Prevention guidelines for contrast-induced nephropathy in contrast-enhanced CT: Appropriate and cost-effective? The Amsterdam, Maastricht, Alkmaar, Contrast Induced Nephropathy-Guideline study (the AMACING study)

Contrast-induced nephropathy (CIN) is a side-effect of intravascular
administration of iodinated contrast media. It is defined as an increase in
serum creatinine within 48-72 hours of iodinated contrast medium administration
and is usually reversible, resolving within two weeks.

CIN prevention guidelines aim to identify patients at risk of CIN, and to
subsequently prevent CIN in those at risk patients through prophylactic
intravenous hydration before and after exposure to iodinated contrast medium.
The CIN incidence in patients receiving intra arterial iodinated contrast
medium is higher compared to patients receiving intravenous iodinated contrast
medium during computed tomography.The greater part of CIN prevention guidelines
is based on data acquired from patients undergoing cardio angiographic
procedures in which intra-arterial high bolus contrast media are administered
in hemodynamic unstable patients.

In addition, different studies including both patients receiving intravenous
iodinated contrast medium and patients not receiving iodinated contrast medium
show that there is no association between increase in serum creatinine (CIN)
and the administration of intravenous iodinated contrast medium in patients
with a decreased renal function. Another large cohort study where propensity
matching was performed in patients receiving intravenous iodinated contrast
medium versus patients not receiving intravenous iodinated contrast medium the
CIN incidence was not significantly different.
This indicates that the risk for CIN in patients receiving intravenous
iodinated contrast medium is low.

These new insights led the European Society of Urogenital Radiology (ESUR) to
review their prevention guideline on CIN. The updated ESUR guideline indicates
not to use intravenous prophylactic hydration in patients with an eGFR * 45
ml/min/1.73m2. This means that prophylactic intravenous hydration for
intravenous contrast administration is superfluous in the largest part of
patients identified as being at risk of CIN by Dutch prevention guidelines (
eGFR 45-60 ml/min/1.73 m2). This is the larger proportion of the patients that
will be included in our randomized controlled trial (RCT).

We will also include patients with eGFR between 30-44 ml/min/1.73 m2. For this
group the risk for CIN after intravenous administration contrast medium appears
also to be minimal. In studies with patients receiving intravenous contrast
medium without prophylactic intravenous hydration or having severely diminished
kidney function, low CIN incidences were seen (range: 1.3% - 5.2%; pooled
incidence 3.6%). In studies on intravenous iodinated contrast medium
administration without prophylactic intravenous hydration, a pooled CIN
incidence of 3.9% (30/760) was described. Of these 30 patients, 25 did not have
an eGFR 30-44 ml/min/1.73 m2, and eGFR range of the other five cannot be
determined from the given data; thus potential CIN incidence in patients with
an eGFR between 30-44 ml/min/1.73 m2 is either zero or at maximum 0.7%
(5/760).

The abovementioned data lead to the question, whether hydration can be omitted,
as there is no evidence that prophylactic intravenous hydration has a
protective effect .
Importantly, the association between the increase in serum creatinine (CIN) and
any adverse event has not been demonstrated.

Another issue is that prophylactic intravenous hydration is not without risk as
patients may develop pulmonary oedema and/or cardiac failure which could lead
to respiratory insufficiency. This risk has not been properly evaluated in the
context of CIN since only few articles mention these risks, and it is unknown
how this risk relates to the risk for developing CIN.

In summary, firstly the risk for CIN is low in patients receiving intravenous
iodinated contrast medium. There is no evidence showing the protective effect
of prophylactic intravenous hydration in patients receiving intravenous
iodinated contrast medium. Thirdly, the association between the increase in
serum creatinine (CIN) and any adverse event has not been demonstrated.
Fourthly, prophylactic intravenous hydration is not without risk.
We therefore hypothesize that intravenous prophylactic hydration can be omitted
in most patients receiving intravenous prophylactic hydration without increase
of CIN incidence and adverse events in these patients.

The objective of our study is to investigate the relative (cost-)effectiveness
of the two Dutch guidelines in patients receiving intravenous iodinated
contrast medium during computed tomography. A cohort study will compare both
screening methods to see which method is most (cost) effective. We will also
analyse which risk factors are best associated with contrast induced
nephropathy in this population.
A randomised controlled trial will determine the efficiency of prophylactic
intravenous hydration with normal saline in the prevention of contrast induced
nephropathy, persistent decreased renal function, morbidity and mortality up
to 30 days after iodinated contrast material administration.

Our study consists of two components and will take place in three medical
centres. One academic hospital: the Academic Medical Centre (AMC); one
peripheral hospital: the Medical Centre Alkmaar (MCA); and one combination
academic-peripheral hospital: the Maastricht University Medical Centre (MUMC+)
. At the AMC and MCA patients are screened and treated according to the VMS
guideline. At the MUMC+ patients are screened and treated according to the CBO
guideline.
The first part of our study is a cohort study comparing the VMS and CBO
screening methods used at the different centres. In order to achieve this, all
information required for the implementation of both guidelines will be
collected at all sites. All patients identified as being at risk of developing
CIN according to the guidelines and being given the indication for intravenous
prophylactic hydration will be included in the randomized controlled trial.
Patients will be randomized to either receive intravenous prophylactic
hydration (standard care) or no intravenous hydration (control group). Patients
included in the randomized controlled trial will receive a 30 day follow-up.
Patients identifed as being at risk by VMS but not by CBO will receive a
similar follow up but will not be included in the randomised controlled trial
as they have no indication for hydration according to standard CBO care.
The primary outcome is net CIN cases prevented. In addition, cost-effectiveness
of VMS & CBO CIN prevention guidelines at the level of screening and CIN
prevention will be assessed.

In the randomized controlled trial patients will be randomized to receive
standard care, i.e. prophylactic intravenous hydration before and after
intravenous iodinated contrast medium administration. The intervention group
will receive no prophylactic intravenous hydration before and after intravenous
administration of iodinated contrast medium.

Patients included in the cohort study will receive standard care, for these
patients there is no increased risk or burden. Patients included in the
intervention group of the randomized controlled trial (i.e. no intravenous
prophylactic hydration) are expected to have no or a minimally increased risk
for developing contrast induced nephropathy. Research carried out in patient
populations receiving intravenous contrast media administration showed minimal
risk of CIN even in patients not receiving prophylactic intravenous hydration.
This has led the European Society of Urogenital Radiology (ESUR) updating their
guidelines for the prevention of contrast induced nephropathy in order to make
a distinction between intra-arterial and intravenous contrast medium
administration, in the assumption that patients receiving intravenous contrast
medium have a smaller risk of developing contrast induced nephropathy and do
not in part require prophylactic hydration. This, in combination with recent
findings showing an absence of clinically relevant effects (i.e. increased
morbidity and mortality risk) after intravenous contrast administration, leads
us to consider the risk incurred by participation in this study to be
acceptable.
Patients will be asked to fill in a questionnaire five times during the course
of the study (before & after the CT scan and/or intravenous hydration, and 2-5,
10-14 & 30 days after the CT scan) , which will take a maximum of 15 minutes
each time. Patients will be asked to give a blood sample in order for us to
determine renal function 10-14 days after the CT scan. This means that patients
will visit the hospital one extra time. If at that time renal function has not
returned to a value similar to baseline, the referring physician will be
informed and the patient will be referred to them for further treatment. We
will ask these patients to return at 30 days after the CT scan to give another
blood sample for renal function determination.