbonate infusion should be started 1 hour prior to the procedure, in addition to hydration in high-risk group. 6. The use of NAC may prevent significant increases in SCr in ­patients with chronic renal insufficiency undergoing contrast procedures. Two doses of oral N-acetylcysteine 600–1200 mg should have been given the day before admission and two doses on the day of the procedure. 7. Maintaining adequate urine output (100 mL/hr) may require the use of a Foley catheter for accurate measurement. 8. Avoiding nephrotoxic medications, including aminoglycosides, amphotericin B, cisplatin/carboplatin, and NSAIDs to prevent further tubular epithelial cell damage. 9. Hypotension should be avoided to prevent low renal perfusion. In the event of hypotension, fluid resuscitation should be used, avoiding dopamine and epinephrine. Underlying cause of hypotension should be treated. 10. Renal function should be assessed 3–7 days after the procedure.

Clinical implications of contrast-induced nephropathy Short-term implications

There is growing research showing an association of CIN with serious short- and long-term outcomes. Besides data from observational studies and clinical trials showing consistent association with small post-angiography decrements in renal function with short-term mortality, it is associated with prolonged hospitalization and increased health care expenditure.93–103

Long-term implication

There is significant data to indicate small decrement in renal function after contrast-enhanced procedures, even if transient to be ­associated with even long-term mortality and progression of CKD.97,104–108 However these observational studies have their inherent limitations and biases, whether CIN is a mediator of serious downstream events or simply serves as a marker of patients at particularly highrisk for these outcomes needs to be seen.109–113 Considering the limitation of studies concerning clinical consequences of CIN, one should not preclude the routine performance of clinically indicated and ­potentially life-saving procedures. There has been growing concern about the clinical implications of CIN may contribute to suboptimal clinical care and there are observational studies showing less frequent performance of angiography in patients with acute coronary events who had underlying CKD. Provider concern for adverse outcomes-related to CIN may at least in part, motivate decisions on the performance of angiography in patients with CKD.113–115 Conclusion With increasing number of contrast-enhanced procedures being conducted in otherwise normal or impaired renal function, CIN stands out as an important cause for in hospital morbidity and mortality. Thus aim of treating such high-risk patients should involve strategies targeted in mitigating its occurrence. Injury to renal cells occurs during exposure to contrast media. Our ability to detect such injury clinically is limited. The use of an imperfect marker of kidney function (SCr) may result in a false sense of safety, as only the ‘tip of the iceberg’ is being exposed by such measurements. Although series of observational and retrospective analysis have shown close association of CIN with long- and short-term serious adverse effects, evidences that CIAKI is a mediator rather than marker of patients at risk for adverse outcomes is lacking. There is growing number of studies showing underperformance of angiography procedures when required in CKD in whom it was clearly indicated, is a serious concern. Research should be focused on prevention of CIN and also on efficacy of interventions for prevention of hard outcomes that matter most to patients.

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