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

Assessment of Worldwide AKI in Pediatrics, Renal Angina and Epidemiology

Pediatric acute kidney injury (AKI) is associated with increased morbidity and mortality in critically ill patients. Currently, understanding of the epidemiology and diagnosis of AKI in children is limited by single center retrospective data and inconsistent diagnostic and stratification criteria. The hypotheses of the AWARE study is that 1) renal angina, a composite of early injury signs and risk of disease, will predict severe subsequent AKI in critically ill children and 2) the incorporation of urinary biomarkers into the renal angina scoring system will improve the prediction of the severe injury. The AWARE study is conducted to describe AKI epidemiology in a heterogeneous multinational cohort of critically ill children, characterize AKI risk factors and associated morbidity, and validate the KDIGO AKI criteria as a predictor of pediatric AKI outcomes. The multi-center, multi-national registry will create the largest ever repository of information available on AKI in children.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury

Detailed Description

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:

  • Nonsteroidal anti-inflammatory drugs (NSAIDS)
  • Aminoglycosides,
  • anti-viral therapy,
  • Vancomycin,
  • Piperacillin/Tazobactam,
  • Calcineurin inhibitors,
  • IV radio-contrasts ( Including Gadolinium for MRI)
• use of vasoactive support (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 from baseline creatinine calculated as = Daily Cr/Baseline Cr

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

  • Stages 1,2 ,3 assessed by both creatinine and urine output (Table-1)31
  • % 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 = composite of risk strata and AKI clinical injury score

  o Risk strata (AKI risk tiers):

• 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 receive both invasive mechanical ventilatory support AND vasoactive medication at any time in the first 12 hours of ICU admission.

  o AKI Clinical Injury scores:

• 1 (ICU status and no increase from baseline creatinine or <5% fluid overload FO)
• 2 (> 5% FO or change from baseline creatinine of 1-1.49x)
• 4 (>10% FO or increase from baseline creatinine of 1.5-1.99x)
• 8 (>15% FO or increase from baseline creatinine of >= 2x).

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 4°C for fifteen minutes. The supernatant will then be divided into up to nine 1-mL aliquots 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.

• Study Type: Observational
• Enrollment (Actual): 5237

Contacts and Locations

Study Locations

• Australia
  • Sydney, Australia, NSW 2031
    • The Sydney Children's Hospitals Network
  • New South Wales
    • Westmead, New South Wales, Australia
      • Children's Hospital at Westmead
• Canada
  • Edmonton, Canada, AB T6G 2R3
    • University of Edmonton
  • Montreal, Canada, QC H3H 1P3
    • Montreal Children's/McGill
  • Vancouver, Canada
    • University of British Columbia and Children's and Women's Health Center of British Columbia Branch
• China
  • Nanjing, China
    • Nanjing Children's Hospital
• Indonesia
  • Jakarta, Indonesia
    • Dept of Child Health Cipto Mangunkusumo/University of Indonesia
  • Surabaya, Indonesia
    • Dept of Child Health Airlangga University/Dr. Soetomo Hospital
• Italy
  • Rome, Italy, 00165
    • Ospedale Pediatrico Bambino Gesù
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Children's Hospital
• Serbia
  • Belgrade, Serbia
    • University Children's Hospital
  • Belgrade, Serbia
    • Mother and Child Health Care
• Singapore
  • Singapore, Singapore
    • University Children's Medical Institute, National University Hospital
• United Kingdom
  • London, United Kingdom, WC2R 2LS
    • King's College Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35203
      • University of Alabama
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States
      • Children's Hospital Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours/Alfred I. duPont Hospital for Children
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Iowa
    • Des Moines, Iowa, United States, 52242
      • University of Iowa
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • St. Louis, Missouri, United States, 63130
      • Washington University in St. Louis
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • New Hyde Park, New York, United States, 11354
      • Cohen Children's Medical Center of NY
    • Stony Brook, New York, United States, 11794
      • Stony Brook Long Island Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Virginia
    • Richmond, Virginia, United States, 23284
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

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

Description

Inclusion Criteria:

• Age greater than 90 days
• Age less than 25 years

Exclusion Criteria:

• Patients on maintenance hemodialysis, peritoneal dialysis, or with chronic kidney disease with a baseline eGFR of <15 mL/min/1.73m2
• Patients with renal transplant received less than 90 days from the ICU admission.
• Patients admitted to ICU immediately post-operative to within three months following surgical correction of congenital heart disease.
• Patients with uncorrected congenital heart disease. This criteria does not include patients with isolated uncorrected ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (PDA) and patent foramen ovale (PFO).
• Patients following cardiac catheterization.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Pediatric Intensive Care Unit Patients; All patients will be included in a single cohort initially (admission to the PICU) and then cohorted into groups based on development of severe AKI (Stage 2-3 KDIGO by either Cr or UOP criteria) within the first seven days, renal angina risk strata, medical admission diagnoses, and outcomes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe AKI in first seven days of ICU Admission	AKI as defined by KDIGO stage 2 or 3 (by either changes in creatinine or UOP) assessed within 7 days of ICU admission	Within 7 Days of ICU admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AKI Conferred Risk on Mortality	After adjustment for covariates, will analyze the independent conferred risk on mortality within 28 days of severe AKI (detected within the first seven days of ICU admission).	28 days
Comparison of AKI by Creatinine and Urine Output	Epidemiology and AKI outcomes for patients will be separated into diagnosis by changes in creatinine, urine output, or both. Independent associations with AKI diagnosed by urine output and outcome will be identified.	7 and 28 days
Determination of AKI Progression	The stage by stage increase or decrease in AKI severity will be followed - with associations determined - to identify risk factors for AKI progression to severe injury.	7 days
Identification of Predictors of Severe AKI	Variables with independent associations for increased risk of severe AKI in the first seven days will be identified.	7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in pre-test probability of AKI risk using the renal angina index	Assessing all patients with complete data for the presence of renal angina 12 hours after admission using the renal angina index will allow for determination of the heightened prediction of Day 3 - AKI versus standard methods of severity of illness or changes in creatinine alone.	3-4 days
Biomarker incorporation into renal angina index	Incorporating values of measured urinary biomarkers, we will determine the additive effect on discriminatory precision for the renal angina index on prediction of Day 3 - AKI	3-4 days

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Rajit K Basu, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Stuart Goldstein, MD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Basu RK, Kaddourah A, Terrell T, Mottes T, Arnold P, Jacobs J, Andringa J, Goldstein SL; Prospective Pediatric AKI Research Group (ppAKI). Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in critically ill children (AWARE): study protocol for a prospective observational study. BMC Nephrol. 2015 Feb 26;16:24. doi: 10.1186/s12882-015-0016-6.
• Basu RK, Kaddourah A, Terrell T, Mottes T, Arnold P, Jacobs J, Andringa J, Armor M, Hayden L, Goldstein SL. Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in Critically Ill Children (AWARE): A Prospective Study to Improve Diagnostic Precision. J Clin Trials. 2015;5(3):222. doi: 10.4172/2167-0870.1000222. Epub 2015 Apr 17.
• Basu RK, Bjornstad EC, Gist KM, Starr M, Khandhar P, Chanchlani R, Krallman KA, Zappitelli M, Askenazi D, Goldstein SL; SPARC Investigators. Acute kidney injury in critically Ill children and young adults with suspected SARS-CoV2 infection. Pediatr Res. 2022 Jun;91(7):1787-1796. doi: 10.1038/s41390-021-01667-4. Epub 2021 Jul 30.
• Ayalon I, Woo JG, Basu RK, Kaddourah A, Goldstein SL, Kaplan JM; AWARE Investigators. Weight as a Risk Factor for Mortality in Critically Ill Patients. Pediatrics. 2020 Aug;146(2):e20192829. doi: 10.1542/peds.2019-2829. Epub 2020 Jul 3.
• Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL; AWARE Investigators. Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults. N Engl J Med. 2017 Jan 5;376(1):11-20. doi: 10.1056/NEJMoa1611391. Epub 2016 Nov 18.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: November 13, 2013
• First Submitted That Met QC Criteria: November 19, 2013
• First Posted (Estimate): November 20, 2013

Study Record Updates

• Last Update Posted (Estimate): September 27, 2016
• Last Update Submitted That Met QC Criteria: September 25, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Pediatrics; Acute kidney injury; Critical Care
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: Pediatric AWARE Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual center data will be distributed per patient/location. Sites will not receive data for patients enrolled at other sites. All data will be centrally housed at Cincinnati Children's Hospital.