712

Reactive oxygen species (ROS) also may play
an important role in contrast-induced n­ ephropathy
(CIN). ROS are known to scavenge nitric oxide
and cause cellular damage, but they may also
mediate the actions of vasoconstrictors thought to
be of importance in the development of CIN [26].
All of the abovementioned pathways may
contribute to renal injury. Patients with chronic
kidney disease have a higher filtered load of the
contrast media per nephron in addition to prolonged tubular exposure of the agent, placing
them at increased risk for toxicity. Overall, preexisting renal disease with decreased renal function is one of the most important risk factors for
the development of CIN.
The extra-renal side effects of contrast media
can be minor (flushing, nausea, vomiting, pruritus, headache, urticaria), intermediate (hypotension, bronchospasm), or severe (seizure,
pulmonary edema, cardiac arrest, cardiac arrhythmias). The incidence of adverse reactions is very
low, especially with the use of contemporary
LOCM agents. Minor adverse reaction rates with
LOCM occur at a frequency of 0.2–0.7% of all
patients [12]. Serious adverse reactions with
LOCM injection are extremely rare, occurring at
a frequency of 0.04%.There are several case
reports and case series of contrast-related side
effects in patients with renal failure which include
skin disorders (iododerma), vasculitis, and sialadenitis (also known as iodide mumps) [32–35].
Younathan et al. studied 10 patients with ESRD
on chronic hemodialysis (HD) who underwent 11
procedures requiring intravascular administration
of LOCM [36]. The investigators did not find significant changes in blood pressure, electrocardiogram, serum osmolality, extracellular fluid
volume, or body weight in these patients. None

of the patients required emergent dialysis after
the administration of contrast. A similar observation was reported by Hamani et  al. in eight
chronic HD patients after the administration of
LOCM [37]. The largest group of 22 dialysis
patients who received LOCM was reported by
Harasawa et  al. The patients were followed for
5 days, and only one developed a localized urti-

V. R. Dharnidharka and D. C. Rivard

carial reaction [38]. These reports suggest that
the risk for extra-renal toxicity in ESRD patients
after the administration of contrast is low and that
immediate post-procedural dialysis is not
necessary.

 ialysis in the Removal of Iodinated
D
Contrast Media
Contrast media have a molecular weight ranging
from 700 to 1550 Da and their water solubility,
low protein binding, and minimal intracellular
penetration allow for efficient removal from
blood by HD. Treatment variables such as blood
flow rate, membrane surface area, membrane
material, additional ultrafiltration, and dialysis
time will influence contrast media clearance.
Currently, there are multiple published studies
evaluating the removal of all classes of iodinated
contrast media by HD (Table  37.1) [39–50].

Comparison between these studies is difficult due
to variations in contrast media molecules, time
period between contrast administration and initiation of dialysis, blood flow rates, membrane
type/size, time on dialysis, ultrafiltration rate,
and presence of residual renal function.
Nevertheless, several important observations can
be made from these investigations.
The mean reduction rate of iodine by HD
increases with longer dialysis time reaching over
70% at 3 h in most studies [39, 47, 48, 50]. The
relationship between contrast media clearance
and blood flow rate was addressed by Teraoka
et  al. These investigators observed that when
blood flow rates were set at 100, 150, and
200  mL/min, the clearance of iopromide
increased to 45.35 ± 2.54, 53.88 ± 6.46, and
57.61 ± 4.72 mL/min, respectively [46].
A study by Matzkies et al. evaluated the clearance of iopromide using dialyzers with two different membrane materials and sizes [41]. A
significant increase in the plasma clearance of
iodine was observed when larger dialyzers were
used. The clearance was also higher for the polysulfone as compared to the cuprophan dialyzers.


37  Role of Radiological Assessment and Intervention in Pediatric Dialysis

713

Table 37.1  Hemodialysis removal of contrast media
Study
Kierdorf et al. [40]

Waaler et al. [49]

Molecular
Contrast agent weight (D)
Iopromide
791
Iohexol
821

Moon et al. [43]

Iohexol

821

Ueda et al. [48]

Ioversol

807

Polycarbonate
Cellulose
Cuprophan
Cuprophan
Polysulfone
Cellulose

Ueda et al. [47]


Iomeprol

777

Cellulose

Johnsson et al. [50]

Iohexol

821

Cellulose

Matzkies et al. [42]

Iopromide

791

Horiuchi et al. [39]
Matzkies et al. [41]

Iohexol
Iopromide

821
791

Sterner et al. [45]


Iodixanol
Iohexol
Iopromide
Iopromide

1550
821
791
791

Haemophan
Polyamide
Cellulose
Cuprophan
Polysulfone
Low flux

Schindler et al. [44]
Teraoka et al. [46]

Overall, most studies have reported that high-flux
membranes were more efficient than low-flux
membranes in the elimination of contrast media
[42, 44]. In contrast, one report by Matzkies et al.
studied the elimination of iopromide in chronic
HD patients using low-flux (haemophan) and
high-flux (polyamide) dialyzers and found a
comparable difference in the clearance rates for
both membranes [42].

The post-dialysis rebound or redistribution
of contrast media has been reported in only
three studies [42, 45, 50]. One study found no
significant rebound when measuring the iodine
concentration 1 hour after treatment [41].
However, a study by Johnsson et al. reported an
increase in the blood concentration of iohexol
at 1 and 24  h as compared to the immediate
post-dialysis level [50]. Sterner et  al. found
similar results [24, 45]. These investigators
measured iodine concentrations 2 and 45  min
after the conclusion of HD.  When using the
45 min post-dialysis plasma level, they reported
an 8–10% decrease in clearance, representing

Dialyzer

Hemophan
Cuprammonium

Contrast clearance
(mL/min)
80
81  ±  15

Contrast
removal
41% in 3 h
72  ±  11% in
4 h


70.4  ±  24.6

60–90% in 6 h

114–129

82.5 ± 5.1% at
4 h
81.4  ±  4.6%
at 4 h
71% at 3 h
79% at 6 h
62% at 3 h
58% at 3 h
72.9% at 3 h
57–63% at 2 h
60–68% at 2 h

131.4–133.3

108  ±  1.9
110  ±  1.4
87–121
147–162
58  ±  11
69  ±  16
82  ±  2.3
57.6


64% at 4 h

what they termed “hemodialysis clearance of
extracellular space.” The clinical significance
of the rebound effect is not known.
Peritoneal dialysis (PD) is relatively ineffective in removing contrast media. A total of ten
patients on continuous ambulatory peritoneal
dialysis (CAPD) were studied after the administration of iopamidol [51]. CAPD removed an
average of 53.6% of the administered dose during
the study period using 8 L of dialysate per day.
An average of 93% of the total dose was cleared
when dialysis and renal clearances were combined. A study by Moon et  al. reported three
patients who received iohexol [43]. Using
36–60  L of dialysate, 43–72% of the administered dose was removed over 16–18 h. In another
group of 14 patients with and without residual
renal function, CAPD removed 75% of the
administered iomeprol after a period of 4  days
[52]. When compared to HD, the clearance of
contrast media with PD is slower. However, no
adverse events as a result of contrast exposure
were reported in any of these studies.


714

 ialysis as a Strategy to Minimize
D
Contrast-Induced Nephropathy
Post-procedural dialysis to prevent extra-renal
complications in patients with ESRD does not

seem to be warranted and was addressed in an
above section.
Immediate dialysis after the administration of
iodinated contrast media has been advocated for
patients considered at very high risk for toxicity:
ESRD patients on chronic dialysis and those with
advanced chronic renal failure as a way to protect
residual renal function and avoid further
decreases in GFR.  Several studies have shown
that the administration of HD does not reduce the
risk of CIN.
In a prospective, randomized study, Lenhnert
et al. evaluated the influence of HD on CIN in 30
patients with chronic renal failure [53]. Both
groups received pre-hydration with intravenous
0.9% saline. In addition, the patients randomized
to Group 1 received HD for 3 h with a high-flux
polysulfone membrane after the administration
of iopentol. The rate of CIN was similar for both
groups (53% for Group 1 and 40% for Group 2)
despite data indicating that HD removed the
iopentol effectively.
In a similar study, Sterner et  al. reported 32
patients who were randomized to receive either
HD plus pre- and post-procedural hydration or
hydration alone after an angiographic examination [45]. HD was started within 2 h after the end
of contrast administration. The treatment was
prescribed for 4  h using low-flux cellulose acetate or cellulose diacetate hemodialyzers. The
GFR was determined by iohexol clearance 1 day
prior to and 1  week after the procedure. There

was no significant difference in the renal iohexol
clearance between the groups. The investigators
concluded that HD was not effective in preventing CIN in patients with chronic renal failure.
The largest prospective, randomized study of
113 patients addressing this issue reported that
the rate of CIN did not differ between the HD and
standard hydration alone treatment groups [54].
The same conclusion held true even for the subgroup of patients receiving a larger volume of
contrast media. In this study, HD was started at a

V. R. Dharnidharka and D. C. Rivard

median of 120  min after the administration of
contrast and was prescribed for a mean of 3  h
using a high-flux polysulfone dialyzer.
The lack of protection against CIN could be
the result of starting HD “late” after contrast
administration given the fact that renal injury
may occur rapidly. A study by Frank et al. evaluated the influence of simultaneous HD at the
time of contrast media administration on renal
function [55]. Creatinine clearance was measured prior to 1 and 8 weeks after the procedure.
In each of the study groups, the creatinine clearance was not different. Two patients from each
study arm developed ESRD requiring subsequent dialysis treatments. With a small sample
size of 17 patients, the study failed to demonstrate a protective effect of “early” HD on development of CIN.
More recently, hemofiltration has been
reported by Marenzi et al. as a successful strategy
for the prevention of CIN [56]. A total of 114
patients were randomized to receive pre-contrast
hydration or hemofiltration 4–6  h prior to and
18–24 h after the angiography. CIN occurred in

5% of patients in the hemofiltration group and in
50% of patients in the control group. A follow-up
study compared patients receiving hemofiltration
after contrast administration to those receiving
hemofiltration 6 h prior to and after the procedure
[57]. The rate of CIN was significantly less in the
pre-/post-hemofiltration group as compared to
the post-hemofiltration group (26% vs. 3%). The
mechanisms involving the protective effects of
hemofiltration remain unclear, and further studies
with this form of therapy are needed.

Negative Contrast Media
The negative radiological contrast media are the
gases: air, oxygen, nitric oxide (N2O), or carbon
dioxide (CO2). CO2 has been used as an intravascular imaging agent for over 30 years and as an
alternative to iodinated contrast agents or gadolinium in patients with advanced renal failure.
CO2 has certain unique properties: it is not nephrotoxic, lacks allergic potential, and is eliminated
by one pass through the lungs.


37  Role of Radiological Assessment and Intervention in Pediatric Dialysis

Several animal studies have reported the
lack of renal toxicity of CO2. Hawkins et  al.
evaluated the effects of selective CO2 injection
in the renal arteries of dogs [58]. The investigators found no dose-dependent effect of CO2
on renal function or renal histology. Palm et al.
compared the effects of CO2 with those of ioxaglate in the rat kidney [59]. The pronounced
decrease in medullary blood flow and PO2

observed after injection of ioxaglate was not
present in the animals injected with CO2.
Furthermore, a review of the published literature did not reveal any cases of CIN secondary
to CO2 administration.
CO2 is indicated for angiography in patients
with renal failure. However, it is not recommended to evaluate the cerebral or coronary circulations. Animal studies have suggested but
failed to confirm its neurotoxicity [60, 61].
However, widespread ST segment elevation,
decrease in coronary flow velocity, and profound
global left ventricular dysfunction were documented after administration of small doses of
intracoronary carbon dioxide in swines [61].
Overall, CO2 angiography is well tolerated
and can be successfully used in patients with
renal failure in order to avoid CIN (for a review,
see Ref. [62]).

715

reticuloendothelial system, eliminate ferumoxytol from circulation [65]. The ability of ferumoxytol to remain largely in the intravascular
space for an extended period of time has important implications in its use as a contrast agent:
longer imaging studies can be attained, covering
larger anatomical areas. This is in contrast to
GBCAs, which have a relatively short intravascular half-life and thus limited time for acquisition of imaging. Ferumoxytol causes strong
enhancement on T1-weighted images [66],
which allows depiction of vessels while ferumoxytol remains in the intravascular space. In
contrast, ultrasound and MRI with GBCA can
only cover limited vascular territories. Various
studies have shown that ferumoxytol can be
used effectively as a contrast agent for ceMRA
with comparable quality to GBCA, good visibility of occlusions, and the ability to image large

areas of the body. Figure 37.1 shows a coronal
T1 image from a ferumoxytol enhanced MRI in
a patient with renal failure, depicting fat saturated with ferumoxytol. Figure  37.2 is a 3D
reconstructed image from ferumoxytol MRI,
demonstrating stenosis and internal jugular
veins with collateral venous structures.

Ferumoxytol
Ferumoxytol is a superparamagnetic iron oxide
particle that is currently Food and Drug
Administration (FDA) approved for intravenous
iron replacement for treatment of iron deficiency anemia in patients with chronic kidney
disease. The FDA label additionally states that
ferumoxytol alters MRI studies, and more
recently, its use as a contrast agent for MRI has
been studied and explored. Ferumoxytol acts as
a blood pool agent, as it is a relatively large molecule with a long intravascular half-life of
14–15  hours [63], compared to about 90  seconds for traditional GBCA [64]. Eventually,
phagocytic cells, especially macrophages of the

Fig. 37.1  Images from a ferumoxytol-enhanced MRI in
a patient with renal failure. Coronal T1 shows fat saturated with ferumoxytol


716

Fig. 37.2  Three-dimensional reconstructed image from
ferumoxytol MRI demonstrating stenosis and internal
jugular veins with collateral venous structures


Gadolinium
Gadolinium is a rare earth metallic element in the
lanthanide series of the periodic table, with an
atomic number of 64 and molecular weight of
157.25 Da. This element has the unusual property
of possessing seven unpaired electrons in its
outer shell, thereby making Gd an ideal “paramagnetic” substance to disturb the relaxation of
surrounding water molecule protons and generate
contrast in MRI [67]. The GBCA are classified
into four main categories based on their biochemical structure (macro-cylic or linear) and their
charge (ionic or nonionic). The different properties of each category are important in order to
understand their potential for toxicity as a result
of liberation of free Gd from its chelate. Overall,
macro-cyclic chelates tend to be more stable and
have lower dissociation rates.

Renal Handling of Gadolinium
The GBCA have a molecular weight ranging
from 500 to 1000 Da, are highly soluble in water,
and have low binding to plasma proteins. Hence,

V. R. Dharnidharka and D. C. Rivard

after intravenous administration, GBCA distribute into the extracellular space and rapidly
­equilibrate with the interstitial space. There is no
intracellular penetration. These properties
account for the small volume of distribution of
GBCA (0.26–0.28 L/kg body weight) [68].
Chelated Gd is freely filtered by the glomeruli, is neither secreted nor reabsorbed by the renal
tubules, and is eliminated unchanged in the urine.

In the presence of normal renal function, GBCA
clearance approximates GFR.  Their mean half-­
life is typically under 2 h with 95% of the administered dose eliminated in the first 24 h. In renal
failure, the half-life can be prolonged up to
30–120  h. Extra-renal elimination of GBCA is
negligible with less than 3% being excreted in the
stool [68, 69].

Mechanisms for Toxicity
of Gadolinium
Though free Gd+ can be toxic, the chelated form
of Gd was believed for many years to be nontoxic
and generally safe. Only 64 adverse reactions,
mostly mild, were reported after 158,439 doses
in one study [70] and only 36 adverse reactions in
21,000 patients in another study [71]. Two case
reports described a spurious hypocalcemia after
Gd administration [72, 73].
When compared to iodinated contrast media,
GBCA are considered to be less nephrotoxic. This
is likely attributed to their lower viscosity and the
need to administer significantly lower volumes.
Several studies in healthy patients as well as individuals with mild and moderate renal failure suggested that overall nephrotoxicity is quite low
ranging from 0% to 5% [74, 75]. The risk of nephrotoxicity has been reported to be much higher in
patients with more advanced renal disease and
after intra-arterial injection of GBCA [76–79].
The exact mechanism of nephrotoxicity of GBCA
is not well known. However, GBCA and iodinated
contrast media share the same pharmacodynamics, their nephrotoxic effects are often clinically
similar, and they may cause renal damage through

similar mechanisms.


37  Role of Radiological Assessment and Intervention in Pediatric Dialysis

More recently, Gd has been associated with a
newly recognized condition called nephrogenic
systemic fibrosis (NSF), which is discussed in a
later section.

Dialysis in the Removal
of Gadolinium
Though GBCA clearance is delayed in renal failure, these compounds are of low molecular
weight, not protein bound, and have a small volume of distribution [80–82]. These properties
allow for good clearance with HD. Okada et al.
reported the removal rate of gadopentetate in 11
patients after a 4 h HD treatment [81]. The average Gd removal was 78.2% of the administered
dose after the first, 95.6% after the second, 98.7%
after the third, and 99.5% after the fourth treatment. A similar observation was reported after
administering gadodiamide to 13 patients. An
average of 98.9% of the administered dose was
removed after three HD treatments.
Ueda et al. evaluated the clearances of three
different GBCA in an in  vitro system using
low-­flux cellulose diacetate and higher-flux cellulose triacetate hemodializers [83]. The clearance of all three GBCA was significantly higher
when using the cellulose triacetate dialyzer
with larger pore size.
The clearance of GBCA using PD is much
slower. Joffee et  al. evaluated the removal of
gadodiamide in nine CAPD patients. After

22 days only 69% of the administered dose had
been removed [84]. Hence, the clearance of
GBCA by PD is inefficient and generally considered inadequate.

Nephrogenic Systemic Fibrosis
In 2000, Cowper et al. described a new condition
characterized by unusual, debilitating, and frequently fatal skin induration in patients with
acute or chronic renal failure [85]. The induration
presented as tender plaques or nodules on the
limbs and trunk, differentiable from scleromyxedema by absence of facial involvement and neg-

717

ative
serological
features.
Histological
characteristics included a markedly thickened
dermis yet unremarkable epidermis, increased
mucin deposition between widely separated collagen bundles, and absence of necrosis or ulceration. The disease was initially labeled as
nephrogenic fibrosing dermopathy [86]. As more
patients were recognized [87–93], other systemic
manifestations of the disease became clear, leading to a change in the name to NSF.  The exact
cause of this disease was and still remains
unknown. However, in 2005, multiple reports
emerged of a strong association with prior Gd
administration in patients who developed NSF
disease 4–8  weeks later [94, 95]. Subsequently,
Gd was detected in the skin lesions of some
patients with NSF, increasing the likelihood that

the association was causal [96, 97].
In renal failure, free Gd can potentially be liberated into tissue. Several GBCA are marketed
(Table 37.2). The potential for free Gd dissociation depends on several factors, including presence or absence of ionic charge (more ionic = less
likely to dissociate), chemical structure (linear
more likely to dissociate than cyclic ring of chelate around Gd), and kinetic stability (half-life at
pH  0.1; shorter stability more likely to dissociate). Consistent with this paradigm, the nonionic,
linear chelate with a short half-life (gadodiamide)
has been associated with the highest incidence of
NSF.  Macrocyclic GBCA result in the lowest
possible gadolinium deposition in tissues. The
dose of GBCA administered may also play a role.
GBCA were approved for use in MRI at a dose of
Table 37.2  FDA-approved GBCAs
Commercial
name
Dotarem
Eovist
Gadavist
Magnevist
MultiHance
Omniscan
OptiMARK
ProHance

Generic name
Gadoterate
meglumine
Gadoxetate disodium
Gadobutrol
Gadopentetate

dimeglumine
Gadobenate
dimeglumine
Gadodiamide
Gadoversetamide
Gadoteridol

Chemical
structure
Macrocyclic
Linear
Macrocyclic
Linear
Linear
Linear
Linear
Macrocyclic