Iohexol for measuring renal function.

Approximately 25% of all children admitted to the PICU will develop AKI during
the first seven days after admission. AKI is associated with a worse outcome,
including an increased risk of mortality compared to patients without AKI.
However, this AKI prevalence estimation is based on serum creatinine based GFR
(eGFR), which is known to be inaccurate.

We postulate that measured GFR (mGFR) based on iohexol clearance in critically
ill children will detect a higher prevalence of AKI than currently used methods
based on endogenous markers. Furthermore, we hope to get a better understanding
of the value of a new biomarker to estimate GFR. If an underestimation of the
prevalence of AKI is indeed demonstrated by our study, we aim to identify
certain patient groups that are especially prone to underdiagnosis by the
currently used methods. In the future, this could lead to earlier adjustment of
therapy and treatment in AKI patients. All gained information will lead to
better mechanistic insight in the relative contribution of GFR and renal
tubular transporter function to renal function in this critically ill
population, including knowledge on the maturation of transporter function and
the interplay with critical illness.

Primary objective: To determine the prevalence of AKI in critically ill
children based on clearance of iohexol.

Secondary objectives:
1. To determine the prevalence of AKI in critically ill children using serum
creatinine, creatinine clearance, cystatin C and/or blood urea nitrogen based
eGFR equations as well as urinary iohexol clearances.
2. To determine serum PENK levels in critically ill children.
3. To compare the prevalence of AKI when diagnosis is based on plasma iohexol
clearances with the prevalence of AKI based on serum creatinine, creatinine
clearance, serum cystatin C, PENK and/or BUN based eGFR and to assess agreement
between those methods.
4. To determine risk factors for the development of AKI when based on iohexol
clearance.

Exploratory endpoints:
1. To explore the relationship of genetic variation with the development of AKI.
2. To assess whether calculation of single point GFR leads to accurate GFR
determination in critically ill children and neonates when using a population
PK model and Bayesian feedback in comparison with the gold standard.
3. To explore the relation between the clearance of iohexol and GFR determined
using endogenous markers in children direct post kidney transplantation as well
as in children receiving extra corporeal membrane oxygenation (ECMO).

Observational study with minimal invasive procedures. Diagnostic study.

Risks:
In the context of this study, iohexol will be administered as a diagnostic
marker. Iohexol is used in pediatric standard care in several European
countries (including the Netherlands; Amsterdam UMC) in children of all ages
with chronic kidney disease.
As the rate of adverse events related to the use of iohexol is only 0.0066% in
15,000 routine GFR measurements in Italian adults, the risks and burdens
associated with this study are negligible. Blood samples are only taken from an
indwelling catheter (already in place for clinical purposes) or concomitantly
with regular blood work. The urine sample will be collected by using a urine
catheter (if already placed for clinical purposes).

Benefits:
Individual patients will not benefit from the iohexol clearance measurements as
those are not part of clinical care routines and will not be evaluated on the
same date. However, potential benefits of participating patients will be an
ongoing extensive assessment with reference to their kidney function by
determining creatinine as well as cystatin C and blood urea nitrogen
concentrations, both two to four times a day. This may enable earlier
interventions in patients at risk by the treating physician.

Group relatedness:
This research is group-related as data from healthy adults or healthy children
cannot be extrapolated to critically ill children as GFR differs significantly
between those groups. It is known that GFR changes with age, however, the
impact of critical illness on GFR in those children is still unknown. This
study will help to identify critically ill children with AKI. eGFR-calculations
based on endogenous markers can be improved for critically ill children when
gold standard GFR measurements are available. In the future, this will decrease
the risk of toxicity in patients with AKI.