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CONTRAST INDUCED NEPHROPATHY
CARMEN CALDARARU1, KENNETH CHRISTOPHER2, MARIA
DOGARU3, GRIGORE DOGARU1
1
Department of Nephrology, University of Medicine and Pharmacy Târgu Mureş
Renal Division, Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA
3
Department of Pharmacology, Faculty of Pharmacy, University of
Medicine and Pharmacy Târgu Mureş
2
Abstract
Contrast induced nephropathy is a common and potentially serious complication
of the use of contrast media, especially in the patients with pre-existing renal impairment.
Although today there is a better understanding of the disease, the incidence does
not appear to have demonstrably changed. With the lack of treatment options and lack of
agreement for therapeutic prevention strategies, it is clear that identification of patients at
high risk is essential.
The purpose of this article is to provide an overview of the importance and the
recent understanding of contrast induced nephropathy so as to assist referring physicians
understanding of the identification and management of patients at high risk for contrast
nephropathy.
Rezumat
Nefropatia de contrast reprezintă o complicaţie frecventă şi importantă
determinată de administrarea substanţelor de contrast, care apare în special la pacienţii cu
afectare preexistentă a funcţiei renale. Deşi la ora actuală reprezintă o entitate bine
cunoscută şi mult studiată, incidenţa nefropatiei de contrast este nemodificată semnificativ.
În lipsa unor metode terapeutice particulare şi a unei profilaxii medicamentoase terapeutice,
este evident că identificarea pacienţilor cu risc reprezintă metoda cea mai importantă de
limitare a morbidităţii dată de nefropatia de contrast. În lucrarea de faţă sunt prezentate
principalele aspecte clinice necesare pentru înţelegerea nefropatiei de contrast, în scopul de
a sprijini identificarea pacienţilor cu risc de către specialiştii care propun efectuarea
investigaţiilor cu substanţe de contrast.
Keywords: contrast induced nephropathy; contrast media; acute renal failure
“I must admit that when I began performing coronary angiography in 1965 and even in the
late 1970s, I never encountered contrast nephropathy because I never looked for it.” [1].
Contrast induced nephropathy (CIN) is a significant but
underestimated cause of iatrogenic acute renal impairment in clinical
practice. Unfortunately, many physicians who refer patients for contrast
procedures are not fully informed about the risk of CIN.
The use of iodinated contrast media (CM) has increased greatly
over the last 30 years, with an estimated 60 million doses applied worldwide
each year. In this setting, contrast media-associated acute renal failure
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FARMACIA, 2009, Vol.LVII, 1
represents the third most common cause of in-hospital renal function
deterioration after decreased renal perfusion and post-operative renal
insufficiency [2] causing not only significant morbidity and mortality, but
an increase of hospital length of stay and costs.
The purpose of this article is to provide an overview of the
importance and the recent understanding of this condition helping referring
physicians to understand how to identify and manage the patients at high risk.
Definition
Although there is no universally accepted definition, contrast agent
nephropathy is usually defined as impairment of renal function occurring
within 48 hours after administration of contrast media.
Contract Induced Nephropathy is also known as contrast
nephropathy, contrast nephrotoxicity, contrast media nephropathy, contrast
agent nephropathy and radiocontrast-induced nephropathy. The multiplicity
of names is, perhaps, emblematic of the level of understanding of this
condition.
The most common definition of CIN is an increase of 25% or more,
or an absolute increase of 0.5 mg/dl or more in serum creatinine from
baseline value, at 48–72 h following the exposure to contrast media [3].
The definition of CIN includes three necessary components: an
absolute or relative increase in serum creatinine as compared to baseline, a
temporal relationship between the rise in serum creatinine and exposure to a
contrast agent, and the exclusion of alternative explanations for renal
impairment (e.g. cholesterol embolism).
The degree of increase in creatinine in definitions used in various
studies has a rather wide range (20%–50%), making difficult the
comparison of the results and the assessment of the true incidence of CIN.
Because creatinine peaks between four and five days after contrast
administration, CIN may escape in a considerable number of patients
relying on the creatinine concentration assessed only up to 48 h.
Furthermore, serum creatinine is an inaccurate estimate of
creatinine clearance [4], which is better calculated according to the formula
of Cockcroft and Gault or the modification of diet in renal disease (MDRD)
study equation when the patient is in a steady state.
Epidemiology
The great variation in studies assessing the incidence of CIN is
explained by multiple factors: the type of study (prospective or
retrospective), the definition of CIN, prophylactic measures and different
risk factors evaluated [5].
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In the general population, the incidence of CIN is between 1 to 6%
of hospitalized patients, with a peak of 50% in high risk patients [6, 7].
In a retrospective analysis Rihal and colleagues showed that of
7586 patients undergoing percutaneous coronary intervention 3,3%
experienced acute kidney injury (AKI) as defined as an increase in serum
creatinine with more than 0,5 mg/dl from baseline after contrast
administration. Among hospital survivors with AKI, 1- and 5-year estimated
mortality rates were 12.1% and 44.6%, respectively, much greater than the
1- and 5-year mortality rates in patients without AKI (3.7% and 14.5%
respectively, P<0.0001) [8].
Prospective studies have also produced extremely varied estimates
of the incidence of CIN. These discrepancies are easily explained by the
differences in the definition of renal failure as well as differences in patient
comorbidities and the presence of other potential causes of acute renal
failure. In a series of approximately 1800 consecutive patients undergoing
invasive cardiac procedures, McCullough et al reported an incidence of
acute renal failure or acute renal failure requiring dialysis of 14.5%. [9]
McCullough also demonstrated that patients who develop CIN have high inhospital mortality and poor long-term survival.[9]
Pathophysiology
The pathophysiology of CIN is not fully understood. Prolonged
vasoconstriction and impaired autoregulation induced by the contrast media
predispose the medulla to hypoxia. Medullary hypoxia combined with a
direct cytotoxic effect of contrast media are the most important factors in
the development of CIN. In addition, generation of reactive species, changes
in blood rheology or some systemic factors like hypovolaemia or changes in
calcium physiology can contribute to the development of this condition [10].
Contrast agents
Most contrast media in use are complex organic compounds of
iodine, their function being closely related to the chemical structure.
Iodinated contrast media are categorized on the basis of their
osmolality which is determined by the ratio of iodine atoms to osmotically
active particles [11].
There are three categories of contrast media: high-osmolar contrast
media are approximately 2,000 mOsm/kg H2O - all of the available highosmolar media are ionic, low-osmolar contrast media are 600 to 800
mOsm/kg H2O - some are ionic and some are nonionic and iso-osmolar
contrast is 290 mOsm/kg H2O- are nonionic.
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Osmolality of contrast media seems to be the most important
characteristics for CIN; in some studies low- and iso-osmolal agents being
associated with a relative decreased incidence of renal injury [12]. In a
meta-analysis of data from 2727 patients, McCullough and colleagues
showed that use of isoosmolar iodixanol is associated with smaller rises in
serum creatinine and lower rates of CIN than low-osmolar contrast media,
especially in patients with chronic kidney disease [13].
Unfortunately, the literature is confusing even in this case. The
CARE study was a direct comparison of the renal tolerability of the lowosmolality contrast medium iopamidol with that of the iso-osmolality
contrast medium iodixanol in high-risk patients, but the result does not
support any clinically significant difference between the agents [14].
Even with the uncertainty regarding the degree of nephrotoxicity
attributable to the osmolality of contrast media, in current practice non ionic
low-osmolar contrast media are preferred for patients with renal impairment.
The volume of contrast seems to be important for CIN development
especially in patients with pre-existing renal impairment, despite the fact
that some studies reported no relationship between the amount of contrast
administrated and the occurrence of renal impairment [14].
In a study on a diabetic population, Nikolski and colleagues showed
that each 100 ml increment in contrast volume resulted in 30% increased in
the odds of CIN (OR 1.30, 95% confidence interval 1.16-1.46) [15].
Clinical presentation
The increase in serum creatinine levels is observed within 24 hours
after the administration of contrast medium. Creatinine levels typically peak
on the second and third day following contrast, returning to baseline values
within two weeks. Acute renal failure due to contrast- induced nephropathy
is generally nonoliguric and reversible [16, 17].
Mild proteinuria may also be observed. Because contrast media in
urine may interfere with some of the protein, assay techniques can lead to
false positive results. This is probably a pH effect and care must be
exercised in interpreting tests for proteinuria in the presence of any contrast
agent in the urine.
Although unusual, there are reports of persistent elevation of serum
creatinine or for progression to end-stage renal disease which may be related
to concomitant cholesterol emboli.
Risk factors
A large number of factors have been associated with the
development of CIN: pre-existing renal impairment, diabetes mellitus,
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reduction of effective intravascular volume (congestive heart failure, liver
cirrhosis, nephrosis, diuretic treatment), hypotension (induced by diuretics
or ACE inhibitors), sepsis, advance age, metabolic multiple myeloma,
hyperuricaemia, hypercalcemia, concomitant potential nephrotoxic
medication (NSAIDs, aminoglycoside, antibiotics, etc) volume and type of
contrast media [18].
Prior renal impairment has been identified as the greatest
independent predictor of CIN; the condition directly correlates with the
incidence of CIN [19].
In one study performed on patients with renal transplant, the
incidence of CIN was 21.2%, being especially high (42.8%) among those
who have not received pre-procedure hydration [20].
Diabetes mellitus seems to be an independent risk factor; the
association between chronic kidney disease and diabetes mellitus increases
the risk of CIN to 50% [21]. The incidence of CIN in diabetic patients varies
from 5.7 to 29.4% [15].
In an attempt to assess the influence of diabetic and pre-diabetic
state on the development of contrast-induced nephropathy (CIN) in chronic
kidney disease patients undergoing coronary angiography, Toprak
demonstrated that patients with diabetes mellitus are at a higher risk of
developing CIN, but patients with pre-diabetes mellitus are not at as high a
risk for developing CIN as diabetes patients [22].
It is impossible to assess the independent role of risk factors in
renal impairment after contrast administration. Some authors showed that
there is an exponential relationship between the risk of renal impairment and
the number of risk factors [23].
Recently, attempts have been made to develop risk scores in order
to stratify the risk of CIN in patients undergoing coronary angiography [24].
In a study performed on 208 patients with coronary angioplasty
Marenzi and colleagues showed that the incidence of contrast nephropathy
was 19% and that age and volume of contrast were independent predictors
of CIN [25].
Prophylactic measures
CIN is a form of acute kidney injury (AKI) which can be prevented
because the administration of contrast agents is planned in the majority of
cases, so the population with a higher risk can be identified before
procedure.
Several agents have been suggested for CIN prevention including
hydration, dopamine, N-acetylcysteine, atrial natriuretic peptide, alprostadil, etc.
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Hydration
Observations comparing hydrated patients with controls shows that
volume supplementation is the best measure for preventing CIN [26]. It is
considered that the effectiveness of this measure is definitely proved. For
CIN prevention normal saline is administered at a rate of 1ml/kg of body
weight/hour for 12 hours before the radiocontrast procedure and for 6-12
hours after the last dose of radiocontrast [27].
The effectiveness of saline volume supplementation is now well
documented by observational as well as randomized studies. Moreover, a
very low incidence of CIN was obtained using intravenous volume
supplementation started on the day of percutaneous coronary intervention
combined with strongly encouraged oral fluids after the intervention [28].
Dussol and colleagues demonstrated, in a study on 312 patients
with chronic renal failure, that oral saline hydration was as efficient as
intravenous saline hydration for the prevention of CIN and that furosemide
and theophylline were not protective [29]. In addition to timing and route of
hydration, other factors, such as fluid tonicity and fluid composition, may
also play a role.
In a group of 1620 patients scheduled for coronary angioplasty,
Mueller and al showed that isotonic hydration is superior to half-isotonic
hydration for prevention of CIN [30]. The REMEDIAL trial compared 326
patients with chronic kidney disease (GFR < 40 ml/min/1,73m2) with three
prophylactic strategies: the administration of 0,9% saline plus NAC or
sodium bicarbonate infusion plus NAC or 0,9% saline plus ascorbic acid
plus NAC; the second one (bicarbonate infusion plus NAC) was superior in
preventing CIN [31].
Apart from normal saline, other intravenous solutions have been
used to test their effectiveness regarding CIN prevention. Sodium
bicarbonate may provide additional renoprotection by alkalinizing renal
tubular fluid and thereby minimizing tubular damage.
Pretreatment with sodium bicarbonate is more protective than
sodium chloride in animal models of acute ischemic renal failure.
Trying to examine the efficacy of sodium bicarbonate compared
with sodium chloride for prevention after radiographic contrast, in a
prospective, randomized, double-blind placebo-controlled trial, Merten et al
demonstrated that hydration with sodium bicarbonate before contrast
exposure is more effective than hydration with sodium chloride for
prophylaxis of contrast-induced renal failure [32].
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Antioxidants
Used primary as a mucolytic agent, N-acetylcysteine (NAC) is an
abundant source of sulfhydryl groups, its metabolites being able to act as
free radical scavengers and thus attenuate the cytotoxic effects of contrast
media [33]. NAC is inexpensive and without significant side effect.
The improvement in renal function induced by post-contrast
administration of N-acetylcysteine (NAC) is strongly associated with
suppression of oxidant stress-mediated proximal tubular injury [34].
Recent meta-analyses have shown an important role of NAC in
reducing the risk of CIN especially when combined with hydration [35, 36].
In a randomized trial Marenzi and colleagues noted that intravenous and oral
N-acetylcysteine may prevent contrast-medium–induced nephropathy with a
dose-dependent effect in patients treated with primary angioplasty [35].
Results are inconstant because there are authors who showed that
oral NAC does not prevent CIN in patients with low to moderate risk [37, 38].
A meta-analysis based on prospective studies on N-acetylcysteine
and the incidence of radiocontrast nephropathy suggests that the role of oral
NAC in the prevention of radiocontrast-induced nephropathy has yet to be
defined, so it is impossible to make a recommendation for its routine use [39].
Ascorbic acid is a potent, water-soluble antioxidant who may
protect against CIN in high-risk patients following oral administration in
patients with preexisting renal dysfunction [40].
Drugs acting on the renal circulation
Fenoldopam
Fenoldopam mesylate is a selective dopamine-1 receptor agonist
that produces renal arterial vasodilatation, an increase of blood flow and
glomerular filtration rate. It had been postulated that these renal
hemodynamic effects might effectively prevent CIN.
In a study on 315 patients with creatinine clearance less than 60
ml/min, fenoldopam does not prevent further deterioration of renal function
after contrast administration [41].
The benefit of fenoldopam has not been validated in large studies,
thus routine use of the drug is not recommended in the prevention of CIN.
Dopamine
Dopamine acts at specific dopaminergic receptors in the kidney and in
low doses (1.0-2.5 µg/kg per minute) might selectively dilate renal arterioles
and counter the renal hemodynamic effects of contrast media, the presumed
benefit of dopamine being the maintenance of glomerular perfusion.
Unfortunately, dopamine does not offer renal protection in CIN [42].
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Some investigators even suspect that dopamine might increase
patients mortality which could be related to the positive chronotrop effects
of this catecholamine [43].
Theophylline
Contrast media stimulate the intrarenal secretion of adenosine,
which binds to the renal adenosine receptor and acts as a potent
vasoconstrictor, primarily in the efferent arterioles, reducing renal blood
flow. In experimental animals this vasoconstrictive response can be blunted
with theophylline.
Findings about the protective effect of theophylline are
inconsistent. In a meta-analysis of 9 randomized trials involving 585
patients, Bagshaw et al concluded that theophylline may reduce the
incidence of CIN with an efficacy comparable to that reported in studies of
NAC [44].
Other studies shows that theophylline prophylaxis significantly
reduced the incidence of CIN (4% versus 16%, p=.046) in patients with
chronic renal insufficiency [45], or that the prophylaxis of CIN with
theophylline is superior to acetylcysteine in patients who are admitted to
intensive care unit.
Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) may have a benefit in reducing
CIN incidence by increasing glomerular filtration and renal blood flow.
Clinical studies have not yet demonstrate that ANP treatment can reduce the
risk of CIN, so ANP cannot be recommended for prophylaxis of CIN [46].
Hemodialysis and hemofiltration
Because hemodialysis effectively removes radiocontrast,
“prophylactic hemodialysis” has been proposed to prevent contrast-induced
nephropathy especially in patients with GFR < 30 ml/min.
In a study on 113 patients with advanced renal insufficiency
undergoing different procedures with administration of nonionic, lowosmolality contrast agent it was not demonstrated any benefit of
hemodialysis [47].
Hemofiltration is another form of renal-replacement therapy
proposed to prevent CIN. In a group of 114 patients with chronic renal
failure who are undergoing percutaneous coronary interventions,
periprocedural hemofiltration given in an ICU setting appears to be effective
in preventing the deterioration of renal function due to contrast-agent–
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induced nephropathy and is associated with improved in-hospital and longterm outcomes [48].
Conclusions
Contrast induced nephropathy is an iatrogenic disorder, resulting
from administration of contrast media.
The condition occurs more frequently in patients with underlying
renal dysfunction or other well defined risk- factors which acts
synergistically to increase the probability of developing acute renal failure.
Because treatment is limited only to supportive measures until
renal function improvement, and because of associated significant morbidity
and mortality with raised hospital length of stay and costs, high-risk patients
must be recognised.
After a careful risk-benefit analysis before referral to contrast
agents investigations, there are four strategies to be mindful of to prevent
CIN: 1) IV isotonic NaCl or NaHCO3 hydration, 2) iso-osmolar contrast in
high risk patients with limited volume of contrast to < 100 ml for
interventional cases, 3) consideration of pre-, intra-, and postprocedural
endorgan protection with high dose antioxidants, 4) and postprocedural
monitoring and expectant care.
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Manuscript received: 11.09.2008