Observational Study of Pediatric Acute Kidney Injury, Risk Factors and Outcomes

The AWARE study is a multicenter prospective observational study designed to achieve the
following three goals:

1. Establish the first international pediatric AKI registry to describe in detail the
epidemiology and outcome of AKI in different pediatric and cardiac ICUs around the
world.

2. Validate the precision of RAI in ruling out AKI in a large, heterogeneous study
population.

3. Evaluate the predictive value of using RAI before and after the incorporation of four
different urinary AKI biomarkers used in different combinations.

To achieve these primary goals, children admitted to PICUs and/or pediatric cardiac ICUs
from different US and international centers will be screened for enrollment eligibility.
Patients admitted to general PICU and non-surgical patients admitted to cardiac ICUs are
considered the target population of AWARE. Patients admitted to neonatal ICUs and
post-surgical admissions to cardiac ICUs are not included in AWARE. Both clinical variables
and urinary biomarkers would be needed to accomplish the analysis.

A- Clinical variables: Clinical data of interest at study entry will include age, gender,
race, ethnicity, height, weight, date of ICU admission, date of ICU discharge, date of
hospital discharge, admission diagnosis(es) and primary co-morbidities. Creatinine clearance
(eCrCl) will be estimated by the modified Schwartz formula29. Baseline creatinine will be
collected if the patient had a listed value in the medical record in the 90 days prior to
admission, with the lowest value selected if multiple measurements are present. In cases
where no baseline data is available, reference eCrCl will be estimated as 120 mL/min/1.73m2.
30

Clinical data will be recorded on admission and on a daily basis for the first seven days of
the PICU admission or till discharge from the PICU whatever is earlier. Another set of data
will be collected to evaluate the primary and secondary outcomes of the study (see later).
The outcomes data will be collected on day 28 after ICU admission when available or by most
recent available data before hospital discharge for patients with no available data on day
28.

Clinical parameters of interest include:

- use of fluid resuscitation in peri-ICU period ( normal saline, PlasmalyteTM ,Ringer's
Lactate, 5% Albumin, starch based fluids including dextran composites)

- daily first shift heart rate (beats per minute) from day 1 through day 7 (at the most)
of ICU admission

- daily first shift respiratory rate (breaths per minute) from day 1 through day 7 (at
the most) of ICU admission

- daily first shift systolic and diastolic blood pressure and mean arterial pressure
(arterial line measurements will be used when available) from day 1 through day 7 (at
the most) of ICU admission

- daily first shift temperature from day 1 through day 7 (at the most) of ICU admission

- use of mechanical ventilation (yes/no)

- daily first shift mean airway pressure when applicable from day 1 through day 7 (at the
most) of ICU admission

- duration of mechanical ventilation

- daily first shift oxygen blood saturation ( SpO2) from day 1 through day 7 (at the
most) of ICU admission

- daily first shift fraction of inspired oxygen (FiO2) (%) from day 1 through day 7 (at
the most) of ICU admission

- use of nephrotoxins (yes/no) from day 0 through day 7 (at the most) of ICU admission

- types of nephrotoxic agents:

o Nonsteroidal anti-inflammatory drugs (NSAIDS)

- Aminoglycosides,

- anti-viral therapy,

- Vancomycin,

- Piperacillin/Tazobactam,

- Calcineurin inhibitors,

- IV radio-contrasts ( Including Gadolinium for MRI)

- use of inotropy (yes/no) from day 0 through day 7 (at the most) of ICU admission

- use of diuretics on day 0 and during admission (yes/no)

- class of diuretics used (Loop diuretics, Thiazides, Potassium sparing, Carbonic
anhydrase inhibitors, Vasopressin antagonist, Osmotic diuretic,)

- serum creatinine (SCr) (mg/dl) from 3 months prior to ICU admission through up 28 days
after admission

- fraction of inspired oxygen (FiO2) (%) from day 1 through day 7 (at the most) of ICU
admission

- total fluid in (mL) from day 0 through day 7 (at the most of ICU admission)

- total fluid out (mL) from day 0 through day 7 (at the most of ICU admission)

- total urine output (mL) from day 0 through day 7 (at the most of ICU admission)

- urine output per 12-hour shift (mL/hr) from day 0 through day 7 (at the most of ICU
admission)

- use of renal replacement therapy (RRT) (yes/no)

- modality of RRT when available

- use of ventricular assisted devices or extracorporeal Membrane Oxygenation (ECMO)

- outcome data

- mortality

- PICU length of stay

- hospital length of stay

Calculated daily values include:

- % change in estimated creatinine clearance

- calculated as = Daily eCrCl - Baseline eCrCl) / (Baseline eCrCl) *100

- AKI stage per Kidney Disease Improving Global Outcomes (KDIGO) guidelines

o Stages 1,2 ,3 assessed by both creatinine and urine output (Table-1)31

o % Fluid overload: cumulative PICU fluid overload percentage (% FO), calculated as =
((total PICU Fluid in (L) - total PICU fluid out (L)) / PICU admit weight (kg))*100

- urine output per kg per 8 hour interval

- Renal angina index (RAI) will be assessed on Days 0 and 1.

- RAI will be derived as a composite of risk strata and clinical injury signs of
AKI.

- Risk strata and risk scores of AKI:

o

1 (moderate risk): This stratum include all patients admitted to PICU and not fulfilling the
criteria of high risk or very high risk strata 3 (high risk): This include all patients with
history of solid organ or bone marrow transplantation ( BMT) 5 (very high risk): This
include all patients who are BOTH intubated AND on an inotropy medication.

AKI risk strata definitions and risk scores of children admitted to PICUs Patients
Risk Risk Score Any PICU admission Moderate 1 History of BMT
High 3 Ventilated and Inotropy Very high 5

Clinical renal injury signs and injury scores of AKI are:

1 (ICU status and no decrease in estimated creatinine clearance (eCrCl) or <5% fluid
overload FO) 2 (> 5% FO or eCrCl decrease of 0-24.99%) 4 (>10% FO or eCrCl decrease of
25-49.99%) 8 (>15% FO or eCrCl decrease of > 50%).

Clinical injury signs definition and injury scores of children admitted to PICU Injury by
fluid overload (FO) Injury by decreased eCrCl Injury score < 5%
No change 1 5 to <10% Decreased by 0-24% 2
10 to < 15% Decreased by 25 - 49% 4

≥ 15% Decreased by ≥ 50% 8

RAI = Risk score X Injury Score The range of indices is therefore: 1, 2, 3, 4, 5, 6, 8, 10,
12, 20, 24, and 40. RAI >= 8 indicates fulfillment of renal angina ( Basu et al5)

Urine samples: The collection of urine samples is optional for the participating sites. The
urine samples will be collected in the morning between 6 and 10 A.M. and/or in the afternoon
between 3 and 7 P.M. for up to four days (day 0 through day 3) on all enrolled patients.
Some centers may collect daily urine samples, others may choose to collect samples in both
time windows. Urine will be drained only from the collection apparatus of an indwelling
urinary drainage system or intermittent catheterization. Patients will not be bagged or
catheterized separately/independently for the purposes of this study. Collected urine
samples will be kept on ice or in 4° C refrigerator until they are processed. During
processing, specimens will be centrifuged at 3000 RPM at 4°C for fifteen minutes. The
supernatant will then be divided into up to nine 1-mL cryovials depending on the collected
urine volume and stored at minus 80°C. The stored urine samples from all participating sites
will be shipped to the Center for Acute Care Nephrology Biomarker Core Laboratory in the
Division of Nephrology and Hypertension at Cincinnati Children's Hospital Medical Center
when the coordinating site request the samples to be shipped at the time point set forth by
the coordinating site. The shipping supplies and instructions will be provided by the
coordinating site.

Inclusion Criteria:

- Age greater than 90 days and up to 25 years old

- All medical and surgical patients admitted to the pediatric intensive care unit

Exclusion Criteria:

- History of recent renal transplant or end stage kidney disease

- Post-surgical cardiac patients and patients following cardiac catheterization