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| Professor Norbert Lameire is
Emeritus Professor of Medicine
at the Medical Faculty of Ghent
University. He received his
training in internal medicine and
nephrology at the University
of Ghent, Faculty of Medicine.
He was appointed Professor of
Medicine in 1991 and he became
Chief of the Renal Division at
the University Hospital and was
Chairman of the Department of
Medicine from 1999-2004. He
is Co-Chair of Kidney Disease
Improving Global Outcomes
(KDIGO), a global nephrology
initiative. Professor Lameire
serves on the editorial boards
of many medical societies and
associations; he is Editor-in-Chief of Nephrology, Dialysis,
Transplantation and Acta Clinica
Belgica. His research interests
include both basic research
(renal circulation in experimental
ARF and the peritoneal
circulation) and clinical topics,
including clinical ARF, peritoneal
dialysis, and organisational and
economic aspects of chronic
renal replacement therapy and
transplantation. |
Screening of renal function prior to administration of iodinated contrast medium
Norbert Lameire
Emeritus Professor of Medicine,
University Hospital, Ghent, Belgium
Address for correspondence:
Professor Norbert Lameire
Department of Medicine, University Hospital
185 De Pintelaan, 9000
Ghent, Belgium
Tel: +32 (0)9-240-4402 Fax: +32 (0)9-240-4403
Email: norbert.lameire@ugent.be
Assessment of baseline renal function
Abstract
Renal impairment at baseline (estimated glomerular
filtration rate [eGFR] <60 ml/min/1.73 m2) is the most
important risk marker to predict the risk of contrastinduced
nephropathy (CIN) in patients receiving iodinated
contrast media. A number of strategies have been shown
to be helpful in managing the risk of CIN in patients at
risk of CIN. Hence, it is important to assess renal function
before administration of contrast medium to ensure that
appropriate steps are taken to reduce the risk. Serum
creatinine alone does not provide a reliable measure of
renal function, and thus the National Kidney Foundation
Kidney Disease Outcome Quality Initiative (K/DOQI)
recommends that clinicians should use an eGFR
calculated from the serum creatinine as an index of renal
function. eGFR should be determined prior to contrast
administration, using the abbreviated Modification of
Diet in Renal Disease (MDRD) formula, recommended by
K/DOQI as the preferred equation for the calculation of
eGFR in adults. Where a serum creatinine measurement
or eGFR is not available, a simple survey or questionnaire
can be used before contrast agent administration to
identify patients at higher risk for CIN than the general
population. In emergency situations, where the benefit
of very early imaging outweighs the risk of waiting, the
investigation or procedure can be undertaken without
assessment of renal function.
Introduction
Contrast-induced nephropathy (CIN) is a common and
clinically important complication of the use of iodinated
contrast media for clinical investigations or therapeutic
procedures.(Ref: 1-4) The presence of chronic kidney disease
(CKD) at baseline is associated with an increased risk
of CIN, particularly when diabetes is also present.(Ref: 5) The
evidence also supports an association between the
severity of pre-existing renal impairment and the risk of
CIN.(Ref: 5) The occurrence of CIN is associated with increased
in-hospital mortality and a longer hospital stay, as well
as being a predictor of late mortality.(Ref: 3,6) Moreover, a larger
post-procedure decline in renal function is associated
with an increased risk of adverse outcomes.(Ref: 6)
Renal impairment is acknowledged as the most important
risk factor for CIN(Ref: 5) and an independent predictor of risk
in multivariate analyses.(Ref: 5,7) The evidence indicates that the
risk of CIN is elevated and becomes clinically important
when the estimated glomerular filtration rate (eGFR)
is less than 60 ml/min/1.73 m2, equivalent to serum
creatinine levels ³1.3 mg/dl (114.9 µmol/l) in men and
³1.0 mg/dl (88.4 µmol/l) in women.(Ref: 1,5) Various strategies
are available to reduce the risk of CIN, including adequate
volume expansion, appropriate choice of contrast medium
and limiting the volume of contrast medium to <100 ml.(Ref: 1)
Hence, it is important to identify prospectively the
patients at risk so that appropriate measures can be
taken. The most appropriate approach to risk prediction
is a simple one focusing on renal function, the most
important risk marker, and diabetes mellitus, which can
be considered as a risk multiplier.(Ref: 5) This review considers
the most appropriate approaches to the assessment
of baseline renal function before contrast medium
administration in routine clinical practice.
Estimation of renal function
The glomerular filtration rate (GFR), which is
conventionally corrected for body surface area, is
considered the best overall index of renal function.(Ref: 8)
The most accurate method of determining GFR is to track
the clearance of a marker that is freely filtered at the
glomerulus and not reabsorbed or secreted in the tubule
(such as inulin or a suitable isotopic marker) but this
is a burdensome procedure. Clearance of creatinine, an
endogenous marker, is often measured as an alternative;
creatinine clearance is higher than GFR, because there is
some secretion of creatinine in the tubules, but it does
provide a reasonable indication of renal function.
Direct measurement of renal clearance is not realistic in
routine clinical practice, since it is inconvenient (24-hour
urine collection required) and expensive. Consequently,
the GFR is often estimated from the serum creatinine
level using an equation such as the Modification of Diet
in Renal Disease (MDRD) or Cockcroft-Gault formula
Serum creatinine measurements are readily available and
can provide a useful indication that a patient is suffering
from CKD. However, serum creatinine does not provide
an accurate measurement of renal function, since the
relationship with GFR is non-linear, and a substantial
reduction in renal function may occur before the serum
creatinine concentration is significantly elevated.(Ref: 9) The
creatinine concentration in the blood is affected by
a number of factors other than creatinine filtration
including diet, muscle mass and gender.(Ref: 10,11) Older patients
and women have a lower muscle mass and hence the
renal function (GFR) may be lower than expected from
the serum creatinine; for example, an elderly female may
have significant loss of renal function despite having a
serum creatinine in the normal range.(Ref: 12)
Various methods are available for the calculation of an
eGFR from the serum creatinine. The National Kidney
Foundation Kidney Disease Outcome Quality Initiative
(K/DOQI), with the endorsement of Kidney Disease:
Improving Global Outcomes (KDIGO),(Ref: 13) recommends that
laboratories should supply clinicians with a report of the
eGFR with the results of serum creatinine measurement.(Ref: 9)
Laboratory-reported eGFR may be easier for patients and physicians to interpret
than serum creatinine levels.(Ref: 14)
Equations for estimating GFR
The most widely used equations are the Cockcroft-Gault
formula(Ref: 15) and the MDRD formula.(Ref: 12)
The Cockcroft-Gault equation was originally developed to
estimate creatinine clearance but has been evaluated as a
predictor of GFR. It incorporates serum creatinine, age and
body weight in the calculation and estimates creatinine
clearance in ml/min, uncorrected for body surface area.
The abbreviated (4-variable) MDRD equation incorporates
age, gender and ethnicity, but not body weight and the
result is an eGFR already corrected for body surface
area (ml/min/1.73 m2). This equation was developed as
part of the MDRD Study(Ref: 12) and the K/DOQI guidelines
recommend its use as the preferred method for estimating
GFR in adults.(Ref: 9) The addition of more variables (albumin,
urea) adds little to its accuracy.
The modified MDRD equation is based on a validated
method for measuring GFR (renal clearance of
125I-iothalamate) and the alkaline picrate method for
measuring serum creatinine and it has been validated
extensively in different patient populations including
Caucasians, African-Americans, patients with diabetic
and non-diabetic kidney disease and renal transplant
recipients.(Ref: 13) Table 1 shows the range of serum creatinine
levels that correspond to an estimated GFR of 60 ml/
min/1.73 m2 or creatinine clearance of 60 ml/min in
different patient groups using these 2 equations.(Ref: 9)
The MDRD calculation is more complex than the
Cockcroft-Gault one. However, calculators that compute
the eGFR from serum creatinine level and patient
characteristics are widely available on the internet (e.g.
http://www.kidney.org/professionals/kdoqi/gfr_calculator.
cfm and http://nk dep.nih.gov/professionals/gfr_
calculators/index.htm). Many laboratories now report the
eGFR with the serum creatinine and this value is likely to
be more accurate as it may incorporate laboratory-specific
correction factors.
A recent review of the literature supported the use of the
modified MDRD equation as a better estimate (than the
Cockcroft-Gault formula) of GFR in people with moderate
or advanced chronic kidney disease.(Ref: 16) The modified MDRD
formula has the advantage of not requiring body weight
data, which may not be available in the clinical laboratory,
for the calculation of GFR. Both the modified MDRD and
Cockcroft-Gault equations lack precision at high GFR values (low serum creatinine concentrations),
but this is of little relevance when screening patients
for renal impairment.
If the eGFR is not available, serum creatinine levels
³1.3 mg/dl (114.9 µmol/l) in men and ³1.0 mg/dl
(88.4 µmol/l) in women are useful cut-off values to
indicate an increased risk of CIN. However, a recent
study highlighted the disadvantage of relying on serum
creatinine levels to assess CIN risk: among emergency
patients being considered for a computed tomography
scan with intravenous contrast medium, the serum
creatinine was <1.4 mg/dl (123.8 µmol/l) in 40% of
those with creatinine clearance below 60 ml/min.(Ref: 17)
Serum creatinine assay
Since the eGFR is calculated from the serum creatinine
level, it is important that creatinine measurements are
accurate and standardised across laboratories to allow
consistent interpretation. However, this has not yet been
achieved. A number of studies have documented some
inter-laboratory variation and lack of precision in serum
creatinine assay.(Ref: 14,18,19)
Current laboratory methods are subject to less
interference from chromogens than the older alkalinepicrate
or Jaffé method and hence normal levels of serum
creatinine are lower than previously. This results in higher
values for creatinine clearance and overestimation of
GFR.(Ref: 9) Equipment manufacturers and clinical laboratories
may calibrate instruments to report higher serum
creatinine values in order to minimize this overestimation
of GFR but this calibration is not standardized, leading to
variation within and across laboratories.(Ref: 9)
 |
MDRD = Modification of Diet in Renal Disease
†1 mg/dL = 88.4 µmol/L. ‡Concentration corresponding to an estimated glomerular filtration rate of 60 mL/min1.73 m2.
*Concentration corresponding to a creatinine clearance of 60 mL/min
Table 1. Serum creatinine concentrations in various populations and ages corresponding to an eGFR of 60 mL/min/1.73
m2 (MDRD equation) or a creatinine clearance of 60 mL/min (Cockcroft-Gault equation). Calculations assume a body
weight of 72 kg and body surface area of 1.73 m2. (Reprinted from Am J Kidney Dis. Copyright 2002, with permission
from the National Kidney Foundation.)(Ref: 9) |
Risk factor questionnaires
It is strongly recommended that prior to the administration
of iodinated contrast medium, renal function and hence,
the risk of CIN should be assessed by calculating the eGFR
from a recent serum creatinine measurement. However,
in some clinical situations and particularly emergency
situations, this may be impractical. Where renal function
data are unavailable, a simple survey or questionnaire
to determine the presence of risk factors can be used to
identify patients at higher risk for CIN than the general
population prior to contrast agent administration. Several
groups have evaluated such questionnaires covering
risk factors such as a history of kidney disease, diabetes
mellitus, hypertension and advanced age.(Ref: 20-22)
 |
| Table 2. The Choyke Questionnaire.(Ref: 21) |
Choyke et al showed that 94% of patients giving
negative answers to a simple 6-point risk factor
questionnaire (covering a history of renal problems,
proteinuria, hypertension, gout and diabetes) before
computed tomography had normal serum creatinine levels
(Table 2).(Ref: 21) Hence, the use of a questionnaire could reduce
the number of patients in whom creatinine measurement
was necessary prior to imaging studies.(Ref: 21) In another study
in 640 emergency room patients requiring a contrast
procedure, serum creatinine was measured and risk factors
were assessed. Thirty-five patients (5.5%) had a serum
creatinine level ³1.6 mg/dl and most of these (27 patients)
had recognized risk factors for renal insufficiency. The
authors concluded that almost 99% of patients at risk for
CIN can be identified by evaluation of risk factors.(Ref: 22)
The European Society of Urogenital Radiology (ESUR)
recommends a risk factor analysis based on the Choyke
questionnaire to identify patients with a higher risk of
abnormal renal function. A history of renal disease, renal
surgery, proteinuria, diabetes mellitus, hypertension, gout
or the intake of nephrotoxic drugs may imply an increased
probability of abnormal serum creatinine levels, and in such
cases consideration should be given to serum creatinine
measurement before contrast agent administration.(Ref: 23)
Although none of these screening methods have been
validated, a survey or questionnaire may be a useful guide
for identifying patients at higher risk for CIN than the
general population.
Emergency situations
In the setting of emergency procedures, where the benefit
of very early imaging outweighs the risk of waiting for the
results of a blood test, it may be necessary to proceed
without serum creatinine assessment or GFR estimation.
However, where possible, an indication should be obtained
of the likelihood that the patient has impaired renal
function that may increase the risk of CIN, to enable
suitable precautions to be taken.
Risk management strategies
Identification of patients at risk - mainly through
assessment of renal function - is an essential first step in
managing the risk of CIN. Intravenous volume expansion
has a well-established role in reducing the risk of CIN.(Ref: 24)
There are limited data on the most appropriate choice of
intravenous fluid, but the evidence indicates that isotonic
saline is more effective than half-normal saline.(Ref: 25) The
results of two studies, one comparing sodium chloride
and sodium bicarbonate(Ref: 26) and the other comparing the
combination of sodium bicarbonate and N-acetylcysteine
(NAC) with normal saline plus NAC(Ref: 27) suggest that
bicarbonate may be more effective than saline.
Numerous pharmacological strategies have been assessed
for their potential to reduce the risk of CIN.(Ref: 24) In particular,
the use of NAC to reduce the risk of CIN in patients at risk
has been extensively evaluated in clinical trials.(Ref: 24,28) These
trials have given inconsistent and conflicting results, with
some showing a reduction in the risk of CIN and others
showing no evidence of benefit. One study(Ref: 29) suggested
that the apparent benefit of NAC observed in some trials
may be a consequence of an effect on serum creatinine
levels that does not reflect a real improvement in GFR,
since there was no effect on serum levels of cystatin C,
another marker of renal function. Other pharmacological
agents that could be considered for further evaluation for
CIN prophylaxis include theophylline, statins, ascorbic acid
and prostaglandin E1.(Ref: 24)
The choice of contrast medium also plays a role in
reducing the risk of CIN in patients at risk of CIN. The
osmolality of contrast media is a physical characteristic
believed to contribute to CIN.(Ref: 30-32) Clinical trials have
demonstrated that low osmolar contrast media (LOCM)
result in less CIN than high osmolar contrast media
(HOCM).(Ref: 33-35)
Use of the newer iso-osmolar contrast media (IOCM)
is probably associated with a low rate of CIN compared
with LOCM in high-risk patients.(Ref: 36-39) Similar rates have
been observed with IOCM and LOCM in lower-risk
patients.(Ref: 40,41) However, in these studies, some bias might
have been introduced because of a higher proportion of
diabetic patients in the IOCM group and use of a single
non-standardised serum creatinine measurement during
follow-up(Ref: 40,41) or use of larger volumes of contrast media
in the IOCM group.(Ref: 40) One group of researchers recently
concluded that IOCM better preserves short- and
long-term renal function. In 27 elderly patients with
severe renal impairment (mean serum creatinine
3.0 mg/dl) receiving IOCM during elective cardiovascular
catheterization, the mean serum creatinine at 6 months
and the absolute and percentage increases at 3 and
6 months were all lower than in historical case-matched
controls receiving LOCM.(Ref: 42)
Conclusions
The identification of patients at risk of CIN is an essential
step in reducing the risk through implementation of
appropriate risk reduction strategies. The eGFR provides
the best indicator of impaired renal function at baseline
and should be calculated using the abbreviated MDRD
formula which takes into account the patient's age, gender
and race as well as serum creatinine concentrations. Risk
factor assessment using a survey or questionnaire can facilitate the identification of patients at risk. Selection
of contrast media is an important consideration and the
use of contrast media with osmolality closest to that of
blood, such as iso-osmolar agents, has been shown to
be associated with low rates of CIN in high-risk patients.
In emergency situations, where the benefit of very early
imaging outweighs the risk of waiting, the investigation
or procedure can be undertaken without determining the
serum creatinine or eGFR.
Key Learning
• Renal impairment at baseline is the most important risk marker for contrast-induced nephropathy (CIN)
• Renal function should be assessed before the administration of iodinated contrast medium to identify patients at
risk of CIN and enable appropriate steps to be taken to reduce the risk
• The estimated glomerular filtration rate (eGFR) is recommended as the most appropriate index of renal function
• The Modification of Diet in Renal Disease (MDRD) is the preferred equation for calculation of eGFR from the serum
creatinine level in adults
• Where no measure of renal function is available, a questionnaire may be useful in identifying patients at
increased risk |
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