Maastricht Investigation of Renal function in Absence of- and post- Contrast in patients with estimated glomerular filtration rate LEss than 30mL/min/1.73m2 (MIRACLE)

Intravascular iodinated contrast administration has become crucial to modern
medicine. Currently it is estimated that over 250 million injections are given
each year worldwide during medical scans and interventions.1 For over 50 years
now, acute kidney injury caused by intravascular administration of iodinated
contrast material has been considered a leading cause of hospital-acquired
renal failure.2 As a result, contrast has been withheld in fear of kidney
injury leading to misdiagnoses and delayed appropriate patient management.

An acute predefined increase in serum creatinine is considered an indicator of
acute kidney injury (AKI).KDIGO, NVvR When such an acute increase in serum
creatinine occurs within 2-5 days post-contrast in absence of another
aetiology, it is assumed to be iodinated contrast administration induced acute
kidney injury. However, careful review of the enormous amount of existing
literature on the subject leads to the conclusion that risks of post-contrast
acute kidney injury and clinical consequences thereof have been grossly
overestimated. Reasons for this may be manifold. A bias exists in literature
toward studies in cardiac angiography, where both inherent population and
procedural risk factors abound and confuse the issue.3 Furthermore, all
prospective studies published in literature lack control groups not receiving
iodinated contrast material.4 Serum creatinine, changes in which are used to
determine the presence or absence of acute kidney injury, is a non-specific
surrogate and imperfect marker for renal function.5 It is influenced by factors
such as muscle mass, diet, hydration, activity, blood pressure, and (changes
in) medication, it shows diurnal and seasonal fluctuations, and is often
unstable in patients with health issues.6,7 Without control groups, rises in
creatinine are attributed to contrast administration without considering normal
creatinine fluctuations or other causes. The implications of the often
transient and acute rise in serum creatinine that represents PC-AKI are also
unclear, and it is unsure whether longer-term negative outcomes are inherent to
the population studied or a result of contrast administration. Several studies
have shown correlations between PC-AKI and increased morbidity and mortality
risk, but whether PC-AKI is a marker or part of a causative process is not
known.8-12 There are several studies that have attempted to evaluate the causal
relationship between contrast exposure and nephrotoxicity.13-15 However, most
of these are observational and retrospective in nature. Serum creatinine
increase indicating acute kidney injury has been shown to occur in absence of
iodinated contrast, and incidences are sufficient to eclipse those of
post-contrast acute kidney injury (PC-AKI).14,15 In other words, measuring
post-contrast change in serum creatinine yields mostly noise, with only a few
instances of acute kidney injury. The issue with retrospective studies is that
they often cannot control for confounders and therefore cannot give us
causation, only association. Furthermore, selection bias plays a role, since
only patients with repeated renal function measurements can be included in such
studies. No prospective studies on incidences of AKI in absence of contrast
have been done.

Another reason for overestimation of the risk for renal function is that the
basis of PC-AKI has been laid in another era of contrast material
administration. Many advances have been implemented since PC-AKI and associated
long-term risk were first reported.16 Not only have contrast media greatly
evolved - from toxic cell-invading salts, through high-osmolality ionic, an
finally to non-ionic low-osmolality structures -,17 injection protocol
parameters have also been the subject of many optimisation studies.18-30
Reductions in contrast volumes of up to 75% have been achieved using relatively
low-iodine concentration contrast agents whilst maintaining sufficient
diagnostic image quality. In other words, we currently operate in a new, safer
era of iodinated contrast administration.31 Contrast toxicity in clinical
practice can be expected to likewise have changed.

Guidelines on the use of intravascular iodinated contrast material the world
over have changed in accordance with the above insights. Whereas intravascular
iodinated contrast was thought to pose a risk for renal function of all
patients in the past, the high risk group has been adjusted to include ever
smaller subgroups of patients with chronic kidney disease (i.e., eGFR <60
ml/min/1.73m2).32-33 Since 2018 it is widely accepted that patients with eGFR
<30 mL/min/1.73m2 are most at risk of renal injury after intravascular
iodinated contrast material injection.34-38 This consensus is not based on
available data, since data on eGFR <30 ml/min/1.73m2 patients is rare in
literature.39-40

Studies to date have not been able to distinguish acute kidney injury caused by
iodinated contrast administration from that for which no causal link is
established, and the question at this time is whether iodinated contrast
administration (still) induces renal damage in the current clinical setting in
patients with eGFR <30 mL/min/1.73m2. This would best be answered by randomised
controlled trials comparing eGFR <30 mL/min/1.73m2 patients receiving iodinated
contrast versus a placebo injection. However, such trials are unlikely given
evident ethical issues.

The current controlled prospective observational study proposes a solution to
the above dilemma: intra-patient comparisons of peak changes in renal function
(serum creatinine) in absence of- and post- intravascular iodinated contrast
administration, to elucidate the relationship between renal function and
contrast administration in elective patients with eGFR <30 mL/min/1.73m2. Risk
of short-term dialysis and mortality will also be evaluated.

The current prospective observational study proposes to use intra-patient
comparisons of periods without and with contrast to elucidate the relationship
between renal function and contrast administration in this population. The
central question is: is there a difference between peak change in serum
creatinine within 5 days in absence of- and post-contrast?

Primary objective:
The primary aim is to evaluate the effect of intravascular iodinated contrast
administration on renal function as represented by changes in serum creatinine,
in patients with eGFR <30 mL/min/1.73m2.

Secondary objectives:
Secondary aims are to determine the following in patients with eGFR <30
mL/min/1.73m2: time to post-contrast peak change in serum creatinine;
incidences of classic and KDIGO definitions of acute kidney injury in absence
of contrast compared to post-contrast; changes in eGFR within 5 days from
baseline in absence of and post-contrast. In addition, effects up to 1-month
post-contrast will be evaluated through change in eGFR, incidences of eGFR
decline >=5 mL/min/1.73m2, and incidences of dialysis and mortality. A final
aim is to determine urine elimination time of intravascular iodinated contrast
in patients with eGFR <30 mL/min/1.73m2.

To evaluate whether the effect of contrast administration on renal function is
modified by specific situations, exploratory subgroup analyses will be
prespecified (see section 3).

MIRACLE is a single centre study at Maastricht UMC+, amongst patients referred
for an elective procedure with intravascular iodinated contrast and with an
eGFR <30 mL/min/1.73m2.

The study design is a prospective observational study using intra-patient
comparisons, so that each patient functions as his/her own control (see Section
J, Table 1).

In order to determine the effect of intravascular iodinated contrast
administration on renal function, most guidelines on safe use of contrast
material recommend measuring post-contrast serum creatinine within 2-3 days
(the Dutch guideline recommends measuring serum creatinine within 2-7 days,
presumably for logistic reasons). However, although serum creatinine rises
within 48 h, it has been shown to peak between 4- and 5-days post-contrast on
average.30 Therefore, in this study, peak changes in serum creatinine within 5
days will be determined. This will be done before (= in absence of contrast),
after (=post-contrast), and at 1-month post contrast (=1-month post contrast in
absence of contrast).

In addition, peak changes in eGFR, 1-month change in eGFR and incidences of
dialysis and mortality will be recorded. Patients will also be asked to collect
urine every time they naturally urinate and to note time and date on the
container provided. Urine will be collected during approximately 4 days: from
first urination after intravascular iodinated contrast administration until the
time of visit 2.5 (see Section J, Table 1). Both urine and serum samples will
be stored at the biobank Maastricht UMC+ for renal function/renal damage marker
assays.

The study will include 72 patients. Each patient will be followed for the
duration of approximately 40 days.

Exploratory subgroup analyses will be performed to evaluate whether specific
situations result in higher vulnerability of patients to an increase in peak
change after contrast administration (when compared with the peak change before
contrast administration). Patients will be categorized into two subgroups
according to the following pre-defined factors:

1. Intravenous prophylactic hydration (yes vs no),
2. Administration route (intra-arterial versus intravenous contrast
administration)
3. Volume of contrast (high versus low)
4. Co-morbidity (presence vs absence of diabetes)

To find out whether there is effect modification (interaction), it will be
explored whether the magnitude of the mean difference in peak change in serum
creatinine before and after contrast administration varies between subgroups.

Table 1 (see Section J) gives a representation of data collection and the
burden of participating in this study. Patients will follow standard care.
Participation in this study entails 11 days of study contact, followed by 25
days without, then another 6 days of study contact. The intake visit should
take less than 30 minutes, all other study visits are expected to last no
longer than 10 minutes. No filling in of questionnaires is required. Baseline
characteristics and medication may be orally checked with the patient during
all three baseline and the final visits. Adverse events will be asked after at
each visit. Inasmuch as possible, or inasmuch the patient wishes, follow-up
venepunctures will be done at home.

In routine care renal function of patients with eGFR <30 mL/min/1.73m2 is
monitored relatively frequently, and two blood samples - before and once within
2-5 days after any intravascular iodinated contrast material administration -
are standard care at Maastricht UMC+. Sometimes another two blood samples are
also standard care: at the time of referral and at 1-month post-contrast. In
total thirteen to fifteen extra venepuncture blood samples will be taken for
this study over the course of approximately 40 days (see Section J, Table 1);
never more than one in one day and not more than 10 mL at a time. The risks of
venepuncture and participation in this study are deemed negligible.

Longer elimination time of contrast will potentially increase renal toxicity.
In order to determine elimination time and identify which patients retain
contrast, patients will be asked to collect urine every time they naturally
urinate and to note time and date on the container provided. Urine will be
collected for approximately 4 days: from first urination after intravascular
iodinated contrast administration until the study visit on day 5 post-contrast
(visit 2.5; see Section J, Table 1). Containers will be collected during
visits.

Benefits:
Patients are not expected to personally benefit from participating in this
study, although their renal function will be monitored extra closely. Patients
with eGFR <30 mL/min/1.73m2 are most at risk of renal injury after
intravascular iodinated contrast material injection. Whereas such contrast
administration appears to be safe for the majority of patients even amongst
those with eGFR <30 mL/min/1.73m2, reports of individuals with post-contrast
adverse events persist. On the other hand, contrast has been withheld in fear
of kidney injury with misdiagnoses and delayed appropriate patient management
as a result. Results of this study may help better determine the causal
relationship between contrast exposure and nephrotoxicity, identify which
individual patients are at risk, and help to better determine safety of
intravascular iodinated contrast administration in future.