Prevention of radiocontrast-induced nephropathy

Prevention of Radiocontrast-Induced Nephropathy Arif Asif, MD, and Murray Epstein, MD ● Radiocontrast administration is a common cause of hospital-acquired acute renal failure. It is associated with significant in-hospital and long-term morbidity and mortality and increases the costs of medical care by at least extending the hospital stay. Although individuals with normal renal function generally are not considered to be at particular risk, patients with preexisting renal failure are much more likely to experience this complication after radiocontrast agent administration. Typically, serum creatinine levels begin to increase at 48 to 72 hours, peak at 3 to 5 days, and return to baseline within another 3 to 5 days. A variety of therapeutic interventions, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, and dopamine, have been used in an attempt to prevent radiocontrast-induced nephropathy. Of these, saline hydration is the sole efficacious therapy to protect against radiocontrast-induced nephropathy. Recent advances have examined the impact of fenoldopam (dopamine-1 [DA-1] receptor; DA-1 agonist), the antioxidant N-acetylcysteine, iso-osmolar contrast agents, hemodialysis, and hemofiltration in ameliorating radiocontrast-induced nephropathy. This review focuses on current interventions to ameliorate radiocontrast-induced acute renal failure and provides an analysis of some of the recent studies conducted to halt radiocontrast-induced nephropathy. Am J Kidney Dis 44:12-24. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Radiocontrast-induced nephropathy; fenoldopam; N-acetylcysteine (NAC); ultrafiltration; isoosmolar agents.

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ADIOCONTRAST-INDUCED nephropathy remains a common cause of acute renal failure in patients undergoing radiocontrast study.1 Radiocontrast-induced acute renal failure increases the costs of medical care by extending the hospital stay and increases morbidity and mortality.1-6 With more than a million radiocontrast procedures performed annually, the incidence of radiocontrast-induced nephropathy is approximately 150,000 cases/y.4,5 At least 1% of these episodes require dialysis therapy with prolongation of hospital stay to an average of 17 days, with an additional cost of approximately $32 million annually.4,5 For episodes that do not require dialysis, prolongation of the hospital stay by 2 days (at $500/d) would translate into an added cost of $148 million annually.5 The proposed pathophysiologic mechanisms of radiocontrast-induced acute renal failure are complex, with a variety of factors (intrarenal vasoconstriction with resultant medullary hypoxia, reactive

oxygen species production, direct tubular toxicity) acting together to induce acute renal failure.7,8 Whereas individuals with normal renal function are not considered to be at particular risk for radiocontrast-induced nephropathy, patients with certain comorbid conditions, such as preexisting renal insufficiency and diabetes with microvascular and macrovascular disease, are much more likely to experience acute renal failure after contrast administration.7 Although no effective treatment for radiocontrast-induced nephropathy exists, there has been intense investigative interest in and several publications on therapeutic measures aimed at preventing this common and life-threatening syndrome. In this report, we focus on recent advances to forestall radiocontrast-induced nephropathy.

From the Department of Medicine, Division of Nephrology, University of Miami School of Medicine, Miami, FL. Received February 10, 2004; accepted in revised form April 2, 2004. Address reprint requests to Murray Epstein, MD, Professor of Medicine, University of Miami School of Medicine, 1600 NW 10th Ave (R 7168), Miami, FL 33136. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4401-0001$30.00/0 doi:10.1053/j.ajkd.2004.04.001

Recently, a variety of therapeutic interventions have been used to prevent radiocontrastinduced acute renal failure. These include administration of a dopamine-1 (DA-1) receptor stimulant (fenoldopam), antioxidant use (Nacetylcysteine [NAC]), iso-osmolar radiocontrast medium administration, hemofiltration and hemodialysis therapy, and hydration with normal saline (Tables 1 to 4).

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RECENT ADVANCES IN PROPHYLAXIS AGAINST RADIOCONTRAST-INDUCED NEPHROPATHY

American Journal of Kidney Diseases, Vol 44, No 1 (July), 2004: pp 12-24

RADIOCONTRAST-INDUCED NEPHROPATHY Table 1.

Reference

13

Studies With Intravenous Fenoldopam Against Radiocontrast-Induced Nephropathy

Study Design

No. of Patients

Hunter et al12

Case series

29

Madyoon et al13

Retrospective analysis

46

Kini and Sharma15

Case series

Tumlin et al16

Stone et al17

No. of Hypotensive Events

0.1-0.5 Escalating dose 0.1-0.5 Escalating dose

0 0

110

0.1

4

Multicenter randomized trial

45

0.1

3

Multicenter randomized trial

315

0.05-0.1 Escalating dose

Several patients

Fenoldopam and Radiocontrast-Induced Nephropathy Fenoldopam is a vasodilator that was derived by modifying the phenethylamine structure of dopamine.9 It is a specific DA-1 agonist and even at high doses, it is devoid of DA-2, ␣-adrenergic, or ␤-adrenergic stimulation and thus free of the unwanted effects of the coincidental DA-2, ␣-adrenergic, or ␤-adrenergic receptor stimulation accompanying less selective agents, such as dopamine.9,10 Fenoldopam induces renal vasodilatation. Renal effects of fenoldopam include a decrease in renal vascular resistance and, Table 2.

Fenoldopam Dose (␮g/kg/h)

Confounding Factors

State of hydration not specified State of hydration not specified and lack of randomization Type of coronary interventions may have induced hypotension Dose of fenoldopam infused may have not been optimal Dose of fenoldopam infused may have not been optimal

preferentially, increases in blood flow to the outer medulla, glomerular filtration rate (GFR), and urinary sodium and water excretion.9,10 Preclinical Studies Bakris et al11 were the first to evaluate the effect of fenoldopam on renal hemodynamics after radiocontrast administration. They examined the effects of fenoldopam and a DA-1 antagonist (Schering 23390; Schering-Plough, Kenilworth, NJ) in an animal model of radiocontrast-induced intrarenal vasoconstriction and reduction of GFR. The objective of the study was

Studies Evaluating Antioxidant Use for Prophylaxis Against Radiocontrast-Induced Nephropathy

Reference

Study Design

No. of Patients

Intervention Used

Protection Against RadiocontrastInduced Nephropathy

Tepel et al36 Diaz-Sandoval et al37 Shyu et al39 Kay et al40 Baker et al51 Briguori et al38 Durham et al35

Randomized Randomized Randomized Randomized Randomized Randomized Randomized

83 54 121 200 80 183 79

NAC, 600 mg, orally* NAC, 600 mg, orally* NAC, 400 mg, orally* NAC, 600 mg, orally* NAC infusion† NAC, 600 mg, orally‡ NAC orally§

Yes Yes Yes Yes Yes No No

*Treatment was initiated a day before the radiocontrast study and NAC was administered twice a day for 2 days. †NAC infusion consisted of 150 mg/kg in 500 mL of normal saline over 30 minutes immediately before the procedure, followed by 50 mg/kg in 500 mL of normal saline over 4 hours after contrast administration. ‡Increased dose of radiocontrast material used in the study compared with the other studies highlighted in this table could have been a confounding factor and contributed to the lack of protection against radiocontrast-induced nephropathy. §NAC, 1,200 mg, was administered 1 hour before and 3 hours after angiography. In this study, use of a nonstandard dose and schedule may have confounded the results.

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ASIF AND EPSTEIN

Table 3.

Osmolarity of Various Radiocontrast Media

Radiocontrast Agent

HOCM Diatrizoate (Urografin; Bracco Diagnostics, Princeton, NJ) Iothalamate (Conray 60; Mallinckrodt, St Louis, MO) LOCM Iohexol (Omnipaque; Nycomed Inc, Princeton, NJ) Iopamidol (Isovue; Bracco Diagnostics) IOCM Iotrolan (Isovist; Schering SPA, Milan, Italy) Iodixanol (Visipaque; Nycomed, New York, NY)

Ratio of Iodine Atoms to Dissolved Particles

Osmolarity (mOsm/kg)

1.5

2,070

1,400

3.0

780

796

6.0

320 290

Abbreviations: HOCM, high-osmolar contrast medium; LOCM, low-osmolar contrast medium; IOCM, iso-osmolar contrast medium. Data from Katzberg.46

to test the hypothesis that DA-1 stimulation blunted the decline in renal blood flow (RBF) and GFR. Six anesthetized volume-depleted adult mongrel dogs (baseline GFR, 35 mL/min) were evaluated. Fenoldopam was infused at 0.01 ␮g/ kg/min into the renal artery. Results of the study showed that fenoldopam prevented reductions in GFR (control, ⫺17 ⫾ 2 mL/min versus fenoldopam, 2 ⫾ 1 mL/min; P ⬍ 0.001). Conversely, GFR was decreased further in the presence of antagonist (control, ⫺15 ⫾ 2 mL/min versus Schering 23390, ⫺23 ⫾ 1 mL/min; P ⬍ 0.05). Table 4.

Similarly, the maximal reduction in RBF was blunted with fenoldopam (control, ⫺17 ⫾ 12 mL/min versus fenoldopam, ⫺3 ⫾ 2 mL/min; P ⬍ 0.01), whereas Schering 23390 intensified the radiocontrast-induced reduction in RBF (control, ⫺85 ⫾ 11 mL/min versus Schering 23390, ⫺119 ⫾ 14 mL/min; P ⬍ 0.05). The investigators concluded that DA-1 stimulation with fenoldopam protected against the adverse effect of radiocontrast on renal hemodynamics in this animal model. Clinical Observations These observations recently were expanded to humans (Table 1). Several investigators evaluated the protective role of fenoldopam against radiocontrast-induced acute renal failure.12-17 Hunter et al12 evaluated the renal effects of fenoldopam in 29 patients with decreased renal function (mean serum creatinine level, 2.3 mg/dL [203 ␮mol/L]) who underwent radiocontrast study. Fifty-nine percent of patients had diabetes. Fenoldopam infusion was started 2 hours before radiocontrast administration at a rate of 0.1 ␮g/ kg/min. The dose was increased in increments of 0.1 ␮g/kg/min every 20 minutes until a rate of 0.5 ␮g/kg/min was achieved or systolic blood pressure decreased by more than 40 mm Hg or to less than 110 mm Hg. After radiocontrast administration, the fenoldopam infusion was continued for up to 4 hours at the highest achieved dose. Twenty-four to 48 hours after contrast infusion, mean serum creatinine level was 12% lower than baseline. At 24 hours, 16 of 29 patients showed decreases in serum creatinine levels ranging from 0.2 mg/dL (18 ␮mol/L) to 1.4 mg/dL (124 ␮mol/ L), whereas 3 patients showed increases in serum creatinine levels ranging from 0.2 mg/dL (18

Studies Evaluating the Role of Renal Replacement Therapy to Prevent Radiocontrast-Induced Nephropathy

Reference

Study Design

No. of Patients

Intervention Used

Protection Against RadiocontrastInduced Nephropathy

Vogt et al63 Frank et al64 Marenzi et al6

Randomized Randomized Randomized

113 17 114

High-flux hemodialysis* High-flux hemodialysis† Continuous venovenous hemofiltraion‡

No No Yes

*Hemodialysis session was initiated immediately after contrast administration for 4 to 6 hours. †Hemodialysis was performed simultaneously during radiocontrast administration for 4 hours. ‡Continuous venovenous hemofiltration was performed 4 to 6 hours before radiocontrast administration and continued for 18 to 24 hours thereafter.

RADIOCONTRAST-INDUCED NEPHROPATHY

␮mol/L) to 0.9 mg/dL (80 ␮mol/L). The investigators did not observe a decrease in systemic blood pressure. Although these data suggest that fenoldopam administration protects against radiocontrast-induced nephropathy, several limitations of the study do not allow a definite conclusion because of the small sample size, absence of a control group, and failure to control other factors, such as state of hydration. In a retrospective analysis, Madyoon et al13 evaluated 46 consecutive radiocontrast procedures in patients with and without diabetes with serum creatinine concentrations greater than 1.5 mg/dL (⬎133 ␮mol/L) and 1.7 mg/dL (⬎150 ␮mol/L), respectively. These investigators used the protocol of Hunter et al12 to infuse fenoldopam as described. The incidence of radiocontrastinduced nephropathy was 13% (6 of 46 patients) in the fenoldopam group compared with 38% (19 of 50 patients) in the comparator group.18 Although results of the study were encouraging, lack of randomization and use of a historic comparison group make it difficult to conclude that routine use of fenoldopam for this purpose is warranted. However, the study confirmed the successful application of a dose range of 0.1 to 0.5 ␮g/kg/min of fenoldopam, as used in the previous study by Hunter et al.12 Kini and Sharma15 examined the beneficial effects of fenoldopam against radiocontrastinduced nephropathy in the setting of patients undergoing percutaneous coronary interventions. Inclusion criteria were baseline serum creatinine level exceeding 1.5 mg/dL (⬎133 ␮mol/L) and at least 1 of the following risk factors: diabetes, compensated heart failure, age older than 70 years, or hypertension. Fenoldopam (0.1 ␮g/kg/min) was infused 15 to 20 minutes before administration of contrast medium and continued for 6 hours after the procedure. In addition, hydration was ensured with halfnormal saline administered intravenously for 10 to 12 hours before and 10 to 12 hours after the procedure. Patients with matching baseline demographics (n ⫽ 177) were used as historic controls for the prospectively studied group (n ⫽ 110). Radiocontrast-induced nephropathy was defined as an increase in serum creatinine level greater than 25% from baseline within 48 to 72 hours after the procedure or an absolute increase in serum creatinine level greater than 0.5 mg/dL

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(⬎44 ␮mol/L). Compared with historic controls, fenoldopam-treated patients had a significantly lower incidence of radiocontrast-induced nephropathy (4.5% versus 18.8%; P ⫽ 0.009). These investigators used a dose of fenoldopam that was significantly lower than that used by Hunter et al12 and Madyoon et al.13 Nonetheless, the investigators reported a significant decrease in blood pressure (systolic pressure ⬍ 90 mm Hg) after fenoldopam infusion in 4 patients (3.8%). Blood pressures rapidly returned to baseline after decreasing the dose of fenoldopam, and no serious adverse effect was attributed to hypotension. Interestingly, the incidence of hypotension was not significantly different from that in the historic control group (fenoldopam, 3.8% versus control, 1.7%; P ⫽ not significant). Coronary interventions in this study included stent, Rotablator (SCIMED, Boston Scientific Corp, Boston, MA), Rota plus stent, and AngioJet (Possis Medical Inc, Minneapolis, MN) plus stent, all known to carry the risk for bradycardia and hypotension.19-25 The study documented the beneficial effect of fenoldopam against radiocontrastinduced nephropathy in patients with kidney disease, both with and without diabetes. However, half-normal saline administered 10 to 12 hours before and continued for 12 hours after the study could have been a confounding factor. In this study, the lack of randomization does not allow for the definite conclusion of fenoldopam’s protective role against radiocontrast-induced nephropathy. Based on positive results from these studies and a small, multicenter, randomized, doubleblind trial to evaluate the use of fenoldopam for the prevention of radiocontrast-induced nephropathy,16 Stone et al17 conducted a large-scale study to settle the protective effects of fenoldopam against radiocontrast-induced nephropathy. In this prospective, placebo-controlled, double-blind, multicenter trial, 315 patients with a creatinine clearance less than 60 mL/min (⬍1.00 mL/s) were hydrated and randomly assigned to administration of fenoldopam infusion (0.05 ␮g/kg/ min titrated to 0.1 ␮g/kg/min [n ⫽ 157]) or matching placebo (n ⫽ 158). Radiocontrastinduced nephropathy was defined as at least a 25% increase in serum creatinine levels from baseline values. Nearly 50% of patients had diabetes. Radiocontrast-induced nephropathy oc-

16

curred in 33.6% of patients in the fenoldopam group compared with 30.1% in the placebo group (P ⫽ 0.61). The study concluded that fenoldopam did not protect against radiocontrast-induced nephropathy when administered at a dose range of 0.05 to 0.10 ␮g/kg/min. However, in this study, the dose of fenoldopam was titrated up to a maximum dose of only 0.1 ␮g/kg/min. Conversely, fenoldopam infusions up to 0.5 ␮g/kg/min have been administered successfully in multiple studies evaluating renal function in healthy subjects and hypertensive and critically ill patients and for the prophylaxis of radiocontrast-induced nephropathy. Moreover, previous studies documented that fenoldopam increased RBF in a dose-dependent manner.26,27 Hence, a dose greater than 0.1 ␮g/kg/min may be needed to achieve optimal prophylactic action against radiocontrast-induced nephropathy. However, increasing the dose increases the risk for hypotension with resultant intrarenal vasoconstriction. Many studies failed to show a significant decrease in blood pressure, even at 0.5 ␮g/kg/ min.12,13,26-29 However, in the study of Kini and Sharma,15 3.8%, whereas in the study of Tumlin et al,16 11% of patients experienced hypotension (systolic pressure ⬍ 90 mm Hg). Hypotension was reversed promptly (within 5 minutes) by withholding the drug and infusing saline. No adverse effects, including the development of radiocontrast-induced nephropathy, were documented in these studies. In summary, based on the current information, use of fenoldopam cannot be endorsed for prophylaxis against radiocontrast-induced acute renal failure. However, additional studies should be conducted in which the appropriate study design would obviate the confounding factors cited, including type of coronary intervention, left versus right heart catheterization, timing of the contrast injection, and medications administered during coronary interventions. The Antioxidant NAC and Radiocontrast-Induced Nephropathy Recent attention has focused on the use of NAC to prevent radiocontrast-induced nephropathy (Table 2). NAC, a scavenger of reactive oxygen species, is a thiol-containing antioxidant. It is a potent vasodilator known to increase the expression of nitric oxide synthase and the bio-

ASIF AND EPSTEIN

logical effects of nitric oxide.30-34 In addition, NAC prevents tolerance to the vasodilatory effects of nitrates, has inhibited the immediate early gene response, and ameliorates ischemic renal failure.33 Finally, NAC also may exert its antioxidant effect indirectly by facilitating glutathione biosynthesis. Animal studies support a protective role of antioxidants against radiocontrast-induced renal dysfunction.30-33,35 To this end, multiple studies of humans have evaluated the impact of NAC against radiocontrast-induced nephropathy.35-44 In a randomized study by Tepel et al,36 83 patients with chronic renal failure (baseline serum creatinine level, 2.4 ⫾ 1.3 mg/dL [212 ⫾ 115 ␮mol/L]) were randomly assigned to administration of either NAC (600 mg every 12 hours 1 day before and the day of the radiocontrast study) plus half-normal saline (1 mL/kg/h for 12 hours before and 12 hours after the study) or placebo and half-normal saline. Radiocontrast-induced nephropathy was defined as an increment of at least 0.5 mg/dL (44 ␮mol/L) in serum creatinine level above baseline. The incidence of radiocontrast-induced nephropathy in the NAC group was 2% compared with 21% in placebo-treated patients (P ⫽ 0.01). The investigators concluded that administration of NAC with half-normal saline was protective against radiocontrastinduced nephropathy in patients with chronic renal insufficiency undergoing radiocontrast study. These finding were confirmed by Diaz-Sandoval et al37 in a randomized, double-blind, placebocontrolled study; these investigators also found acetylcysteine to be protective against radiocontrast-induced nephropathy. Fifty-four patients were randomly assigned to administration of either 600 mg of NAC twice daily for 4 doses or placebo. All patients were administered 0.45% saline infusion for 2 to 12 hours before and 12 hours after the contrast study. The incidence of radiocontrast-induced nephropathy was 8% in the acetylcysteine group versus 45% in the placebo group (P ⫽ 0.005). Of note, the incidence of contrast-induced renal failure in the placebo group was unusually high (45%) compared with the previously reported incidence (⬃10%) with saline infusion alone. In contrast to these reports, a few studies documented that NAC did not protect against

RADIOCONTRAST-INDUCED NEPHROPATHY

radiocontrast-induced nephropathy. A recent study by Briguori et al38 failed to find a significant effect of acetylcysteine on the occurrence of radiocontrast-induced nephropathy. One hundred eighty-three patients with preexisting renal insufficiency undergoing contrast study were randomly assigned to administration of acetylcysteine at a dose of 600 mg twice daily on the day before and the day of the contrast study plus saline infusion or saline alone. Saline (0.45%) infusion was administered at a rate of 1 mL/kg/h for 12 hours before and after contrast exposure. The incidence of radiocontrast-induced nephropathy was 6.5% in the acetylcysteine group versus 11% in the control group (P ⫽ 0.22). The investigators did not find a significant effect on the occurrence of radiocontrast-induced nephropathy between the 2 groups. However, in contrast to the study of Tepel et al,36 in which only a modest dose of contrast material (75 mL) was administered to all patients, Briguori et al38 administered a large amount of contrast dye (mean, 200 ⫾ 144 [SD] mL). It has been documented that increasing the dose of radiocontrast medium increases the risk for radiocontrast-induced nephropathy.6 In this context, an increase in antioxidant dose should have been considered accordingly. In this study, analysis of a subgroup of patients administered a lower dose of contrast (⬍140 mL) clearly showed that radiocontrast-induced nephropathy occurred in 5 of 60 patients (8.5%) in the control group and none of 60 patients in the acetylcysteine group (P ⫽ 0.02). Several of the problems that confound an ostensibly definitive study are represented in a recent report by Durham et al.35 These investigators reported that NAC administration failed to protect against radiocontrast-induced nephropathy. Seventy-nine patients with serum creatinine levels exceeding 1.7 mg/dL (⬎150 ␮mol/L) were randomly assigned to administration of NAC (1,200 mg orally 1 hour before and 3 hours after the contrast study) plus conventional therapy (0.45 normal saline at 1 mL/kg/h) or placebo plus conventional therapy. Results of the study showed no significant difference in incidence of radiocontrast-induced nephropathy between the 2 groups (NAC, 26.3%; placebo, 22.0%; P ⫽ not significant). However, several elements of the experimental design may have confounded the

17

interpretation of the study. Rate and duration of saline infusion were not specified; consequently, we cannot infer to which extent the confounders confounded the results. The investigators were permitted to modify the hydration regimen based on clinical status of the patient. Hence, volume status of the patients in this study was not controlled. The study also used a nonstandard treatment dose and schedule of NAC. Whereas previous studies used 600 mg administered twice a day started 1 day before and continued for 1 day after radiocontrast administration, Durham et al35 used 1,200 mg of oral NAC 1 hour before and 3 hours after the contrast study. It is conceivable that a metabolite of NAC may have antioxidant or other favorable properties against radiocontrast-induced nephropathy and provided the protection against radiocontrast-induced nephropathy seen in other studies using this agent for prophylaxis against radiocontrast-induced acute renal failure. Although there were no significant differences between groups in terms of diuretic use, urine output after the saline infusion was not recorded. Consequently, the possibility that the diuresis in 1 group exceeded that in the other group cannot be excluded. Recently, in a randomized trial, Goldenberg et al43 also concluded that NAC did not protect against radiocontrast-induced nephropathy in patients with mild to moderate renal insufficiency. However, the small sample size (n ⫽ 80) and relatively low dose of contrast medium precluded a definitive conclusion that NAC did not confer protection against radiocontrast-induced nephropathy. Subsequent to these studies, multiple wellconducted randomized studies from separate centers evaluating more than 400 patients have established the superiority of NAC over saline infusion.39,40 In a recent randomized study, Brigouri et al44 tested whether a double dose (1,200 mg) of NAC is more effective to protect against radiocontrast-induced acute renal failure. Two hundred twenty-four consecutive patients with chronic renal failure (serum creatinine level ⱖ 1.5 mg/dL [ⱖ133 ␮mol/L]) undergoing coronary and/or peripheral radiocontrast studies were randomly assigned to administration of 0.45% saline intravenously and NAC (standard dose, 600 mg; n ⫽ 110) or 0.45% saline and NAC (double dose, 1,200 mg; n ⫽ 114). NAC administration

18

was initiated a day before the contrast study and continued a day for after. The incidence of radiocontrast-induced nephropathy (defined as an increase of at least 0.5 mg/dL [44.2 ␮mol/L] in creatinine concentration 48 hours after the procedure) was 11% in the single-dose group versus 3.5% in the double-dose group (P ⫽ 0.038). In the subgroup with a low dose (⬍140 mL; n ⫽ 114) of contrast agent, there was no significant difference in deterioration of renal function. However, in patients administered a large volume of contrast agent (⬎140 mL; n ⫽ 109), radiocontrast-induced nephropathy occurred significantly more frequently in the group administered the standard dose of NAC (18.9%) versus the cohort administered the double dose (5.4%; P ⫽ 0.039). In addition to oral NAC, a rapid protocol using intravenous administration of NAC when time constraints preclude adequate oral prophylaxis to protect against radiocontrast-induced nephropathy also was evaluated recently. In this study, Baker et al41 randomly assigned 80 patients with chronic renal failure to administration of either NAC infusion (n ⫽ 41; 150 mg/kg in 500 mL of normal saline over 30 minutes immediately before the procedure, followed by 50 mg/kg in 500 mL of normal saline over 4 hours after contrast administration) versus saline infusion (n ⫽ 39; 1 mL/kg/h started 12 hours before and continued for 12 hours after contrast administration). Radiocontrast-induced acute renal failure developed in only 2 patients (5%) in the NAC group versus 8 patients (21%) in the saline group (P ⫽ 0.04). The investigators concluded that NAC infusion protects against radiocontrast-induced nephropathy. However, this protocol must be used with caution in patients for whom volume overload may be a concern. A recent meta-analysis by Birck et al42 comparing NAC and hydration versus hydration alone also documented a positive impact of NAC prophylaxis against radiocontrast-induced nephropathy. Seven randomized controlled trials evaluating more than 800 high-risk patients (serum creatinine level, 1.4 to 2.8 mg/dL [124 to 248 ␮mol/L]) for developing this complication after radiocontrast administration were included in this meta-analysis. The mean amount of radiocontrast media ranged from 75 to 187 mL. All 7 studies used nonionic low-osmolality radiocontrast agents. This analysis showed that compared

ASIF AND EPSTEIN

with periprocedural hydration alone, administration of NAC and saline hydration significantly reduced the relative risk for radiocontrast-induced acute renal failure by 56% (relative risk, 0.435; 95% confidence interval, 0.215 to 0.879; P ⫽ 0.02). In summary, based on available data, administration of acetylcysteine to high-risk patients protects against radiocontrast-induced nephropathy. The low cost of acetylcysteine; its limited side effects, general availability, and ease of administration; and the importance of the magnitude of the impact of radiocontrast-induced nephropathy in addition to the available studies with positive results are compelling reasons to use this agent in high-risk populations. Osmolality of Contrast Media and Radiocontrast-Induced Nephropathy Currently used contrast media possess iodine atoms, ionizing carboxyl group, sodium, meglumine, and hydroxyl group.45,46 Iodine atoms provide opacification, whereas the dissolved particles are believed to be potentially nephrotoxic. The relationship between imaging quality and osmotoxic effects of contrast medium is described by the ratio of iodine atoms to dissolved particles. Higher ratios are associated with better opacification and less nephrotoxicity. Radiocontrast media with an iodine atom to dissolved particle ratio of 1.5 are known as high-osmolarity contrast media (HOCM), whereas agents with ratios of 3 and 6 are low-osmolar contrast media (LOCM) and iso-osmolar contrast media (IOCM), respectively (Table 3).46 In addition to differences in osmolality, radiocontrast agents also are characterized as ionic versus nonionic. Nonionic agents are water soluble and yet do not dissociate in solution; hence, they do not increase the number of dissolved particles in a solution. Theoretically, a nonionic contrast medium with higher iodine atom to dissolved particle ratio would possess the highest opacification and least nephrotoxicity. Although safer than HOCM, the nephrotoxicity of low-osmolar nonionic contrast agents has been well documented.47-54 Recently, studies have been initiated to evaluate the protective role of IOCM beyond that of LOCM against radiocontrast-induced acute renal failure.55-61 Several studies documented the safety of IOCM administered to healthy individuals and patients

RADIOCONTRAST-INDUCED NEPHROPATHY

with chronic renal failure.55-61 IOCM are isoosmolar to blood and posses a lower level of general toxicity compared with LOCM. Chalmers and Jackson59 were the first to suggest a protective role of IOCM against radiocontrastinduced nephropathy compared with LOCM. One hundred twenty-four consecutive patients with chronic renal failure (one third had diabetes) undergoing angiography were included in this study. Patients were randomly assigned to administration of either iodixanol (IOCM) or iohexol (LOCM). Both groups were administered similar doses of radiocontrast agents. Serum creatinine levels were measured at 24 hours and at variable intervals until discharge. The maximum increase in creatinine levels during the first week was recorded. A greater than 10% and 25% increase in serum creatinine levels from baseline were recorded and compared between the 2 groups. One hundred two patients completed the study. Two of 54 patients (3.7%) in the iodixanol group and 5 of 48 patients (10%) in the iohexol group had at least a 25% increment in serum creatinine levels. Similarly, 8 of 54 patients (15%) in the iodixanol group and 15 of 48 patients in the iohexol group (31%) had an increase in serum creatinine levels of less than 10% (P ⬍ 0.05). The investigators concluded that IOCM offered better protection against radiocontrast-induced nephropathy compared with LOCM. These observations recently were confirmed by a well-executed, randomized, double-blind, multicenter trial.61 This trial included 129 patients with diabetic nephropathy (serum creatinine level, 1.5 to 3.5 mg/dL [133 to 309 ␮mol/ L]). Each patient was randomly assigned to administration of either iodixanol or iohexol. Baseline characteristics showed no differences between the 2 groups. All patients were well hydrated before the contrast study (angiography). Hydration included 500 mL of water orally, 500 mL of isotonic saline intravenously, or both. From the start of the procedure, all patients were administered 1 L of normal saline or similar fluids. Serum creatinine levels were measured before (baseline; day 0) and after contrast administration at days 2, 3, and 7. The peak increase in serum creatinine levels between days 0 and 3 was the primary endpoint, whereas secondary endpoints were numbers of patients with a peak increase in serum creatinine level of at least 0.5

19

mg/dL (44 ␮mol/L) and 1.0 mg/dL (88 ␮mol/L; parameters commonly used to define radiocontrast-induced nephropathy) days 0 through 3. Change in serum creatinine level from day 0 to day 7 also was recorded. All 129 patients completed the study (iodixanol, n ⫽ 64; iohexol, n ⫽ 65). Results showed a significantly smaller peak increase in mean serum creatinine level in the iodixanol group (0.13 mg/dL [12 ␮mol/L]) compared with the iohexol group (0.55 mg/dL [49 ␮mol/L]; P ⫽ 0.001) within 3 days after radiocontrast administration. Two of 64 patients in the iodixanol group (3%) and 17 of 65 patients (26%) in the iohexol group had an increase in serum creatinine levels of at least 0.5 mg/dL (44 ␮mol/L; P ⫽ 0.002). No patient in the iodixanol group had an increase in serum creatinine concentration of 1.0 mg/dL (88 ␮mol/L), whereas 10 of 65 patients (15%) showed this occurrence in the iohexol group. Finally, mean change in creatinine concentrations from day 0 to day 7 was significantly lower in the iodixanol (0.07 mg/dL [6 ␮mol/L]) compared with the iohexol group (0.24 mg/dL [21 ␮mol/L]; P ⫽ 0.003). Aspelin et al61 clearly documented that IOCM offer protection against radiocontrast-induced nephropathy that is above and beyond the prophylaxis offered by LOCM in the high-risk group. Of note, in this study, 4 patients in the iodixanol group and 7 patients in the iohexol group were administered NAC as a prophylactic agent against radiocontrast-induced nephropathy. However, exclusion of these patients from analysis did not alter the findings of the study. In conclusion, for patients at particularly high risk (patients with diabetes with advanced renal failure) for developing radiocontrast-induced nephropathy, it is reasonable to use IOCM to minimize the risk for radiocontrast-induced acute renal failure. The risk for radiocontrast-induced nephropathy in patients with normal renal function is equal for either LOCM or HOCM. Hence, the use of these agents is not justified in patients who are not at risk for radiocontrast-induced acute renal failure. Additionally, the smallest possible dose of contrast should be administered to minimize the risk for radiocontrast-induced nephropathy.7,62 A dose less than 2 mL/kg has been suggested to be relatively safe; however, doses as low as 20 to 30 mL are capable of inducing radiocontrast-induced nephropathy.7,62

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Renal Replacement Therapy and Radiocontrast-Induced Nephropathy Both hemodialysis and peritoneal dialysis remove contrast medium effectively; however, in a randomized study (n ⫽ 113), prophylactic hemodialysis immediately after radiocontrast administration was not shown to provide protection against the subsequent development of radiocontrast-induced nephropathy63 (Table 4). In contrast to a hemodialysis session immediately after dialysis, a recent study evaluated the protective role of simultaneous hemodialysis against radiocontrast-induced nephropathy.64 This randomized study included 17 patients with advanced renal failure (serum creatinine level ⱖ 3 mg/dL [ⱖ265 ␮mol/L]). All patients were hydrated with normal saline and randomly assigned to undergo simultaneous high-flux hemodialysis for 4 hours (n ⫽ 7) or to a control group (n ⫽ 10). Creatinine clearance was measured at baseline and 1 and 8 weeks after contrast administration. Using highpressure liquid chromatography, plasma levels of radiocontrast material were measured at 15, 30, and 60 minutes and 2, 4, 12, 24, 48, and 72 hours. Baseline demographic characteristics were similar in both groups. Consistent with previous findings, total clearance of radiocontrast agent (iomeprol) was significantly greater (54 ⫾ 15 mL/min) in the group that underwent hemodialysis compared with the control group (20 ⫾ 12 mL/min; P ⬍ 0.001). Similarly, the area under the curve was significantly lower in the hemodialysis group (23 ⫾ 10 g ⫻ h/L) compared with the control group (94 ⫾ 57 g ⫻ h/L; P ⬍ 0.001). However, the incidence of radiocontrast-induced nephropathy was similar in both groups; 2 patients in each group developed radiocontrastinduced nephropathy. Simultaneous hemodialysis during radiocontrast administration did not protect against radiocontrast-induced nephropathy. In contrast to intermittent hemodialysis, a recent study provided evidence that hemofiltration offered protection against radiocontrast-induced nephropathy. In this randomized study, Marenzi et al6 studied the role of prophylactic hemofiltration against radiocontrast-induced nephropathy. One hundred fourteen consecutive patients with advanced chronic renal failure undergoing percutaneous coronary interventions were randomly

ASIF AND EPSTEIN

assigned to either hemofiltration (n ⫽ 58; mean serum creatinine level, 3.0 ⫾ 1.0 [SD] mg/dL [265 ⫾ 88 ␮mol/L]) or isotonic saline hydration (n ⫽ 56; mean serum creatinine level, 3.1 ⫾ 1.0 mg/dL [274 ⫾ 88 ␮mol/L]). Hemofiltration was performed in an intensive care unit using a femoral catheter. Fluid replacement rate was set at 1,000 mL/h. Treatment was initiated 4 to 6 hours before radiocontrast administration, stopped for the duration of the procedure, and resumed and continued for 18 to 24 hours after the procedure. The control group was administered intravenous saline at a rate of 1 mL/kg/h (0.5 mL/kg/h for patients with heart failure [ejection fraction ⬍ 40]) initiated in a stepdown unit 4 to 6 hours before contrast administration and continued for 24 hours thereafter. Radiocontrast-induced nephropathy was defined as at least a 25% increment in serum creatinine level from baseline. Emergency renal replacement therapy (hemodialysis or hemofiltration) was initiated for oligoanuria of greater than 48 hours’ duration despite the administration of intravenous furosemide (ⱖ1 g/24 h). The study also evaluated the rate of in-hospital and long-term (12-month follow-up) outcomes. All patients enrolled in the study completed the study according to the protocol. Results showed a significant difference in incidence of radiocontrast-induced acute renal failure between the 2 groups. This complication developed in only 3 of 58 patients in the hemofiltration group (5%) and 28 of 56 patients in the control group (50%; P ⬍ 0.001). No patient in the hemofiltration group required emergency hemodialysis, whereas 10 of 56 patients in the control group needed hemodialysis. The hemofiltration group showed significantly lower inhospital mortality. There was only 1 death (1 of 58 patients; 2%) in the hemofiltration group compared with 8 deaths (8 of 56 patients; 14%) in the control group (P ⫽ 0.02). Long-term follow-up in the remaining 105 patients showed that 3 patients in the control group and 1 patient in the hemofiltration group ended up on permanent hemodialysis therapy. Five patients in the hemofiltration group and 9 patients in the control group died during the 1-year follow-up. Cumulative 1-year mortality rates in this study were 10% and 30% for the hemofiltration and control groups, respectively (P ⫽ 0.01). In the control group, among patients with a baseline serum

RADIOCONTRAST-INDUCED NEPHROPATHY Table 5.

21

Comparison of Intermittent and Continuous Renal Replacement Therapy for Prophylaxis of Radiocontrast-Induced Nephropathy

Intermittent Hemodialysis

Hemodynamic stability Simultaneous removal and dilution of circulating contrast medium Large-volume fluid replacement without risk for volume overload/pulmonary congestion Protection against radiocontrast-induced nephropathy

Continuous Venovenous Hemofiltration

Likelihood of hypovolemia, intrarenal vasoconstriction, and worsening of renal hypoperfusion Not achieved

Associated with hemodynamic stability Easily achievable

Usually not achievable

Easily achievable

No

Yes

creatinine level less than 4 g/dL (⬍354 ␮mol/L), relative risk for death within 1 year was 1.16 (95% confidence interval, 0.96 to 1.40; P ⫽ 0.11), increasing to 3.53 (95% confidence interval, 1.08 to 1.20; P ⫽ 0.002) among patients with a baseline serum creatinine level of 4 mg/dL or greater (ⱖ354 ␮mol/L) compared with the hemofiltration group. The study documented that prophylactic hemofiltration protected patients with preexisting advanced renal failure against the development of radiocontrast-induced nephropathy. In addition, in-hospital and long-term mortality were significantly lower in the hemofiltration group. Of note, a greater incidence of radiocontrast-induced nephropathy in the control group (50%) compared with previous studies was attributed to the fact that many patients in this study underwent coronary angiography and coronary intervention procedures during the same session, resulting in the need for a greater amount of contrast material. In addition, in approximately 30% of procedures, multiple procedures were performed. In summary, although hemodialysis removes radiocontrast medium effectively, it does not offer protection against radiocontrast-induced nephropathy, even when performed simultaneously during the radiocontrast administration. The lack of benefit may be related to the hemodynamic instability (hypovolemia and hypotension causing intrarenal vasoconstriction) often encountered in this scenario. In contrast to hemodialysis, continuous venovenous hemofiltration is associated with hemodynamic stability, preserving circulating blood volume, and avoiding hypo-

volemia and hypotension. In addition, it offers other benefits, such as hydration at least 10 times more robust than intravenous hydration without causing volume overload (pulmonary congestion) leading to dilution of the contrast agent (Table 5). However, hemofiltration is not inexpensive. The costs of hemofiltration, the catheter, occupying an intensive care unit room, and the staff and complications associated with the use of heparin should be considered when endorsing hemofiltration to prevent radiocontrast-induced nephropathy. Conversely, in the study by Marenzi et al,6 hemofiltration documented a protective role against radiocontrast-induced nephropathy and a positive impact on mortality in a patient population that was at very high risk to develop this complication. Hence, increased costs associated with hemofiltration must be viewed in the context of short- and long-term benefits obtained that may justify its use in patients at very high risk for developing radiocontrast-induced acute renal failure. Isotonic Versus Half-Isotonic Saline An additional variable that merits consideration is whether isotonic saline offers protection above and beyond that achieved by half-isotonic saline. Mueller et al65 conducted a large randomized trial comparing 2 different hydration regimens in 1,620 patients undergoing elective or emergency coronary interventions. Two hundred eighty-six patients had preexisting renal failure (serum creatinine level, 1.25 to 2.56 mg/dL [111 to 226 ␮mol/L]). All patients were administered nonionic LOCM. Radiocontrast-induced nephrop-

22

ASIF AND EPSTEIN

athy was defined as an increase in serum creatinine level of at least 0.5 mg/dL (44 ␮mol/L). The investigators reported that the incidence of radiocontrast-induced nephropathy was significantly lower in the isotonic saline group (0.7%) versus half-isotonic group (2%; P ⫽ 0.04). However, analysis of the group with preexisting renal insufficiency failed to show a significant difference in the incidence of this complication (isotonic saline [n ⫽ 138], 2%; half-isotonic saline [n ⫽ 148], 4%; P ⫽ 0.36). Three predefined subgroups benefited from isotonic saline compared with half-isotonic saline. These included women (isotonic saline [n ⫽ 178], 0.6%; half-isotonic saline [n ⫽ 176], 5.1%; P ⫽ 0.01), patients with diabetes (isotonic saline [n ⫽ 107], 0%, halfisotonic saline [n ⫽ 110], 5.5%; P ⫽ 0.01), and patients administered large amounts (ⱖ250 mL) of radiocontrast dye (isotonic saline [n ⫽ 251], 0%, half-isotonic saline [n ⫽ 268], 3%; P ⫽ 0.01). Unfortunately this study had several limitations. Although this trial included 286 patients with preexisting renal failure, the degree of renal failure was relatively mild. Furthermore, oral fluid intake (tea and mineral water) was not quantified in this study and may have differed, thereby confounding results. Based on the findings of this study, it seems reasonable to advocate the use of isotonic saline compared with half-isotonic saline; however, adequate hydration is mandated regardless of whether isotonic or half-isotonic saline is used. CONCLUSION

To date, there is no effective treatment for established radiocontrast-induced nephropathy. Conversely, therapeutic interventions other than hydration to prevent radiocontrast-induced acute renal failure recently were highlighted by many investigators. Based on available data, use of a pure DA-1 agonist, such as fenoldopam, to protect against radiocontrast-induced nephropathy cannot be recommended at this point. Multiple studies documented a protective role of NAC as a prophylactic agent against radiocontrast-induced nephropathy in a high-risk population. In addition, the low cost, limited side effects, general availability, and ease of administration all justify its use to prevent radiocontrast-induced nephropathy in the high-risk group. IOCM offer

protection against radiocontrast-induced nephropathy above and beyond that offered by LOCM. However, their use might be limited to patients at very high risk for developing radiocontrastinduced nephropathy. Nevertheless, regardless of osmolarity, the lowest possible dose of radiocontrast media should be administered, with particular attention given to the avoidance of intravascular volume depletion. Routine use of hemofiltration to prevent radiocontrast-induced acute renal failure cannot be justified at this point; however, this form of prophylaxis may be reserved for a selected group of high-risk patients, particularly the critically ill and those in intensive care units. We suggest that these newer interventions, especially the use of IOCM and hemofiltration, be used on a case-by-case basis and do not change the fact that optimal hydration and modification of the existing risk factors remain the cornerstones of prevention of radiocontrast-induced nephropathy. REFERENCES 1. Levy EM, Viscoli CM, Horwitz RI: The effects of acute renal failure on mortality. JAMA 275:1489-1494, 1996 2. Heyman SN, Reichman J, Brezis M: Pathophysiology of radiocontrast nephropathy: A role for medullary hypoxia. Invest Radiol 34:685-691, 1999 3. Brezis M, Rosen S: Hypoxia of the renal medulla—Its implications for disease. N Engl J Med 332:647-656, 1995 4. McCullough PA, Sandberg KR: Epidemiology of contrast-induced nephropathy. Rev Cardiovasc Med 4:S3-S9, 2003 (suppl 5) 5. Gruberg L, Mehran R, Dangas G, et al: Acute renal failure requiring dialysis after percutaneous coronary interventions. Catheter Cardiovasc Interv 52:409-416, 2001 6. Marenzi G, Marana I, Lauri G, et al: The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 349:1333-1340, 2003 7. McCullough PA, Wolyn R, Rocher LL, Levin RN, O’Neil WW: Acute renal failure after coronary intervention; Incidence, risk factors, and relationships to mortality. Am J Med 103:368-375, 1997 8. Asif A, Preston RA, Roth D: Radiocontrast-induced nephropathy. Am J Ther 10:137-147, 2003 9. Singer I, Epstein M: In depth review: Potential of dopamine A-1 agonist in the management of acute renal failure. Am J Kidney Dis 31:743-755, 1998 10. Carey RM, Siragy HM, Ragsdale NV, et al: Dopamine-1 and dopamine-2 mechanisms in the control of renal function. Am J Hypertens 3:S59-S63, 1990 (suppl 6) 11. Bakris GL, Lass NA, Glock D: Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors. Kidney Int 56:206-210, 1999 12. Hunter DW, Chamsuddin A, Bjarnason H, Kowalik

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