is a Professor of Medicine and the Associate Dean for Clinical
Education at the University of Pennsylvania School of Medicine,
Since the earliest reports of contrast-induced nephropathy (CIN)
more than 35 years ago, we have learned a great deal about which
patients are at increased risk for this condition and how to
minimize that risk. We do not, however, fully understand the nature
of the injury to the kidney or how to prevent it in all patients.
This article will review what is known about the pathophysiology of
CIN, briefly discuss the pharmacology of contrast agents, and
outline clinical approaches to risk reduction.
Contrast media have dramatic effects on the kidney, not all of
which are important in the pathophysiology of CIN (Table 1). For
example, a biphasic response in renal vascular resistance,
characterized by an initial vasodilatation followed promptly by
renovasal constriction, is observed in both experimental animals
but does not necessarily lead to long-term change in renal
In addition, contrast media cause a very transient decrease in
the glomerular filtration rate. These agents induce osmotic
diuresis and natriuresis, sometimes causing patients to become
volume-depleted as they lose both water and sodium. Finally,
contrast media produce substantial structural changes in the
kidneys of experimental animals, including necrosis of the
medullary thick ascending limbs, and tubular collapse and casts,
which are seen primarily in the outer medullary area of the kidney.
In addition, any hyperosmolar agent will induce structural changes,
including vacuolization of proximal tubular epithelium. These
latter structural changes likely occur most commonly in patients
exposed to hyperosmolar contrast agents, but only a small minority
of patients experience sustained renal injury.
Researchers have studied the physiologic mediators of the
effects of contrast media. Endothelin release, for example, results
in potent renal vasoconstriction and is likely involved in the
vasoconstrictive response to contrast media.
Adenosine, a vasoactive substance ubiquitous in all vascular beds,
can produce either vasoconstriction or vasodilatation, depending on
how much of the agent is present and when its effects are measured.
Some of the vasoactive effects of contrast media likely result from
the vasoconstrictive action of adenosine.
Nitric oxide is an important mediator of vasodilatation.
Impairment of this system may partially account for
vasoconstriction following exposure to contrast media. Finally,
prostacyclin plays a key role in vasodilatation.
Impairment of this system can potentiate the other deleterious
effects discussed here.
Consequences of CIN
Contrast-induced nephropathy is a serious clinical condition. A
1996 study by Levy et al
evaluated >16,000 patients who were administered contrast media
during cardiovascular imaging. Of these, 183 patients developed
CIN, which was defined as an increase in the serum creatinine level
of at least 25% to at least 2 mg/dL. When researchers matched the
patients who developed CIN with 177 controls, the odds ratio for
in-hospital mortality was 5.5 among patients who developed renal
failure, even after adjustment for differences in
The authors concluded that renal failure appears to increase the
risk of developing severe, nonrenal complications that lead to
death, and should not be regarded as a treatable complication of
serious illness. Moreover, they noted, even if patients survive,
increased costs and increased lengths of stay are inevitable.
A separate study by McCullough et al
showed that patients who develop acute renal failure (ARF) and
require dialysis as a result of contrast nephropathy have a high
in-hospital mortality. Patients who experienced no renal
insufficiency after coronary intervention had an in-hospital
mortality of approximately 1%. Those who developed acute renal
failure had an in-hospital mortality of approximately 7%. Those who
developed acute renal failure severe enough to require dialysis had
an in-hospital mortality of nearly 40%.
Many subsequent studies have confirmed that even small increases
in the serum creatinine concentration are more than an interesting
laboratory finding. Instead, such increases have a significant
clinical impact and are associated with prolonged hospitalization,
increased death rates, and increased costs.
Research into CIN has been complicated by the lack of a
standardized definition for this condition. In addition, reliable
measurement of serum creatinine is difficult, requiring the use of
highly standardized techniques. Finally, the serum creatinine level
is not always a good indicator of overall kidney function.
Nonetheless, the following is a reasonable, if imperfect,
definition of CIN: An increase in the serum creatinine level of
>25% or 0.5 mg/dL, within 3 days following intravascular
administration of contrast medium, in the absence of other likely
causes. (In the vast majority of patients who develop CIN, serum
creatinine rises within 24 hours.)
The risk of developing CIN rises in a nearly linear fashion with
the severity of patients' pre-existing renal disease (Figure 1).
McCullough et al
conducted several studies of CIN, particularly in patients
undergoing cardiac catheterization. Using epidemiological
techniques, they showed that the lower the creatinine clearance
rate at baseline, the greater the risk of CIN. The risk is minimal
(<10%) in patients who have normal renal function at the time of
contrast-medium exposure. By comparison, in patients with a
creatinine clearance of 10 to 20 mL/min, the incidence of adverse
renal effects-either a significant rise in serum creatinine or the
need for dialysis-is in the range of 80% to 90%.
Patients with diabetic nephropathy are at particularly high risk
for CIN (Figure 2). Rudnick and colleagues
-this author included-conducted a study of nearly 1200 patients
undergoing cardiac catheterization, comparing the effect of ionic
and nonionic contrast media on the risk of developing acute renal
failure. Our study showed that patients with both diabetes and
renal insufficiency had a 27% chance of developing CIN following
contrast medium exposure. In this study, CIN was defined rigorously
as a rise of at least 1 mg/dL in the serum creatinine level.
The osmolality of contrast media-and, therefore, the osmolar
load delivered to the renal tubules-appears to be critical in the
development of CIN. Our study showed that the use of low-osmolar
contrast material (LOCM) reduced the incidence of CIN by almost two
Other studies, including a meta-analysis of 25 individual trials,
have also concluded that use of LOCM reduces the risk of developing
Isosmolar contrast material appears to further reduce the risk
of CIN (Figure 3). In a randomized, double-blind study, Aspelin et
compared the nephrotoxic effects of iodixanol, an isosmolar,
nonionic contrast agent, to those of iohexol, a low-osmolar,
nonionic contrast agent. The study enrolled 129 patients with
diabetes and a serum creatinine of 1.5 to 3.5 mg/dL who underwent
coronary or aortofemoral angiography. After 3 days, 2 (3%) of 64
patients in the iodixanol group demonstrated an increase in serum
creatinine of ≥0.5 mg/dL, as compared with 17 (26%) of 65 patients
in the iohexol group, a highly significant difference (
= 0.002). No patient in the iodixanol group demonstrated an
increase in serum creatinine of ≥1.0 mg/dL, as compared with 10
patients in the iohexol group (15%).
Differences in the risk of nephrotoxicity may be explained by
differences in the chemical structure of the two contrast agents.
Iohexol is a nonionic monomer. Our study showed that it was less
likely than an ionic contrast agent to cause nephrotoxicity in
patients with diabetes and pre-existing renal disease.
Nonetheless, its osmolality is 600 to 850 mOsm/kg. Iodixanol is a
nonionic dimer. Its osmolality is 300 mOsm/kg and, as shown by the
it is associated with an even lower incidence of nephrotoxicity in
Why is a lower-osmolar agent safer? How does a high-osmolar
contrast medium exert its nephrotoxic effects? Diatrizoate is an
ionic monomer with an osmolality of 1510 mOsm/kg. If we assume an
injection of 250 mL of contrast-a dose that might be used in a
complex cardiac catheterization or coronary intervention-the
initial osmotic load is 378 mOsm in approximately 4 L of blood.
This acutely raises plasma osmolality by approximately 95 mOsm/L,
or roughly 15%.
At the end of the proximal tubule, if approximately 50% of the
water has been removed from the tubular fluid, the increment in
osmolality could be approximately 190 mOsm/L. However, this nephron
segment is very permeable to water, and this characteristic could
blunt the rise in osmolality. This could result in a much higher
osmolality in the proximal tubule than is ever encountered
physiologically. Furthermore, the increase in osmolality is
primarily on the luminal side of the cell, rather than being on
both sides of the cell, as is encountered in other hyperosmotic
conditions, such as hyperglycemia.
By the end of the descending limb of Henle's loop in the inner
renal medulla, the osmolar increment can be as much as 400 mOsm/L.
At the same time, the viscosity of blood flowing through the
microvessels of the kidney increases, a problem that is compounded
by low oxygen tension in the renal medulla.
The dose of contrast material plays an important role in the
risk of CIN. Wang et al
devised an animal model of contrast nephropathy by pretreating rats
with indomethacin, thereby blocking the vasodilatory effects of
prostaglandins. In animals pretreated with indomethacin, they
observed that as the dose of contrast medium increased, so did the
serum creatinine level. In addition, the reduction in creatinine
clearance was greatest in animals that received the highest
contrast doses. Some clinical studies also support the importance
of the dose in CIN.
There are several steps for the prevention of CIN. First, it is
important to use the lowest possible dose of contrast medium, and
to select low-osmolar-or, ideally, isosmolar-contrast material.
Second, it is essential to avoid volume depletion. In every
animal model, the most reliable way to induce acute renal failure
is to volume-deplete the animal prior to exposure to an
experimental risk, whether it be an antibiotic, heavy metal, or
It is not completely understood why volume depletion is so
critical in the development of acute renal failure. One explanation
is that maintaining renal blood flow in the face of volume
depletion necessitates a highly vasodilatory state. It may be much
easier to induce damage under such conditions. If the renal
vasculature is unable to accommodate any further reductions in
blood flow, the kidney may be denied adequate oxygen, particularly
in the very low oxygen milieu of the inner medulla, and injury may
The third step in the prevention of CIN is the promotion of both
high urine flow and blood volume expansion. High urine flow is
probably not critical, but some studies suggest that it is
important in the prevention of nephropathy.
More important is the intrarenal hemodynamic milieu and high blood
flow through the renal tubules, which may or may not ultimately be
expressed in the final urine flow.
The effect of volume expansion on the kidney is striking (Table
2). Blood flow increases dramatically, by at least 40%,
and renal size increases by 30% to 40%. Volume expansion reduces
the risk of all forms of acute renal failure. By increasing
intrarenal blood flow, volume expansion reduces the activity of the
renin-angiotensin system, which may reduce the risk of contrast
nephropathy. Volume expansion also minimizes increases in blood
viscosity and osmolality that are associated with the
administration of contrast material.
Most studies have suggested that infusion of isotonic or
hypotonic saline, 100 mL/hr for 4 to 6 hours prior to the study, is
needed to prevent extracellular volume depletion and avoid
activation of the renin-angiotensin system.
This is not achievable in outpatients, although it can be
accomplished without difficulty in hospitalized patients.
The choice between hypotonic and isotonic saline comes down to
volume. Hypotonic saline expands intravascular volume only half as
much as does isotonic saline. Therefore, in a volume-depleted
patient, isotonic saline is more effective at restoring vascular
volume. It is important to avoid the use of mannitol and diuretics,
as they increase the incidence of CIN in high-risk individuals.
Volume expansion poses risks for patients with heart failure or
other health problems that interfere with their ability to manage
extracellular fluid, but, clearly, avoiding volume depletion is
It is important to note that virtually all controlled trials of
the effect of contrast media on the risk of CIN provide for volume
expansion in the study protocol. Exclusion of volume-depleted
patients may give the impression that CIN occurs less frequently
than it actually does in everyday practice. Patients who receive
contrast medium without pre-existing volume expansion-for example,
in the event of an emergency-may face a much higher incidence of
this complication than clinical studies suggest.
Dialysis and hemofiltration
Some have suggested that prophylactic dialysis may reduce the
risk of CIN. There is no evidence to support this approach,
however. Frank et
found that simultaneous hemodialysis during coronary angiography
reduced the total amount of contrast medium in plasma over time,
but did not influence peak plasma concentration. Moreover, online
dialysis did not influence renal function or the incidence of
end-stage renal failure.
A recent study by Marenzi et al
suggested that prophylactic hemofiltration-continuous fluid and
solute removal through a dialysis membrane-may be helpful in the
prevention of CIN. The study involved 114 very-high-risk patients
with stage 4 chronic kidney disease and an average creatinine
clearance of approximately 26 mL/min. During coronary intervention,
patients received a large dose-approximately 250 mL-of nonionic,
low-osmolar contrast medium.
One group of patients was randomly assigned to undergo
hemofiltration for 4 to 6 hours before, and 18 to 24 hours after,
the procedure. The incidence of contrast nephropathy in this group
was 5%. Patients in the control group received intravenous isotonic
saline hydration for the same time period. The incidence of
contrast nephropathy in this group was 50%. In addition, 3% of
patients who underwent hemofiltration required temporary renal
replacement therapy (hemodialysis or hemofiltration), as compared
with 25% of those in the control group.
Some have interpreted these findings to mean that all high-risk
patients should undergo prophylactic hemofiltration. There are
several problems with this line of reasoning, however. First, CIN
was defined in this study as an increase in the serum creatinine
concentration of >25% above baseline. Continuous hemofiltration
removes creatinine from the blood, which prevents the creatinine
concentration from increasing. In short, the intervention itself
prevents accurate assessment of the study end point.
Second, investigators in the study performed emergency renal
replacement therapy if the patient developed oligoanuria for >48
hours despite the administration of >1 g of intravenous
furosemide for 24 hours. Emergency renal replacement therapy was
performed earlier in cases of concomitant overt heart failure.
Again, the study design prevents accurate assessment of a study
end point-- that is, the need for dialysis as a result of volume
overload. If all patients receive 250 mL of contrast medium, those
assigned to undergo prophylactic hemo-filtration will be less
likely to develop volume overload and, therefore, less likely to
require dialysis as a means of volume reduction.
Third, the rates of both death and renal failure necessitating
dialysis were much higher in the control group than has been
observed in other studies. This raises the possibility that study
participants were too ill to be representative of a larger pool of
patients. Finally, hemofiltration is very expensive and adds
complexity to contrast-enhanced examinations. It cannot be
considered a recommended approach on the basis of a single
The European Society of Urogenital Radiology recently developed
guidelines for the prevention of CIN.
This group advocated the use of extracellular volume expansion
(particularly with normal saline), the selection of low- or
isosmolar contrast media, minimization of contrast-medium dose, and
the use of prophylactic hemofiltration (although, as discussed
earlier, careful evaluation of the study by Marenzi et
does not support this approach). The guidelines also called for the
use of alternative imaging methods, if possible.
The European guidelines also deemed several interventions to be
ineffective and, in some cases, harmful. These include prophylactic
hemodialysis, loop diuretics, mannitol, high-osmolar contrast
medium, and gadolinium-based contrast medium (in the doses
necessary for CT examinations). The guidelines also noted that
half-normal saline, although beneficial, has been shown to be less
effective than isotonic saline.
Finally, it remains uncertain whether there is a role for
pharmacologic manipulation. Renal vasodilators, such as dopamine,
do not improve kidney function in patients with acute renal
The blockade of intrarenal mediators of contrast-medium effects has
not proven to be beneficial. In one study, for example,
endothelin-receptor antagonists were shown to almost double the
rate of contrast nephropathy.
Although there have been criticisms about the kind of endothelin
antagonists used and other characteristics of the study design,
there is no solid evidence in the literature to suggest that
endothelin antagonists are effective in preventing CIN. Some
studies have suggested that theophylline, which blocks adenosine
uptake, is beneficial.
These studies are small, and theophylline may interact with other
agents to produce potentially harmful drug interactions.
The cytoprotective drug acetylcysteine has perhaps been studied
more exhaustively than any other drug in nephrology. Unfortunately,
the results of this research have been inconsistent, leaving
clinicians without a definitive conclusion as to the potential for
acetylcysteine to prevent CIN. Roughly half of studies show that
acetylcysteine is dramatically beneficial, while the other half
show that it has no effect on the incidence of CIN.
A review article by Lin and Bonventre
includes an excellent summary of the optimal approach to the
prevention of CIN:
At the present time, it is prudent to treat the patient at
risk for radiocontrast nephropathy with several hours of
intravenous hydration prior to administration of low-osmolality,
nonionic contrast. Using this approach, one can expect a
radiocontrast nephropathy dialysis requirement rate of less than
1% from the aggregate statistics of the reported clinical trials.
Data about the potential additional protection provided by oral
N-acetylcysteine are inconclusive at this time. The evidence for
regular use of pre-emptive renal replacement therapy,
theophylline, or fenoldopam in addition to pre-procedure
hydration and low-osmolar nonionic contrast for radiocontrast
nephropathy prophylaxis is weak and should not be the standard of
care based on the current published evidence.
ELLIOT K. FISHMAN, MD:
Thanks very much, Dr. Goldfarb. Let me start with a question. One
of the things that is always of interest and of controversy is the
patient at risk. Now, in some form, we could say that everybody's
at risk. But what would you consider, from your perspective, to be
a high-risk patient?
STANLEY GOLDFARB, MD:
Because radiologists are studying so many patients, and they are
primarily in the outpatient setting, identifying which patients
have underlying renal disease becomes a great challenge for you
all. However, it is the patient with underlying renal disease who
is at the greatest risk and, therefore, must be identified prior to
contrast administration. So, how do you know whether or not a
patient has underlying renal disease? There are three paths to
getting this information. One is to do a formal glomerular
filtration rate (GFR) determination before contrast studies, but
this is not feasible. A second way is to estimate the GFRs from the
serum creatinine concentration, using one of several formulae in
existence. The Cockroft and Galt formula is somewhat effective at
estimating GFR from serum creatinine in patients who have normal
renal function. But it is not very precise in patients with renal
disease. The MDRD formula is not perfect but is more widely
accepted as a reasonable tool to identify the relationship between
GFR and serum creatinine in patients with underlying renal
Most of the available studies have used an absolute elevation in
serum creatinine rather than the estimated GFR to identify the risk
factors for contrast nephropathy, but I suspect future studies will
use the more useful estimated values. Typically, patients with a
serum creatinine above 2.0 mg/dL are certainly at increased
A third method to try in the absence of a prestudy serum
creatinine level is a simple questionnaire that has been proposed
by European investigators. The following types of questions are
posed: Do you have gout? Do you have diabetes? Do you have a
history of hypertension? Have you had any surgery on your kidney?
Have you been told that you had any renal disease? Use of this type
of screening questionnaire can identify a large majority of the
patients at risk for underlying renal disease. If you ask those
questions, you will probably identify roughly 95% of patients who
have an elevated serum creatinine. In that particular study, they
asked a few more questions. But roughly 98% of patients who
answered negatively to the questions had a normal serum creatinine.
So that brief questionnaire was enormously effective. On the other
hand, if patients answers positively to these questions, there is a
chance that their serum creatinine will be elevated and they may be
at higher risk. I would recommend that this type of approach be
adopted in the outpatient setting before studies are performed.
Now, the question is whether or not you need to have diabetes as
part of these criteria in identifying patients who are at high
risk. It is somewhat controversial. In a study that Mike Rudnick
and I carried out, that was an important factor. There are studies
that suggest that, in fact, that is not the case, and that even
patients who don't have diabetes, but who have elevated serum
creatinine, are at greater risk.
I personally cannot understand the basis for the variability in
the studies, and most of the consensus in the field is that
diabetes is probably an important co-risk factor. So, in that
questionnaire, if the patient says, "Yes, I have diabetes," that
identifies that patient as high risk. But a patient with known
diabetes who is under treatment and has a serum creatinine >2
has probably on the order of a 25% to 50% chance of having a
further increase in their serum creatinine after they've received
This is a very important practical point--that things are very
different between inpatients and outpatients. In many of our
institutions, 70% of our work is outpatient work. When do I need to
have a creatinine level on patients? Do you have a guide? If I have
a creatinine from 3 or 6 months ago, and nothing's really happened
to that patient, is that good enough? What should I be doing?
A key question is: What is the impact of that elevation in serum
creatinine in the outpatient setting versus the inpatient setting?
We do not fully know the answer to that question. The answer is
known on the inpatient side: The costs are greater, the length of
stay is longer, and the overall risk to patient health is greater.
If a patient develops a rise in serum creatinine in the inpatient
setting, his chances of dying are greater. But exactly what the
impact is on the outpatient side isn't known. So I can't answer the
question with assurance. I would say that the patient providing
this brief medical history in which there is a positive answer to 2
of those questions suggests that the radiologic study should be
postponed until you have a serum creatinine value.
Having a previous serum creatinine level is useful, and it is
very likely that if it was elevated 6 months before, it is elevated
now. But there's just no way to predict whether something has
happened to that patient in the intervening period. Nephrologists
are very much hampered by not having a really good, easy-to-do,
rapid, even bedside assay of kidney function. Since that doesn't
exist, this dilemma you've posed doesn't go away.
I would say that a history is very useful here to give you some
idea of the prior probability that a patient has renal
insufficiency. Certainly on the inpatient side, that information
ought to be in hand. If the patient answers positively to one of
those questions, and you have the luxury of putting off the study,
I would do so. Or if you have the luxury of prehydrating them and
using the proper contrast medium, I certainly would do that as
GEOFFREY D. RUBIN, MD:
To what extent do you think age is an important risk factor? Some
people have advocated using a specific age threshold to screen
serum creatinine. But other studies have suggested that that's not
particularly fruitful. What do you think?
The problem with all of these studies is that there have been great
inconsistencies among the various studies. The most dramatic factor
that I saw most recently that was was the risk of gender. It turns
out that women had a much higher risk of developing
contrast-induced nephropathy. Again, I think this may have to do
with the amount of material that's infused in them; their body
surface compared with the amount of material. It may be a
The same thing may be the case in elderly people. If a study
shows that they are at higher risk, it may very well be because the
conditions of the study were different in the way the dose was
calculated, or the kinds of materials that were used. In general,
older patients have reduced renal function. A serum creatinine of
1.3 in a 60-year-old individual means a GFR probably around 60
mL/minute, which is the lowest level of normality that we accept.
At a GFR of 59 mL/minute, the patient is in stage-two chronic
kidney disease, heading for stage three.
At age 70, the serum creatinine value that indicates underlying
renal disease is approximately 1.2 mg/dL. At age 80, the value is
probably 1.0 mg/dL. So an 80-year-old individual with a serum
creatinine that is apparently in the lower portion of the normal
range actually has a substantially reduced GFR.
I think that some of the recommendations that have come out in
favor of screening elderly patients relate to the fact that they
have higher baseline creatinine levels. One of the interesting
questions then, is whether or not that necessarily means that
they're at higher risk of having a greater detriment in their
creatinine clearance, compared with younger people. By screening
older people, are we just detecting their normal physiologic state?
Or are we really detecting something that will ultimately allow us
to have an impact in their risk downstream?
I think anybody who tries to answer that question with certainty is
really being very speculative. But let me just make a slight
correction. The serum creatinine level of an elderly individual
with underlying renal disease may not be elevated; that's the
dilemma. Their serum creatinine levels are in the normal range, yet
it's not normal for them, because their body production of
creatinine tends to go down as their muscle mass declines, and
muscle mass may be unrelated to body weight and, hence, it is not
helpful to use total body weight in the formula. I can't really
answer the question of whether simply screening an older population
would solve the problem, although it is true that many of the
patients at risk are older individuals. The burden of underlying
atherosclerotic disease in the aorta and renal vessels makes the
risk of atheroemboli during intra-arterial studies an important
issue in these patients as well.
I would go back to the issues of whether or not they are
hypertensive or are diabetic. Do they have chronic illnesses of
some sort? Have they had renal surgery of some kind? Do they have
known renal disease? If the answer to any of those questions were
"yes," I would order a serum creatinine determination. I would then
use one of the standard formulae to estimate their GFR. Then, I
would then either put off the study, or if it were an emergent
situation, I would do everything I could to delay it so I could
administer intravenous hydration to the optimal level in that
patient. I think that's probably the only rational way to approach
Yes, unfortunately, in our era of risk-averse defensive medicine,
in the setting where a high percentage of patients who get CT scans
are elderly, we're faced with this dilemma. I would be interested
in how the other panelists approach screening elderly patients in
their practice for serum creatinine elevation.
JULIA FIELDING, MD:
I don't do creatinine screenings. That questionnaire was initially
was developed by Peter Choyke and now has been adopted across
Europe. I use similar questions: Are you on chemotherapy? Are you
on chronic NSAID? Have you ever been told you had renal disease? If
they answer yes to any of those questions, we get a creatinine
level as an outpatient. Otherwise, you do not. Age is not on my
There was a good article in
a couple of years ago that showed that when you need to get
creatinine levels could be correlated to three basic questions:
First, renal disease of any type. Second, diabetes. Third, age over
We tend to follow those rules. Obviously, renal disease and
diabetes are the biggest risk factors. We tend to use age 65 as our
cutoff to try to get a creatinine level. To get a creatinine level
at many hospitals takes 5 hours. It's not like you're drawing the
blood and going to do it yourself.
I think one of the things we also should talk about is the
effect of contrast volume. A lot of the articles that have been
written talk about cardiology and people giving 200 to 500 mL of
How important is contrast volume? If we're doing CTs now with
64-slice and 16- and 32-slice scanners, and we only give 100 mL of
contrast, how important is that? Does that change the risk
Oh, I think it definitely does. As a matter of fact, you see
comments in the literature that any patient who receives ≤100 mL of
contrast has never been clearly shown to have acute renal failure
from the contrast. That may not be true, but I think volume is very
important because it relates to exposure of the kidney to this
material. With more contrast material, more exposure, and higher
osmolality, there is more osmotic injury. If you can minimize the
volume--and in every set of guidelines that is an important
factor--I think you will reduce the risk of injury. I think that's
But do we have, through experimental data, any kind of a
dose-response curve for contrast-induced nephropathy? In other
words, we've done CT scans now with as little as 30 or 20 mL of a
contrast agent. Then the question is, is the risk effectively zero?
Is it linearly extrapolated down to zero?
There is no animal model for CIN that you can accept as being
really valid and representative. The animal models require
pharmacologic manipulation, NSAID administration, and volume
depletion. Even then, the animals generally recover very quickly,
and this is true of experimental acute renal failure in general, so
the animal models are just not representative of the clinical
disorder. However, I think the consensus of nephrologists and
radiologists is that keeping the contrast volumes <100 mL is
important, and volumes of contrast media below that level rarely
produce acute renal failure.
One of the aspects that has emerged even more prominently recently
in our practice is the desire for us to study people who have
chronic renal dysfunction. People whose serum creatinine levels are
>2 to 2.5, and, in that setting in particular, the question
becomes what if we reduce our dose down to 30 or 40 mL? Is it safe?
Do we have much data for people who already are known to have
chronic renal dysfunction?
You have to understand that with acute renal failure superimposed
on chronic renal failure, approximately 50% of patients go on to
chronic dialysis. So while the problem may occur infrequently in
patients with underlying ad-vanced renal disease in whom you use
very low amounts of contrast, the impact on them will be far
greater than it is on patients whose serum creatinines are just
minimally elevated. That is the dilemma you're going to have to
address and ask the question: Is this really a necessary study?
I think the big, practical challenge is appropriate risk
stratification. One area where we see a substantial growth in the
desire for CT studies in patients who are very sick is for the
assessment of pulmonary embolism. These patients are often acutely
hypoxic, coming from the intensive care units and such. Many times
these are people who are azotemic, perhaps it's chronic; perhaps
there's an element of acuity to it. But you've got a person who is
severely hypoxic and they don't know why. So you're really
Ultimately, I think it would be good to develop some kind of
risk stratification models to give guidance to physicians as to
when it's better to risk CIN than risk not doing the study.
I think if a diagnostic study needs to be done, it should be done.
So the issue is, do you need to do that study? Although dialysis is
an unfortunate outcome, it's not the death of the patient, and if
you've decided that the patient's life is at risk because of not
doing the study, you should do the study and manage the
But it's not always black and white.
Well, I understand that, but when we're consulted, "Should we do
this?" my answer is always, do you need to do this study? If you
need to do the study, use the best equipment, use technology that
you have that might reduce the risk of CIN, and follow the best
protocols that aim to reduce the complication of acute renal
I think that's the single biggest issue that comes up. In many of
the other cases where there's a problem with renal function, I can
move them to MRI, I can do something with them. The patients that
we're talking about here, I do 3 a day who are in that category, in
some cases. We do use hydration at my hospital. Then I cut the dose
of contrast to the minimal amount that I can use and I also use
isosmolar contrast. That's pretty much the best I can do right now,
to use best practices.
Some would argue from what I believe is a flawed study, as I
mentioned in my talk, that you should consider hemofiltration to
prevent acute renal failure.
We don't use that; we just use the hydration, and my nephrologists
tend to use bicarbonate as well, when they're managing those
patients; although that's on their end of it. On my end of it,
we're trying to use low doses of isosmolar contrast and hydrate
beforehand. That's the best.
I have one quick question while we're on hydration. The protocol
you mentioned of giving 100 mL/hour for 4 to 6 hours can be
relatively impractical. I'm wondering if giving 500 mL over an hour
is just as effective. From an outpatient standpoint, as long as a
person isn't at risk for heart failure, it's certainly a lot more
practical to do that.
Well, that is a very large, acute bolus, and patients may not
tolerate it. As you mentioned earlier, much of this information is
derived from studies in cardiovascular disease, where some of the
hydration protocols have been designed to avoid acute pulmonary
Acute boluses are likely to be as effective as prolonged
infusions, but that is simply my own intuition and not based on
experimental data. Again, the key point is patient tolerance of
such an acute load.
So, there's nothing magical about having a 4- to 6-hour
No, as long as patients maintain their volume expansion during the
study and for some reasonable period after the study. They are
going to have a diuresis in response to the material that you
infuse, and a natriuresis. So you need to be sure you have given
enough hydration to make sure that they are in positive balance
during that period, and have repaired any precious extracellular
fluid volume deficit. If some-one's ill, they probably haven't had
access to food and fluids for several hours before you see them.
So, that all contributes to possible deficits in extracellular
In your protocol, you didn't specifically mention hydration
following the contrast administration. We tend to try to hydrate
symmetrically, so whatever we give before, we give afterward. Are
there data to support doing that, or can we give less hydration
after the procedure?
In almost all of the studies in which hydration has been
specifically studied, postprocedure volume expansion has continued.
I think the beneficial effects of volume infusion may be, in part,
due to that received after the infusion of contrast. One of the
classic signs of contrast nephropathy is a radiologic image of the
kidney many hours following the procedure where the kidney is
intensely bright because of residual contrast material remaining
within the renal parenchyma. Postvolume expansion is probably
important. One of the mechanisms of acute renal failure is
intratubular obstruction by debris; damaged tubules slough their
epithelial cells, and may actually block the renal tubule. Part of
the rationale of continuing the volume expansion is that you would
flush out the debris following any injury that might occur.
Is there any value in giving the patients PO water? Would that help
Every liter of saline that you infuse raises the intravascular
volume by 250 mL. Every liter of water raises the intravascular
volume by only 80 mL. If you give patients water without giving
them sodium, the water will diffuse into all body spaces and not
effectively expand extracellular fluid volume and enhance renal
blood flow and intratubular fluid flow, which may be a key factor
in preventing renal failure.
I think one important thing is that so many of the rules and so
much of what's known is based on either renal data from angiograms
or cardiac data. But you almost need to have CT-specific data,
particularly in this era of lower contrast volumes. In the old days
of CT, some people administered 150 to 180 mL of contrast
routinely. Now you're seeing that it is more commonly 80 to 100, or
120 mL. The other issue you commented on is the evolving role of
isosmolar contrast agents. There have been several very strong
articles published supporting that. What is your opinion in a
patient who has a borderline risk, or potential, perhaps in an
older patient, someone over 60 years, whom we'll say is at risk?
What about the simple method of just using an isosmolar contrast
agent? I mean, how strong should we emphasize that method?
I think that the low osmolar or isosmolar nonionic material is
clearly to be recommended in anybody who is at high risk. Are you
asking if we should assume a risk in older patients and just use
isosmolar contrast in those patients?
Then, yes. That would be my suggestion
But that's not cost effective in any way in my hospital at least.
There's no way I could do this. Otherwise, I would use it on every
Remember, we did the same thing with the change from high
osmolar contrast to low osmolar in some patients. Then we switched
to using all the low osmolar.
Now, it's a move from low osmolar to isosmolar. What I'm doing
now is that I'm balancing the risk. Right now, isosmolar contrast
of any type is much more expensive. It would take my entire year's
budget in order to use that for all CT scans. So it's not possible.
I have to pick and choose the patients based on risk factors. I
might like to use it on everybody, but it's not going to
But I think the issue relates to risk stratification. It is
particularly important in the outpatient setting, where you really
don't know the patients and you only know a little about them. You
ask a few questions.
But there is also the need to figure in the costs of the
complications, and the cost for someone who goes on dialysis is
extremely high. So it's not a trivial cost issue. As well again,
it's people who can look at bigger numbers who may have to balance
this. But we can talk about what we do individually. When we're
uncertain, our technologists are told to err on the side of
If the creatinine numbers are borderline, I think that's a very,
very critical thing. I think we almost need to have a study looking
at using isosmolar contrast versus other agents, in a CT population
on a new scanner (64 MDCT), using lower contrast volumes. As you
commented, if you gave patients 100 mL of isosmolar contrast, have
you seen patients have problems?
Well, I think you may actually have the data now. You do not have
to do a prospective, randomized, controlled study to get some
useful information. You have to do that sort of study to prove the
point beyond a shadow of a doubt. But you may have the data now in
various databases to look at a very large number of patients who
have received contrast media and ask the question: Is the risk of
acute renal insufficiency minimized by isosmolar contrast
Well, we can look at prevalence of hemodialysis. I think we can
look at that, to a certain extent, provided that we have good
follow-up with the patients. But what's lacking is good serum
creatinine follow-up, since we know that the serum creatinine can
peak up to 96 hours after the study. It's very difficult--in fact,
impractical--to do good studies of contrast-induced nephropathy,
specifically because of the relatively onerous procedure of getting
patients back in to draw blood.
Among many institutions, you have enough patients to get at an
answer to this question. If the serum creatinine does not rise in
the first 24 hours, it is very unlikely it's going to rise. The
vast majority of patients experience an acute rise in serum
creatinine in the first 24 hours.
Karen, what are you seeing?
KAREN M. HORTON, MD:
I think it's very difficult, and I'm not sure whose problem it is.
As a radiologist, it's a huge problem for us, and we don't know
what medications the patients are taking. You've got to go through
the chart. We're not sure if they're giving them hydration up on
the floor for the inpatients. I think referring physicians need to
think about this to, even in outpatients. Why do they send the
patient for CT in the aorta, when the patient is on all of those
medications and on a diuretic and the creatinine is 2.3? Once the
patients show up for the scans, we have to deal with them. So I
think it's very difficult. We can't hydrate all of our outpatients.
We don't have the people to do it.
We're in an era of all kinds of new metabolites and proteins being
detected that reveal cellular functions that we never anticipated
before. I wonder if anybody has identified some relatively
low-volume, but very specific, renal secretions that perhaps in the
presence of just a test of iodine challenge, might be able to allow
better risk stratification than creatinine levels. Is there
anything on the horizon in terms of new serologic measures?
Nothing that would satisfy this practical issue of how to modify
clinical protocols, since it would require a bedside assessment of
renal function and none exists at this time.
Let me ask a very practical question. Because, I know, in CT we all
need certain rules for whatever the guidelines are. In your
opinion, when would you use an isosmolar contrast agent? Are there
certain cutoff points, or certain types of patients? What do you do
in your practice in Stanford?
We use isosmolar contrast agents in anybody who has some baseline
azotemia. That's typically going to be anybody with a serum
creatinine level ≥1.3. In a diabetic patient, we would reduce that
down to a serum creatinine level of 1.0. That's really the main
criteria that we use. We don't give it to diabetic patients with
normal creatinine levels.
If it weren't a cost issue, would you give it to everybody?
You know what? It may not be a cost issue if you could look at the
entire cost of healthcare system. If you just give isosmolar
contrast to everybody, you might actually save money.
We were talking about this the other day. When I see a patient with
contrast-induced nephrotoxicity, invariably the patient had an
angiogram, particularly a cardiac study with high volumes of
contrast. We all repeat studies in patients who have had CTs, so
it's very rare to see anybody who had 100 mL of contrast have
Well, sometimes you see them a couple of days later. They come back
for a noncontrast CT, but you see the residual contrast in the
kidneys due to nephrotoxicity.
You just catch those. So there must be other things we don't know
Yes. I really think radiologists are too shielded from the
knowledge of when people get contrast-induced nephropathy.
Oh, sure. The outpatient center is the best example. You know that
some outpatients have a bump in serum creatinine after contrast,
and some go into renal failure, but you really don't follow anybody
up. We just don't. I think there are other risk factors in
patients, for example, who have had multiple studies.
One of our rules at Hopkins is that if someone has had a study in
the previous 24 or 48 hours, for whatever reason, even with just
100 mL of contrast, when they come back the second time, we use an
isosmolar contrast agent, regardless of the creatinine level. I
think the second contrast dose tends to be much more an additive
effect, so there is an additive risk. But there are no great
numbers on that either.
One of the things that relates a little bit to contrast at times
and rules, is a lot like the questions on myeloma and sickle cell
disease--a lot of it is like an urban legend. Karen, what numbers
do you find helpful?
Well, we're a little bit higher than you. At serum creatinines of
1.7 or so, I start to ask if the patient really needs the study,
and/or should we hydrate them? We would always use an isosmolar
above that, probably at creatinines ≥1.5. In really old people, I
like to use isosmolar contrast, too, because even with a creatinine
of 1.2, just because they have low muscle mass, they might have
renal insufficiency. You can't tell by the creatinine in older
people. We have a little chart that you can use to estimate, but I
don't know how accurate that is, for old people. In really young
people, too, I think it is safer to use an isosmolar agent.
I was going to ask you, what's an "old" person according to
Certainly anyone 80 or above, I think. You know, we scan people in
their 90s with a creatinine of 1.2 and, at 96, a creatinine of
1.2 cannot be normal renal function. So, if patients are in
their 80s or above, I think we should always use an isosmolar
For us, we use a creatinine of 1.8. Anybody with known diabetes
gets a creatinine drawn, and I use 1.5 for that level. So I guess
we are pretty similar across the board. I don't base it on age at
all, either very young or old.
Again, we continue to evolve. We are using age more as a factor. I
think that patients over 65 are at increased risk, no matter what.
Again, getting creatinine levels just doesn't tell you what you
really want to know. Once you do get a creatinine level, it's still
often borderline to determine risk. So, I think we just decided,
that while there is a cost issue, the risk-reward suggests the use
of isosmolar contrast in any patient who might be at increased risk
I think one of the problems is the majority of my patients are over
65 now. So that means I would have to get many more creatinine
levels in the outpatient setting, and my lab minimum turnover time
is two hours. The cost of getting the creatinine is actually fairly
minimal. But the time issue is huge to us. That's really the
It may take >2 hours at Hopkins to get a creatinine, and that's
why we just go with the isosmolar contrast. The patient has no
issues. If you have to send them downstairs for blood work, they
get frustrated, and I'm not sure of the cost. Even getting a
creatinine level at a major institution is kind of like the
government buying toilets. You may think it costs nothing. But, all
of a sudden, the bill for someone to draw blood and process it ends
up being $75.00 or $150.00, which the insurance may not cover. The
patient gets stuck with the bill, and that costs us far more than
selecting the isosmolar contrast agent. I know it's not as trivial
a cost, because in most big hospitals, there's nothing they do for
less than $50.
Right. But when I go to purchasing, once every three years, and
justify my contrast budget, I am putting out millions of dollars.
So the decision to go wholesale from one contrast to another would
literally break the bank. It cannot be done in a practical setting
right now. Even if I would personally like to, it's not possible.
I'm in a state institution. There's only so much money to go
around. We use it, I think, actually fairly generously, but it
can't be used for every patient.
So listening to everyone's numbers, what creatinine level would you
pick? Geoff has mentioned 1.5, Karen mentioned 15 to 1.8--it's all
pretty close. But is there an actual number we should use?
Given the variability in measurement of serum creatinine between
laboratories, and even for the same laboratory making multiple
measurements on the same patient, and given the importance of age,
muscle mass, gender, and ethnicity in relating serum creatinine to
GFR, I think it would be a mistake to pick a specific borderline
value and assume it is a low risk below that value and a high risk
above it. Certainly, if the serum creatinine is absolutely elevated
for your lab, that is a flag to do everything to avoid the
increased risk of contrast nephropathy. However, I would not feel
safe with a value of 1.5 mg/dL for serum creatinine in an elderly
patient. Also, the risk associated with a borderline value might be
exaggerated if the patient is currently taking an NSAID or is a
diabetic. Economic factors prevent the use of isosmolar material in
every patient, but given the current state of the literature and
our ability to assess renal function, it should probably be used as
widely as possible in patients who may be at risk as well as in
those who are clearly at risk.
Right. That was a great summary. Let me emphasize one thing that
Karen said, which is that it would be very helpful for all of us if
the referring physicians would indicate when this order is for a
high-risk patient. Then we would use isosmolar contrast. This would
be particularly helpful in the environment where we're doing 5
patients an hour on a scanner, where things can easily fall through
the cracks, where the patients often don't fill in the forms
correctly, or don't answer the questions correctly, or there's just
not enough time to ask all the questions.
Or there is a language barrier.
Yes, I think it would be very helpful if the clinicians would say,
"This is a high-risk patient" when they ask for a CT of the chest,
or the abdomen or whatever application.
Well, I think you could get that information if you created a
questionnaire that asked for this information and required the
referring physicians to fill out the form. You can ask some simple
questions: Is there a drug that's compromising renal function? Is
there a condition that's compromising renal function? Or is there
diabetes? Is there hypertension? Is there NSAID use? Is there
volume depletion, etc. If they are willing to say, "Yes, these
factors are present," you would be able to proceed with protocols
designed to reduce risk.
In general, they don't even fill out anything like that. But now,
with in-house order entry, it's a little bit easier to enforce,
because there is a requirement to fill things out to go through to
the next step. But I would say that communication remains a
difficult area for us.
Just to summarize, as you mentioned, there is some variability in
creatinine cutoffs, though it's minimal variability between
institutions. But I think every institution needs to have some
policy and some rules; it can't be the individual radiologist every
day changing the rules. There needs to be some guidance. We'll know
more over time. I think there's no doubt, as we commented, that the
use the newer scanners and the use of lower contrast volumes for
the same study would be helpful. We need to be able to do studies
optimally. I think you can't argue with that.
Actually, I have one comment about the volumes. I think that it's
interesting to note that there has been a trend recently for the
iodine concentration to increase in our contrast medium solutions.
It would be nice if we could evolve to the point where we talk
about the grams of iodine delivered as a drug dose, as opposed to
contrast volume in milliliters. Because if one person uses 300 mg
of iodine, and another person uses 350 mgI/mL--that can have a
substantial difference on the iodine dose with the same volume.
But, it's the physical characteristics of the medium, rather than
the iodine that is the issue.
It's the viscosity of the carrier?
It's the viscosity, and viscosity might rise dramatically at higher
concentrations of contrast material. Iodine itself is probably not
the issue. I understand that the viscosity of the nonionic dimeric
contrast material is quite high.
Yes, quite high.
So again, we're assuming that having less contrast is going to be
better. I think that's the case, but it would be really nice to
have some data to prove that point. We need to understand the
impact of these physical characteristics under very different
Putting aside Visipaque, which I know maintains the same osmolality
regardless of whether you have the 320 or the 270 mgI/mL, we should
look at a particular agent. If you're looking at Omnipaque 300
versus 350 mgI/mL, do you not think it's fair to compare them in
terms of equality in the amount of iodine delivered, which,
therefore, would equal the amount of carrier molecule as well? As
opposed to the volume of material that's being delivered? Because
the way I look at it is that it's just a small amount of additional
water in the 350 mgI/mL that results in the lower (300 mgI/mL)
Well, I'm not a chemist, so I can't speak abut the complexities of
these issues. Going back to my first principles, I think osmolality
is an important issue. The conditions with the kidney are such that
osmolality, and the effect of osmolality, may be magnified by fluid
removal by the kidney from the intratubular fluid and the blood
flowing through the kidney. The viscosity of the material may also
be very important and may also reach levels that tend to compromise
the integrity of the renal tubular cells.
Fair enough. Well, then, maybe what I really mean is the number of
particles or Osms of contrast agent that are packed into the same
volume. It's just something to consider. In other words, once
again, if it's 350 mgI/mL versus 300 mgI/mL, there's certainly more
Osms in the 350 mgI/mL solution than in the 300.
Surely if we want to look at things from a scientific perspective,
that has to be looked at very carefully.
Whole-body CT screening