J Am Soc Nephrol 11: 177–182, 2000
DISEASE OF THE MONTH
Contrast Nephropathy
SEAN W. MURPHY, BRENDAN J. BARRETT, and PATRICK S. PARFREY
Division of Nephrology and Clinical Epidemiology Unit, Memorial University of Newfoundland, St. John’s,
Newfoundland, Canada.
With the increasing use of radiographic contrast media in
diagnostic and interventional procedures, contrast-induced ne-
phropathy (CN) has become an important cause of iatrogenic
acute renal impairment. In fact, CN is the third leading cause
of new acute renal failure in hospitalized patients (1). The
pathophysiology and risk factors for this complication are
becoming better understood, but there is still controversy sur-
rounding many aspects. The purpose of this article is to review
recent developments in the area of CN. Particular emphasis
will be placed on means of minimizing the risk or preventing
this important problem.
Definition and Clinical Features
Many different definitions of CN appear in the literature, but
it is commonly defined as an acute decline in renal function
following the administration of intravenous contrast in the
absence of other causes. For research purposes, a definition
such as a rise in serum creatinine ⱖ25 or 50% above the
baseline value is often used. Patients with CN typically present
with an acute rise in serum creatinine anywhere from 24 to 48 h
after the contrast study. Serum creatinine generally peaks at 3
to 5 d and returns to baseline value by 7 to 10 d (2– 4). The
acute renal failure is nonoliguric in most cases (5,6). Urinalysis
often reveals granular casts, tubular epithelial cells, and mini-
mal proteinuria, but in many cases may be entirely bland.
Most, but not all, patients exhibit low fractional excretion of
sodium (5,7). The diagnosis of CN is frequently obvious if the
typical course of events follows the administration of contrast.
However, other causes of acute renal failure, including ather-
omatous embolic disease, ischemia, and other nephrotoxins
should always be considered. This is particularly true if sig-
nificant renal impairment should occur in patients without risk
factors for CN.
Pathogenesis
CN appears to be the result of a synergistic combination of
direct renal tubular epithelial cell toxicity and renal medullary
ischemia (8). Direct cytotoxicity in CN is suggested by histologic
Received October 25, 1999. Accepted October 27, 1999.
Correspondence to Dr. Brendan J. Barrett and Dr. Patrick S. Parfrey, Division
of Nephrology, Health Sciences Center, St. John’s, Newfoundland, Canada,
A1B 3V6. Phone: 709-737-5157; Fax: 709-737-6995; E-mail:
bbarrett@morgan.ucs.mun.ca
1046-6673/1101-0177
Journal of the American Society of Nephrology
Copyright © 2000 by the American Society of Nephrology
changes of cell injury and enzymuria after contrast administration
(9). The nature of the contrast, associated ions, concentration, and
concomitant hypoxia are all important to the degree of cellular
damage, while the osmolality of the solution seems to be of
secondary importance (8). The injection of contrast induces a
biphasic hemodynamic change in the kidney, with an initial,
transient increase and then a more prolonged decrease in renal
blood flow (2). The mediators of these changes are still unknown.
Alterations in the metabolism of prostaglandin, nitric oxide, en-
dothelin, or adenosine may play a role.
Risk Factors and Epidemiology
Mild, transient decreases in GFR occur after contrast admin-
istration in almost all patient (10). Whether a patient develops
clinically significant acute renal failure, however, depends very
much on the presence or absence of certain risk factors (Table
1). A multivariate analysis of prospective trials has shown that
baseline renal impairment, diabetes mellitus, congestive heart
failure, and higher doses of contrast media increase the risk of
CN (8). Other risk factors include reduced effective arterial
volume (e.g., due to dehydration, nephrosis, cirrhosis) or con-
current use of potentially nephrotoxic drugs such as nonsteroi-
dal anti-inflammatory agents and angiotensin-converting en-
zyme inhibitors. Multiple myeloma has been suggested as a
potential risk factor for CN, but a large retrospective study
failed to demonstrate an increased risk in these patients (11).
Of all these risk factors, preexisting renal impairment appears
to be the single most important; patients with diabetes mellitus
and renal impairment, however, have a substantially higher risk
of CN than patients with renal impairment alone (12,13).
Prospective studies have produced extremely varied esti-
mates of the incidence of CN. These discrepancies are due to
differences in the definition of renal failure as well as differ-
ences in patient comorbidity and the presence of other potential
causes of acute renal failure. A recent epidemiologic study
reported a rate of 14.5% in a series of approximately 1800
consecutive patients undergoing invasive cardiac procedures
(14). Patients without any significant risk factors have a much
lower risk, averaging about 3% in prospective studies (9). On
the other hand, the risk of renal failure after contrast rises with
the number of risk factors present. In one study, the frequency
of renal failure rose progressively from 1.2 to 100% as the
number of risk factors went from zero to four (15).
Clinical Outcomes
The clinical importance of CN may not be immediately
obvious given the high frequency of recovery of renal function,
178 Journal of the American Society of Nephrology
Table 1. Risk factors for contrast nephropathy
Preexisting renal impairment
Diabetes mellitus
Decrease in effective arterial volume
congestive heart failure
dehydration
nephrosis
cirrhosis
High doses of contrast
Concurrent use of nephrotoxic drugs
nonsteroidal anti-inflammatory drugs
angiotensin-converting enzyme inhibitors
but it is by no means a benign complication. Dialysis is
infrequently required (16,17). Some degree of residual renal
impairment has been reported in as many as 30% of those
affected by CN (18). Other comorbid events such as hypoten-
sion, sepsis, and atheroembolic disease certainly contribute.
The occurrence of acute renal failure can prolong the hospital
stay (19). Finally, there is some evidence that mortality may be
increased in patients with CN. In a retrospective study, Levy et
al. compared the outcomes of hospitalized patients with CN to
a control group of patients matched for age, baseline serum
creatinine, and type of diagnostic procedure that received con-
trast but did not develop CN. The mortality in the CN group
was 34% compared with 7% in the control group (P ⬍ 0.001,
odds ratio 5.5), even when severity of comorbid illness was
controlled by matching patients by APACHE II scores (20).
CN is no different from acute renal failure of any other
etiology in terms of the complications that may ensue. The
possibility that patients who are receiving the oral antidiabetic
agent metformin may develop lactic acidosis as a result of CN
has received particular attention. This rare complication can
occur only if the contrast causes significant renal failure and
the patient continues to take metformin. In a recent review of
this subject, no conclusive evidence was found to indicate that
the use of contrast precipitated metformin-induced lactic aci-
dosis in patients with a normal serum creatinine (⬍1.5 mg/dl or
130 ␮mol/L). The complication was almost always observed in
non-insulin-dependent diabetic patients with decreased renal
function before injection of contrast media (21). There is really
no justification to discontinue metformin before the day of the
contrast-requiring procedure. It seems prudent, however, to
instruct patients not to take this drug for 48 h or so after
contrast administration and resume taking the drug only if there
are no signs of nephrotoxicity. This is especially true for
patients in high-risk subgroups.
Strategies for the Prevention of CN
Contrast administration, more often than not, is a planned
procedure, and patients at particularly high risk can often be
identified before the investigation. Much effort has therefore
been directed at avoiding or minimizing the risk of this com-
plication. This process begins with the selection of the proce-
dure. Contrast agents should not be administered without a
J Am Soc Nephrol 11: 177–182, 2000
clear indication. Methods not requiring iodinated contrast such
as magnetic resonance imaging, ultrasound, nuclear medicine
techniques, or carbon dioxide angiography are becoming more
widely available and should be used preferentially if they will
provide the required information. The decision to give contrast
should reflect a risk-to-benefit ratio established for an individ-
ual patient. In most patients, the risk factors for CN can be
identified with a routine history and physical examination.
Renal impairment may be asymptomatic until advanced, but it
is impractical to measure renal function before contrast admin-
istration in all cases. If no other risk factors for renal impair-
ment are present, it is probably not necessary to determine
renal function. When contrast administration is deemed appro-
priate, the lowest dose of contrast possible should be used.
Optimally, any risk factors for CN should be corrected before
contrast administration. If contrast must be administered in the
presence of an uncorrectable or uncorrected risk factor, it is
advisable to monitor renal function by serum creatinine before
and at 48 to 72 h after the procedure.
A variety of specific measures have been used in an attempt
to decrease the risk of CN, particularly in high-risk patients.
The following is a discussion of the evidence supporting the
use of some of the more common practices.
Nonionic and Low-Osmolality Media
These alternative forms of contrast media, which have ap-
proximately one-half to one-third the osmolality of standard
agents, were developed at great expense in an attempt to reduce
the incidence of complications associated with radiocontrast
agents. Unfortunately, they are also capable of inducing CN,
although perhaps less frequently than high-osmolality contrast
agents. Because of their high cost relative to the standard
agents, however, considerable debate has taken place regarding
the role of low-osmolality media in clinical practice. There
have been numerous studies addressing this question, but few
individual studies had the power to determine the relative
clinical nephrotoxicity of high- and low-osmolality agents. For
this reason, Barrett and Carlisle performed a meta-analysis of
all the randomized trials available before the end of 1991
comparing the nephrotoxicity of high- and low-osmolality con-
trast in humans by serial measurement of GFR or serum
creatinine. Pooling the P values from the trials suggested a
reduction in nephrotoxicity with low-osmolality media, which
was of borderline statistical significance (P ⫽ 0.02). In a
subgroup analysis, low-osmolality media were only statisti-
cally significantly less nephrotoxic in patients with renal im-
pairment (22). Data from a study by Rudnick et al., the largest
randomized trial to date, was included in this meta-analysis
despite the fact that the final report was published several years
later. This trial involved 1196 patients, 192 of whom had some
degree of renal impairment before contrast administration. In
patients with normal renal function, low-osmolality contrast
was not found to confer any benefit. In patients with a serum
creatinine ⬎1.6 mg/dl (141 ␮mol/L) before contrast adminis-
tration, however, the use of high-osmolality contrast was as-
sociated with a risk of CN that was 3.3 times greater than that
in the low-osmolality contrast group (17). Because of the large
J Am Soc Nephrol 11: 177–182, 2000
sample size of this trial, the results of the meta-analysis by
Barrett and Carlisle were dependent on it; the conclusion,
however, seemed compatible with the results of all individual
studies (22). The apparent lack of difference between high- and
low-osmolality media in those with normal renal function may
reflect the very low risk of CN in such patients. Based on the
accumulated evidence to date, it makes sense to consider
nonionic low-osmolality contrast for patients with renal im-
pairment, especially due to diabetic nephropathy, to minimize
CN. It is not necessary to use nonionic media to reduce CN in
patients with normal renal function who are at very low risk of
clinically important changes in renal function.
Fluid Administration
The administration of intravenous fluids has long been used
to reduce the likelihood of CN for high-risk patients. The
rationale for this approach is that giving fluids before the study
may correct subclinical dehydration, whereas hydration for a
period of time afterward may counter an osmotic diuresis
resulting from the contrast. Some benefits of this approach
have been suggested by uncontrolled and retrospective studies
(23,24), but there has never been a randomized, controlled trial
of deliberate hydration versus no intervention for the preven-
tion of CN. It is clear that even vigorous fluid administration
does not afford complete protection from CN for high-risk
patients. In a recent study by Solomon et al., for example, 11%
of patients with chronic renal insufficiency developed CN
despite saline administration beforehand (25). Even if only
modestly beneficial, however, this approach is simple and
carries minimal risks of adverse effects if appropriate care is
taken, i.e., close monitoring of the patient’s fluid balance and
clinical status. A reasonable starting protocol might use intra-
venous 0.45% saline at a rate of 1 ml/kg per h, beginning 1 to
2 h before contrast and continuing for up to 24 h, depending on
the duration of the attendant diuresis. The protocol should be
flexible to allow an increase in rate if a negative fluid balance
seems to be developing. For outpatient procedures, a protocol
using oral hydration before the procedure and intravenous
0.45% saline for 6 h afterward has been shown to be as
successful as inpatient hydration in preventing CN (26).
Furosemide
The use of furosemide as prophylaxis for CN has been
controversial. It has been hypothesised that loop diuretics
might reduce the potential for ischemic injury by interfering
with active transport and decreasing the oxygen demands of
medullary tubular segments (27). Recent studies, however,
suggest that furosemide may actually be detrimental in certain
patients. In a randomized trial of patients with renal insuffi-
ciency undergoing cardiac catheterization, Solomon et al.
found that acute renal impairment was more common in a
group treated with saline and furosemide compared with a
group given saline alone. Serum creatinine rose even in those
patients who gained weight, making it unlikely that dehydra-
tion alone accounted for the adverse effects of the diuretic (25).
Weinstein and colleagues also found an increase in the mean
serum creatinine for a group of patients given furosemide,
Contrast Nephropathy 179
while a control group given fluids alone had no change in
serum creatinine following contrast (28). In this study, the
patients in the furosemide-treated group did lose weight, sug-
gesting that dehydration may have played a role. Most recently,
Stevens et al. reported the results of a randomized trial in
which high-risk patients undergoing cardiac catheterization
were treated with a combination of fluid therapy, furosemide,
mannitol, and low-dose dopamine and compared with a control
group treated with hydration alone (29). The investigators
attempted to ensure that each patient maintained extracellular
volume by replacing urine output with intravenous saline.
Although the authors concluded that this regimen of forced
diuresis provided a modest benefit in preventing CN, there was
no statistical difference in the mean rise in serum creatinine at
48 h between the groups. Because CN occurred in 41% of
patients with a urine output ⱕ150 ml/h in the first 24 h
compared with 16.2% of those with urine output greater than
this, the authors suggest that high urine output may be protec-
tive against CN. An alternative explanation is that patients who
developed renal impairment had reduced urine output. Thus,
there is currently more evidence arguing against rather than for
the use of furosemide for the prophylaxis of CN, and its use for
this purpose is not recommended.
Mannitol
Infusions of mannitol have also been widely used to prevent
CN, but again its use is controversial. Mannitol exhibited no
protective effect in the study by Solomon et al. In fact, patients
with chronic renal insufficiency treated with saline and man-
nitol had a higher incidence of CN than those treated with
saline alone (25). Another recent trial found that while man-
nitol did increase the risk of CN in diabetic patients with renal
insufficiency, it was found to reduce the risk in azotemic
nondiabetic patients (30). Overall, however, there is not
enough evidence to recommend mannitol as a means to reduce
CN.
Dopamine
Low-dose dopamine is a renal vasodilator and is effective
even in patients with chronic renal insufficiency. This property
has made it very attractive as a potential means for preventing
CN, but clinical studies thus far have shown mixed results.
Hans and colleagues conducted a randomized trial of 55 pa-
tients with chronic renal insufficiency undergoing abdominal
aortography or arteriography of the lower extremities, 40% of
whom were diabetic. Patients were randomized to receive
either dopamine 2.5 mcg/kg per min beginning 1 h before
arteriography and continuing for 12 h afterward or an equal
volume of saline over the same time period. Serum creatinine
rose linearly in both groups over time, and there was no
statistical difference between the groups except on the first day
after the procedure. In a subgroup of 20 patients with a baseline
serum creatinine ⱖ2.0 mg/dl (175 ␮mol/L), however, there
was a significantly greater rise in creatinine in the control
group over the 4 d of follow-up. Creatinine clearance did not
change in the patients receiving dopamine, whereas it declined
significantly in the control group (31). Hall and coworkers
180 Journal of the American Society of Nephrology
reported that dopamine reduced the risk of CN in azotemic
patients, but there were few diabetic patients in this study (32).
Weisberg et al. randomized patients undergoing cardiac an-
giography to either low-dose dopamine or fluids alone. Patients
with diabetic nephropathy had lower renal blood flow than
nondiabetic patients with a similar degree of renal impairment
and only the diabetic patients had a rise in renal blood flow in
response to dopamine. Paradoxically, dopamine was associated
with an increased rate of CN in the diabetic patients but seemed
to protect the nondiabetic patients (33). Finally, Abizaid et al.
recently reported no difference in the rate of CN in high-risk
patients undergoing coronary angiography randomized to re-
ceive either saline or saline plus dopamine (19). About half of
the patients in this study were diabetic, but subgroup analysis
of the effect of dopamine in diabetic patients versus nondia-
betic patients was not performed. Although it appears that
dopamine may be of some benefit in preventing CN in nondi-
abetic patients, more evidence is required before it can be
recommended for routine use. Dopamine should not be used to
prevent CN in diabetic patients.
Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) may theoretically interfere
with the pathogenesis of CN by increasing renal blood flow,
but clinical studies have not yet shown such a benefit. Kurnik
and colleagues showed that prophylactic ANP was associated
with an increase in renal blood flow in diabetic patients with
renal insufficiency, but this agent was worse than mannitol and
probably deleterious for such patients (34). Similar results
were found in a study by Weisberg et al., in which ANP,
dopamine, and mannitol all caused an increase in global renal
blood flow in diabetic patients with renal failure, but increased
the risk of CN compared to patients given saline alone. ANP
was superior to saline alone in nondiabetic patients, in whom
mannitol and dopamine proved equally beneficial (30). Re-
cently, a randomized, double-blind, placebo-controlled trial of
ANP was reported by the same group, in which 247 patients
were given either saline or one of three doses of ANP infusions
starting 12 h before and lasting 12 h after contrast administra-
tion. About half of the patients were diabetic. ANP treatment
did not reduce the risk of CN overall or in the subgroups
defined by diabetic status (35). Based on this evidence ANP
cannot be recommended for prophylaxis of CN.
Calcium Channel Blockers
Drugs of this class have been shown to blunt the decreases
in renal blood flow induced by contrast in laboratory studies.
Several randomized trials of calcium-blocking agents for the
prevention of CN have been published. Neumayer et al. gave
20 mg of nitrendipine once a day for 3 d beginning before
contrast to 16 patients and matching placebo to another 19
cases. The patients had close to normal baseline renal function.
Inulin clearance fell by 27% at 2 d in the control group,
whereas it was unchanged in the nitrendipine-treated patients
(36). Russo et al. gave 10 mg of nifedipine sublingually just
before high-osmolality contrast for intravenous pyelography in
10 nondiabetic patients. Two control groups were given high-
J Am Soc Nephrol 11: 177–182, 2000
or low-osmolality contrast without a calcium channel blocker.
Nifedipine caused an acute increase in renal plasma flow and
GFR over a 2-h period, whereas these parameters both de-
creased with high- and were unchanged with low-osmolality
contrast (37). Khoury and colleagues randomly assigned 111
patients having mainly nonionic contrast with prophylactic
fluids to a single dose of 10 mg of nifedipine, or no treatment
before contrast. Only 85 patients (76%) were evaluable and
there were more diabetic patients in the group not given nifed-
ipine (37 versus 24%). The proportion with renal dysfunction
is not stated, but the average serum creatinine before contrast
was in the normal range. There was little change in serum
creatinine within 48 h in either group (38). These studies are all
quite small and do not include high-risk patients with renal
insufficiency. Additional large-scale randomized trials are nec-
essary, particularly in high-risk patients, before calcium chan-
nel blockers can be recommended for the prevention of CN.
Patients taking calcium channel blockers for other indications,
however, should continue their therapy uninterrupted.
Theophylline
Because adenosine has been suggested as having a role in
the pathogenesis of CN, theophylline, an adenosine antagonist,
has been investigated as a means to reduce the risk of this
complication. In one of the first studies, Erley et al. compared
placebo to 5 mg/kg theophylline given intravenously before
nonionic contrast in 39 patients. Half of the subjects had a GFR
⬍75ml/min and about 15% were diabetic. There were no
clinically important changes in renal function in either group,
although theophylline prevented the small fall in creatinine,
inulin, and para-aminohippurate clearances seen in the placebo
group (39). Katholi and colleagues compared placebo with
2.88 mg/kg theophylline given orally every 12 h for four doses
starting before coronary angiography in 93 patients. This trial
used a factorial design with patients concomitantly randomized
to high-osmolality or low-osmolality contrast. Another group
received nonionic contrast with dipyridamole, an adenosine
reuptake inhibitor. All patients had a serum creatinine of ⬍2.0
mg/dl (175 ␮mol/L) and about 20% were diabetic, although
none had ⬎ 1⫹ proteinuria. Almost all were receiving calcium
channel blockers, and all were given deliberate hydration.
Theophylline completely prevented the fall in creatinine clear-
ance seen within 24 h after nonionic contrast and reduced that
after ionic contrast by about half. Serum creatinine was not
significantly changed in any group. Dipyridamole enhanced
the rise in urinary adenosine and the fall in creatinine clearance
after nonionic contrast (10). More recent studies have focused
on higher risk patients. Abizaid et al. randomized patients with
serum creatinine ⱖ1.5 mg/dl undergoing coronary angioplasty
to saline hydration alone, saline hydration plus dopamine in-
fusion, or saline hydration plus 4 mg/kg aminophylline fol-
lowed by a drip of 0.4 mg/kg per h starting 2 h before the
intervention. Twenty patients were enrolled in each group, with
more than half of them being diabetic. All patients were
hydrated with 0.45% saline and received nonionic contrast.
Neither dopamine nor aminophylline reduced the incidence of
CN compared with saline hydration alone (19). Erley and
J Am Soc Nephrol 11: 177–182, 2000
colleagues studied 80 patients with serum creatinine ⱖ1.5
mg/dl receiving contrast media. All patients were hydrated, and
patients were randomized to 810 mg of theophylline daily or
placebo. Sixty-four patients completed the entire protocol.
Serum creatinine and creatinine clearance measured at baseline
and for 3 d after contrast administration did not change signif-
icantly in either group, suggesting that theophylline provided
no benefit over hydration alone in these patients. Theophylline,
however, did prevent the increase in N-acetyl-beta-glu-
cosaminidase enzymuria seen in the placebo group (40).
These studies suggest that theophylline prevents some of the
contrast-associated changes in renal function, but a benefit
over saline hydration alone has not been convincingly demon-
strated. This is particularly true with respect to patients with
preexisting renal impairment. Nevertheless, there may be some
value to the use of theophylline for reduction of CN in those at
risk. Although the dose, duration, and route of administration
of theophylline differed in each study, it seems likely that a
dose of ⬍5 mg/kg for less than 2 d, starting before contrast,
would suffice.
Management of Acute Renal Failure Resulting
from Contrast Nephrotoxicity
In most cases the injury resulting from CN is mild and renal
impairment reverses within a week or so. Avoidance of further
nephrotoxic insults and careful control of fluid and electrolyte
balance is generally all that is required. In more severe cases,
dialysis may be necessary to treat the consequences of renal
failure. To date, no specific therapy has been found to be of
benefit in the treatment of CN. A randomized trial of ANP as
a treatment for acute renal failure did not demonstrate an
overall reduction in the need for dialysis in a subgroup of 65
patients with CN (41). Abizaid et al. randomized 72 patients
who developed CN after coronary angioplasty to receive either
0.45% saline or saline plus dopamine 1 ml/kg per h until serum
creatinine returned to its baseline value. Dopamine treatment
proved to be detrimental, as patients in this group had higher
peak serum creatinine and required dialysis more frequently
than patients in the control arm (19).
Summary
CN is an important cause of iatrogenic acute renal failure
and carries significant risks for affected patients. The most
effective strategy for the prevention of this complication is
careful procedure selection and patient assessment. Patients
with risk factors for CN who require contrast administration
should have the risks corrected before exposure to a contrast
agent if possible. Patients with noncorrectable risk factors
should receive the minimal necessary dose of contrast, and
should have their renal function checked by serum creatinine
before and at 48 to 72 h after contrast administration. No
intervention has been convincingly shown to prevent CN in
high-risk patients, with the possible exception of intravenous
hydration and the use of low-osmolaity contrast in select pa-
tients. Furosemide and mannitol should not be used as a means
to reduce CN.
Contrast Nephropathy 181
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