Prevention of Radiocontrast-Induced Nephropathy

● 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; iso-

osmolar agents.

R ADIOCONTRAST-INDUCED nephropa-
thy 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 radiocon-
trast procedures performed annually, the inci-
dence of radiocontrast-induced nephropathy is
approximately 150,000 cases/y.4,5 At least 1% of
these episodes require dialysis therapy with pro-
longation 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 pro-
posed pathophysiologic mechanisms of radiocon-
trast-induced acute renal failure are complex,
with a variety of factors (intrarenal vasoconstric-
tion with resultant medullary hypoxia, reactive
From the Department of Medicine, Division of Nephrol-
ogy, 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, Profes-
sor of Medicine, University of Miami School of Medicine,
1600 NW 10th Ave (R 7168), Miami, FL 33136. E-mail:
murraye@gate.net
© 2004 by the National Kidney Foundation, Inc.
0272-6386/04/4401-0001$30.00/0
doi:10.1053/j.ajkd.2004.04.001
oxygen species production, direct tubular toxic-
ity) acting together to induce acute renal fail-
ure.7,8 Whereas individuals with normal renal
function are not considered to be at particular
risk for radiocontrast-induced nephropathy, pa-
tients with certain comorbid conditions, such as
preexisting renal insufficiency and diabetes with
microvascular and macrovascular disease, are
much more likely to experience acute renal fail-
ure after contrast administration.7
Although no effective treatment for radiocon-
trast-induced nephropathy exists, there has been
intense investigative interest in and several pub-
lications on therapeutic measures aimed at pre-
venting this common and life-threatening syn-
drome. In this report, we focus on recent advances
to forestall radiocontrast-induced nephropathy.
RECENT ADVANCES IN PROPHYLAXIS
AGAINST RADIOCONTRAST-INDUCED
NEPHROPATHY
Recently, a variety of therapeutic interven-
tions have been used to prevent radiocontrast-
induced acute renal failure. These include admin-
istration of a dopamine-1 (DA-1) receptor
stimulant (fenoldopam), antioxidant use (N-
acetylcysteine [NAC]), iso-osmolar radiocon-
trast medium administration, hemofiltration and
hemodialysis therapy, and hydration with normal
saline (Tables 1 to 4).

12 Vol 44, No 1 (July), 2004: pp 12-24

RADIOCONTRAST-INDUCED NEPHROPATHY 13

Table 1. Studies With Intravenous Fenoldopam Against Radiocontrast-Induced Nephropathy

No. of
No. of Fenoldopam Dose Hypotensive
Reference Study Design Patients (␮g/kg/h) Events Confounding Factors

Hunter et al12 Case series 29 0.1-0.5 Escalating 0 State of hydration not

dose specified
Madyoon et al13 Retrospective analysis 46 0.1-0.5 Escalating 0 State of hydration not
dose specified and lack
of randomization
Kini and Sharma15 Case series 110 0.1 4 Type of coronary
interventions may
have induced
hypotension
Tumlin et al16 Multicenter 45 0.1 3 Dose of fenoldopam
randomized trial infused may have
not been optimal
Stone et al17 Multicenter 315 0.05-0.1 Escalating Several Dose of fenoldopam
randomized trial dose patients infused may have
not been optimal

Fenoldopam and Radiocontrast-Induced preferentially, increases in blood flow to the

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, ␣-ad-
renergic, or ␤-adrenergic receptor stimulation
accompanying less selective agents, such as do-
pamine.9,10 Fenoldopam induces renal vasodilata-
tion. Renal effects of fenoldopam include a
decrease in renal vascular resistance and,
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 exam-
ined the effects of fenoldopam and a DA-1
antagonist (Schering 23390; Schering-Plough,
Kenilworth, NJ) in an animal model of radiocon-
trast-induced intrarenal vasoconstriction and re-
duction of GFR. The objective of the study was

Table 2. Studies Evaluating Antioxidant Use for Prophylaxis Against Radiocontrast-Induced Nephropathy

Protection Against Radiocontrast-

Reference Study Design No. of Patients Intervention Used Induced Nephropathy

Tepel et al36 Randomized 83 NAC, 600 mg, orally* Yes

Diaz-Sandoval et al37 Randomized 54 NAC, 600 mg, orally* Yes
Shyu et al39 Randomized 121 NAC, 400 mg, orally* Yes
Kay et al40 Randomized 200 NAC, 600 mg, orally* Yes
Baker et al51 Randomized 80 NAC infusion† Yes
Briguori et al38 Randomized 183 NAC, 600 mg, orally‡ No
Durham et al35 Randomized 79 NAC orally§ 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.
14 ASIF AND EPSTEIN

Table 3. Osmolarity of Various Radiocontrast Media Similarly, the maximal reduction in RBF was
blunted with fenoldopam (control, ⫺17 ⫾ 12
Ratio of Iodine
Atoms to mL/min versus fenoldopam, ⫺3 ⫾ 2 mL/min;
Dissolved Osmolarity P ⬍ 0.01), whereas Schering 23390 intensified
Radiocontrast Agent Particles (mOsm/kg)
the radiocontrast-induced reduction in RBF (con-
HOCM 1.5 2,070
trol, ⫺85 ⫾ 11 mL/min versus Schering 23390,
Diatrizoate (Urografin; ⫺119 ⫾ 14 mL/min; P ⬍ 0.05). The investiga-
Bracco Diagnostics, tors concluded that DA-1 stimulation with
Princeton, NJ) 1,400 fenoldopam protected against the adverse effect
Iothalamate (Conray 60; of radiocontrast on renal hemodynamics in this
Mallinckrodt, St Louis,
MO)
animal model.
LOCM 3.0 780
Iohexol (Omnipaque; Clinical Observations
Nycomed Inc, Princeton, These observations recently were expanded to
NJ) 796
humans (Table 1). Several investigators evalu-
Iopamidol (Isovue; Bracco
Diagnostics) ated the protective role of fenoldopam against
IOCM 6.0 320 radiocontrast-induced acute renal failure.12-17
Iotrolan (Isovist; Schering Hunter et al12 evaluated the renal effects of
SPA, Milan, Italy) 290 fenoldopam in 29 patients with decreased renal
Iodixanol (Visipaque;
function (mean serum creatinine level, 2.3 mg/dL
Nycomed, New York, NY)
[203 ␮mol/L]) who underwent radiocontrast
Abbreviations: HOCM, high-osmolar contrast medium; study. Fifty-nine percent of patients had diabetes.
LOCM, low-osmolar contrast medium; IOCM, iso-osmolar Fenoldopam infusion was started 2 hours before
contrast medium. radiocontrast administration at a rate of 0.1 ␮g/
Data from Katzberg.46
kg/min. The dose was increased in increments of
0.1 ␮g/kg/min every 20 minutes until a rate of
to test the hypothesis that DA-1 stimulation 0.5 ␮g/kg/min was achieved or systolic blood
blunted the decline in renal blood flow (RBF) pressure decreased by more than 40 mm Hg or to
and GFR. Six anesthetized volume-depleted adult less than 110 mm Hg. After radiocontrast admin-
mongrel dogs (baseline GFR, 35 mL/min) were istration, the fenoldopam infusion was continued
evaluated. Fenoldopam was infused at 0.01 ␮g/ for up to 4 hours at the highest achieved dose.
kg/min into the renal artery. Results of the study Twenty-four to 48 hours after contrast infusion,
showed that fenoldopam prevented reductions in mean serum creatinine level was 12% lower than
GFR (control, ⫺17 ⫾ 2 mL/min versus fenoldo- baseline. At 24 hours, 16 of 29 patients showed
pam, 2 ⫾ 1 mL/min; P ⬍ 0.001). Conversely, decreases in serum creatinine levels ranging from
GFR was decreased further in the presence of 0.2 mg/dL (18 ␮mol/L) to 1.4 mg/dL (124 ␮mol/
antagonist (control, ⫺15 ⫾ 2 mL/min versus L), whereas 3 patients showed increases in serum
Schering 23390, ⫺23 ⫾ 1 mL/min; P ⬍ 0.05). creatinine levels ranging from 0.2 mg/dL (18

Table 4. Studies Evaluating the Role of Renal Replacement Therapy to

Prevent Radiocontrast-Induced Nephropathy

No. of Protection Against Radiocontrast-

Reference Study Design Patients Intervention Used Induced Nephropathy

Vogt et al63 Randomized 113 High-flux hemodialysis* No

Frank et al64 Randomized 17 High-flux hemodialysis† No
Marenzi et al6 Randomized 114 Continuous venovenous hemofiltraion‡ 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 investi-
gators did not observe a decrease in systemic
blood pressure. Although these data suggest that
fenoldopam administration protects against radio-
contrast-induced nephropathy, several limita-
tions of the study do not allow a definite conclu-
sion 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 proce-
dures 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 fenoldo-
pam as described. The incidence of radiocontrast-
induced nephropathy was 13% (6 of 46 patients)
in the fenoldopam group compared with 38% (19
of 50 patients) in the comparator group.18 Al-
though results of the study were encouraging,
lack of randomization and use of a historic com-
parison 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 radiocontrast-
induced nephropathy in the setting of patients
undergoing percutaneous coronary interven-
tions. Inclusion criteria were baseline serum cre-
atinine 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. Fenoldo-
pam (0.1 ␮g/kg/min) was infused 15 to 20 min-
utes before administration of contrast medium
and continued for 6 hours after the procedure. In
addition, hydration was ensured with half-
normal saline administered intravenously for 10
to 12 hours before and 10 to 12 hours after the
procedure. Patients with matching baseline demo-
graphics (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
15
(⬎44 ␮mol/L). Compared with historic controls,
fenoldopam-treated patients had a significantly
lower incidence of radiocontrast-induced ne-
phropathy (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 base-
line after decreasing the dose of fenoldopam, and
no serious adverse effect was attributed to hypo-
tension. Interestingly, the incidence of hypoten-
sion was not significantly different from that in
the historic control group (fenoldopam, 3.8%
versus control, 1.7%; P ⫽ not significant). Coro-
nary 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 ben-
eficial effect of fenoldopam against radiocontrast-
induced nephropathy in patients with kidney
disease, both with and without diabetes. How-
ever, 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 ne-
phropathy.
Based on positive results from these studies
and a small, multicenter, randomized, double-
blind trial to evaluate the use of fenoldopam for
the prevention of radiocontrast-induced nephrop-
athy,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 admin-
istration of fenoldopam infusion (0.05 ␮g/kg/
min titrated to 0.1 ␮g/kg/min [n ⫽ 157]) or
matching placebo (n ⫽ 158). Radiocontrast-
induced 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 fenoldo-
pam did not protect against radiocontrast-in-
duced 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 radiocon-
trast-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, in-
creasing the dose increases the risk for hypoten-
sion with resultant intrarenal vasoconstriction.
Many studies failed to show a significant de-
crease 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 docu-
mented in these studies.
In summary, based on the current information,
use of fenoldopam cannot be endorsed for prophy-
laxis 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 ver-
sus 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 nephropa-
thy (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 ef-
fects 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 gluta-
thione 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 pa-
tients with chronic renal failure (baseline serum
creatinine level, 2.4 ⫾ 1.3 mg/dL [212 ⫾ 115
␮mol/L]) were randomly assigned to administra-
tion 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 radiocon-
trast-induced nephropathy in the NAC group was
2% compared with 21% in placebo-treated pa-
tients (P ⫽ 0.01). The investigators concluded
that administration of NAC with half-normal
saline was protective against radiocontrast-
induced nephropathy in patients with chronic
renal insufficiency undergoing radiocontrast
study.
These finding were confirmed by Diaz-Sando-
val et al37 in a randomized, double-blind, placebo-
controlled study; these investigators also found
acetylcysteine to be protective against radiocon-
trast-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 pla-
cebo 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 hun-
dred eighty-three patients with preexisting renal
insufficiency undergoing contrast study were ran-
domly assigned to administration of acetylcys-
teine 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 nephrop-
athy was 6.5% in the acetylcysteine group versus
11% in the control group (P ⫽ 0.22). The investi-
gators did not find a significant effect on the
occurrence of radiocontrast-induced nephropa-
thy 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 pa-
tients, 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 radio-
contrast-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 radio-
contrast-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 investiga-
tors reported that NAC administration failed to
protect against radiocontrast-induced nephropa-
thy. 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 con-
trolled. The study also used a nonstandard treat-
ment dose and schedule of NAC. Whereas previ-
ous 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 radiocon-
trast-induced nephropathy and provided the pro-
tection against radiocontrast-induced nephropa-
thy 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 pa-
tients with mild to moderate renal insufficiency.
However, the small sample size (n ⫽ 80) and
relatively low dose of contrast medium pre-
cluded a definitive conclusion that NAC did not
confer protection against radiocontrast-induced
nephropathy.
Subsequent to these studies, multiple well-
conducted randomized studies from separate cen-
ters evaluating more than 400 patients have estab-
lished the superiority of NAC over saline
infusion.39,40 In a recent randomized study, Bri-
gouri 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 ran-
domly assigned to administration of 0.45% sa-
line 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 radio-
contrast-induced nephropathy (defined as an in-
crease of at least 0.5 mg/dL [44.2 ␮mol/L] in
creatinine concentration 48 hours after the proce-
dure) 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. How-
ever, in patients administered a large volume of
contrast agent (⬎140 mL; n ⫽ 109), radiocon-
trast-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 nephropa-
thy 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 be-
fore 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). Radio-
contrast-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 nephropa-
thy. 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 compar-
ing NAC and hydration versus hydration alone
also documented a positive impact of NAC pro-
phylaxis against radiocontrast-induced nephrop-
athy. Seven randomized controlled trials evaluat-
ing 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 radiocon-
trast media ranged from 75 to 187 mL. All 7
studies used nonionic low-osmolality radiocon-
trast agents. This analysis showed that compared
ASIF AND EPSTEIN
with periprocedural hydration alone, administra-
tion of NAC and saline hydration significantly
reduced the relative risk for radiocontrast-in-
duced 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, adminis-
tration of acetylcysteine to high-risk patients
protects against radiocontrast-induced nephropa-
thy. The low cost of acetylcysteine; its limited
side effects, general availability, and ease of
administration; and the importance of the magni-
tude of the impact of radiocontrast-induced ne-
phropathy 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, meglu-
mine, and hydroxyl group.45,46 Iodine atoms pro-
vide opacification, whereas the dissolved par-
ticles are believed to be potentially nephrotoxic.
The relationship between imaging quality and
osmotoxic effects of contrast medium is de-
scribed by the ratio of iodine atoms to dissolved
particles. Higher ratios are associated with better
opacification and less nephrotoxicity. Radiocon-
trast media with an iodine atom to dissolved
particle ratio of 1.5 are known as high-osmolar-
ity 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 differ-
ences 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 protec-
tive role of IOCM beyond that of LOCM against
radiocontrast-induced acute renal failure.55-61 Sev-
eral studies documented the safety of IOCM
administered to healthy individuals and patients
RADIOCONTRAST-INDUCED NEPHROPATHY
with chronic renal failure.55-61 IOCM are iso-
osmolar to blood and posses a lower level of
general toxicity compared with LOCM. Chalm-
ers and Jackson59 were the first to suggest a
protective role of IOCM against radiocontrast-
induced 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 admin-
istration 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 pa-
tients with diabetic nephropathy (serum creati-
nine 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 (angiogra-
phy). 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 admin-
istration 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 radiocon-
trast-induced nephropathy) days 0 through 3.
Change in serum creatinine level from day 0 to
day 7 also was recorded. All 129 patients com-
pleted 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]) com-
pared with the iohexol group (0.55 mg/dL [49
␮mol/L]; P ⫽ 0.001) within 3 days after radio-
contrast 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 concen-
tration 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 creati-
nine 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 protec-
tion 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 radiocon-
trast-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 ne-
phropathy, it is reasonable to use IOCM to mini-
mize the risk for radiocontrast-induced acute
renal failure. The risk for radiocontrast-induced
nephropathy in patients with normal renal func-
tion 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
20
Renal Replacement Therapy and
Radiocontrast-Induced Nephropathy
Both hemodialysis and peritoneal dialysis re-
move contrast medium effectively; however, in a
randomized study (n ⫽ 113), prophylactic hemo-
dialysis immediately after radiocontrast adminis-
tration was not shown to provide protection
against the subsequent development of radiocon-
trast-induced nephropathy63 (Table 4). In con-
trast to a hemodialysis session immediately after
dialysis, a recent study evaluated the protective
role of simultaneous hemodialysis against radio-
contrast-induced nephropathy.64 This random-
ized 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 high-
pressure 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 simi-
lar 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 hemodialy-
sis compared with the control group (20 ⫾ 12
mL/min; P ⬍ 0.001). Similarly, the area under
the curve was significantly lower in the hemodi-
alysis 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 pa-
tients in each group developed radiocontrast-
induced nephropathy. Simultaneous hemodialy-
sis during radiocontrast administration did not
protect against radiocontrast-induced nephrop-
athy.
In contrast to intermittent hemodialysis, a re-
cent study provided evidence that hemofiltration
offered protection against radiocontrast-induced
nephropathy. In this randomized study, Marenzi
et al6 studied the role of prophylactic hemofiltra-
tion against radiocontrast-induced nephropathy.
One hundred fourteen consecutive patients with
advanced chronic renal failure undergoing percu-
taneous 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 femo-
ral 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 ne-
phropathy was defined as at least a 25% incre-
ment in serum creatinine level from baseline.
Emergency renal replacement therapy (hemodi-
alysis or hemofiltration) was initiated for oligoa-
nuria 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 com-
pleted the study according to the protocol.
Results showed a significant difference in inci-
dence of radiocontrast-induced acute renal fail-
ure between the 2 groups. This complication
developed in only 3 of 58 patients in the hemofil-
tration group (5%) and 28 of 56 patients in the
control group (50%; P ⬍ 0.001). No patient in
the hemofiltration group required emergency he-
modialysis, whereas 10 of 56 patients in the
control group needed hemodialysis. The hemofil-
tration group showed significantly lower in-
hospital 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 perma-
nent hemodialysis therapy. Five patients in the
hemofiltration group and 9 patients in the control
group died during the 1-year follow-up. Cumula-
tive 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. Comparison of Intermittent and Continuous Renal Replacement Therapy for
Prophylaxis of Radiocontrast-Induced Nephropathy
Intermittent Hemodialysis
Hemodynamic stability Likelihood of hypovolemia, intrarenal vasoconstriction,
and worsening of renal hypoperfusion
Simultaneous removal and Not achieved
dilution of circulating contrast
medium
Large-volume fluid replacement Usually not achievable
without risk for volume
overload/pulmonary
congestion
Protection against No
radiocontrast-induced
nephropathy
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 inter-
val, 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 ne-
phropathy. In addition, in-hospital and long-term
mortality were significantly lower in the hemofil-
tration 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 approxi-
mately 30% of procedures, multiple procedures
were performed.
In summary, although hemodialysis removes
radiocontrast medium effectively, it does not
offer protection against radiocontrast-induced ne-
phropathy, even when performed simultaneously
during the radiocontrast administration. The lack
of benefit may be related to the hemodynamic
instability (hypovolemia and hypotension caus-
ing intrarenal vasoconstriction) often encoun-
tered in this scenario. In contrast to hemodialy-
sis, continuous venovenous hemofiltration is
associated with hemodynamic stability, preserv-
ing circulating blood volume, and avoiding hypo-
21
Continuous Venovenous
Hemofiltration
Associated with
hemodynamic stability
Easily achievable
Easily achievable
Yes
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 conges-
tion) leading to dilution of the contrast agent
(Table 5). However, hemofiltration is not inexpen-
sive. 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 associ-
ated 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 consider-
ation is whether isotonic saline offers protection
above and beyond that achieved by half-isotonic
saline. Mueller et al65 conducted a large random-
ized trial comparing 2 different hydration regi-
mens 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
athy was defined as an increase in serum creati-
nine level of at least 0.5 mg/dL (44 ␮mol/L). The
investigators reported that the incidence of radio-
contrast-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 insuf-
ficiency failed to show a significant difference in
the incidence of this complication (isotonic sa-
line [n ⫽ 138], 2%; half-isotonic saline [n ⫽
148], 4%; P ⫽ 0.36). Three predefined sub-
groups 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%, half-
isotonic 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 limita-
tions. 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 find-
ings of this study, it seems reasonable to advo-
cate the use of isotonic saline compared with
half-isotonic saline; however, adequate hydra-
tion 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 pro-
tect against radiocontrast-induced nephropathy
cannot be recommended at this point. Multiple
studies documented a protective role of NAC as
a prophylactic agent against radiocontrast-in-
duced nephropathy in a high-risk population. In
addition, the low cost, limited side effects, gen-
eral availability, and ease of administration all
justify its use to prevent radiocontrast-induced
nephropathy in the high-risk group. IOCM offer
ASIF AND EPSTEIN
protection against radiocontrast-induced nephrop-
athy above and beyond that offered by LOCM.
However, their use might be limited to patients at
very high risk for developing radiocontrast-
induced nephropathy. Nevertheless, regardless
of osmolarity, the lowest possible dose of radio-
contrast media should be administered, with par-
ticular attention given to the avoidance of intra-
vascular 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 pa-
tients, 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 radio-
contrast-induced nephropathy.
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