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Furosemide stress test to predict acute kidney injury progression in critically ill children
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Pediatric Nephrologyhttps://doi.org/10.1007/s00467-024-06387-5
ORIGINAL ARTICLE
Furosemide stress test to predict acute kidney injury progression
in critically ill children
Sudarsan Krishnasamy1 · Aditi Sinha2 · Rakesh Lodha3 · Jhuma Sankar3 · Mohamad Tarik4 · Lakshmy Ramakrishnan4 ·
Arvind Bagga5 · Pankaj Hari2
Received: 31 January 2024 / Revised: 10 April 2024 / Accepted: 10 April 2024
© The Author(s), under exclusive licence to International Pediatric Nephrology Association 2024
Abstract
Background Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI);
however, pediatric studies are limited.
Methods Children 3 months to 18 years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from
Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7 days of admission underwent FST
(intravenous furosemide 1 mg/kg). Urine output was measured hourly for the next 6 h; a value > 2 ml/kg within the first 2 h
was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and
proenkephalin (PENK) were also evaluated.
Results Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7 days of admission and underwent FST.
Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive
group) developed stage 3 AKI within 7 days of FST, nine (17.6%) of whom (seven from non-responsive group) required
kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with
area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84–1.0) and 0.96 ± 0.03 (95% CI 0.9–1.0), respectively. FST
outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the
diagnostic accuracy.
Conclusions Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need
in critically ill children. Further research is required to identify the best FST cut-off in children.
Keywords Acute kidney injury · Biomarker · Furosemide stress test · FST · NGAL · PENK
Introduction
Acute kidney injury (AKI) is common in critically ill chil-
dren, with 27% of patients developing AKI within 7 days of
* Pankaj Hari intensive care unit (ICU) admission [1]. Along with a step-
pankajhari@hotmail.com
wise increase in mortality with increasing severity of AKI,
1
Pediatric Nephrology Services, Department of Paediatrics, there is significant increase in morbidity in the short term
Jawaharlal Institute of Post Graduate Medical Education [1–4]. Studies evaluating the long-term outcomes of AKI
and Research (JIPMER), Pondicherry, India have demonstrated an increased risk of proteinuria, hyper-
2
Division of Nephrology, Department of Pediatrics, All India tension, and chronic kidney disease following an episode
Institute of Medical Sciences (AIIMS), New Delhi, India of AKI [5–9]. Hence, identifying AKI early is important to
3
Division of Pediatric Pulmonology and Intensive Care, improve patient outcomes. As management of AKI is largely
Department of Pediatrics, All India Institute of Medical supportive, considerable effort has gone into early identi-
Sciences (AIIMS), New Delhi, India
fication and risk stratification of affected patients. To this
4
Department of Cardiac Biochemistry, All India Institute end, numerous biomarkers have been identified [10]. Neu-
of Medical Sciences (AIIMS), New Delhi, India
trophil gelatinase-associated lipocalin (NGAL) has been the
5
Director Paediatrics and Senior Consultant Pediatric most researched biomarker in AKI and has been applied in
Nephrology, Indraprastha Apollo Hospitals, New Delhi, India
Vol.:(0123456789)
, Pediatric Nephrology
multiple settings [11, 12]. However, it has its own limitations age-related reference creatinine values from previously pub-
and is not readily available in most centers [13]. lished literature were taken as baseline [22].
Furosemide has been used for the prevention and treat- Written informed consent was obtained from the parents
ment of AKI for decades, but systematic reviews do not or legal guardians of all patients at the time of enrolment
favor its use [14, 15]. Recently, a standardized protocol for into the study. The study was conducted in accordance
furosemide administration and assessment of the subsequent with the Helsinki Declaration of 1975, and Institutional
urinary response, termed the furosemide stress test (FST), Ethics Committee approval (IECPG-590/24.10.2019,
has been devised [16]. This functional biomarker has shown RT-15/28.11.2019) was obtained before commencing the
promise in critically ill adult patients [17, 18], but pediatric study. After taking consent, children were enrolled and the
data so far is confined to infants undergoing cardiac surger- baseline characteristics were recorded in a pre-designed
ies who have different clinical and hemodynamic profiles proforma. PRISM III score was done for all patients at
compared to septic, nephrotoxic medication-induced and the time of enrolment. Two biomarkers were also evalu-
other phenotypes of AKI which are commonly encountered ated in this study: plasma NGAL, the most extensively
in general pediatric intensive care units. Also, FST has not studied; and plasma pro-enkephalin (PENK), an emerg-
been evaluated prospectively in children. Hence, this study ing biomarker [23, 24]. Samples for these biomarkers were
was undertaken to examine the role of FST in predicting taken immediately prior to performing FST. Plasma was
AKI progression in critically ill children. separated by centrifuging blood at 3000 rpm for 10 min
and then stored at − 80 °C within 12 h of venepuncture.
Samples were analyzed in batches using sandwich ELISA
for plasma NGAL (R&D Systems, Minneapolis) and PENK
Materials and methods (Cusabio Biotech, Houston).
FST was performed within 12 h of critical care admission
This prospective observational study was undertaken in the in patients who were already in stage 1 or 2 AKI, or upon
ICU and high dependency unit (HDU) of a tertiary care identification of AKI stage 1 or 2 within the first 7 days
teaching hospital from November 2019 to July 2021. Indi- of critical care admission. After ruling out hemodynamic
cations for ICU/HDU admission included respiratory failure, instability (as defined above and verified by the treating
congestive cardiac failure, shock, AKI, altered sensorium, intensivist), patients were given a single dose of intrave-
acute liver failure, or multi-organ dysfunction. Patients aged nous furosemide at 1 mg/kg (1.5 mg/kg if already received
3 months to 18 years admitted to the ICU/HDU during this furosemide in the past 7 days), and urine output was moni-
period were screened for eligibility and those who devel- tored hourly for the next 6 h. All patients were catheterized
oped AKI stage 1 or 2 by the KDIGO serum creatinine or prior to performing FST. As the FST cut-off in children is
urine output criteria within 7 days of critical care admission unknown, an a priori assumption was made and patients
(admission to the ICU or HDU) were enrolled. Children with were considered furosemide responsive if urine output in the
an anticipated critical care stay of < 48 h, KDIGO stage 3 first 2 h after furosemide administration was ≥ 2 ml/kg. FST
AKI or hemodynamic instability at enrolment, presumed was performed only once for a patient and all patients were
cause of AKI other than acute tubular injury (nephrotic followed up daily until discharge/death. Serum creatinine,
syndrome, acute glomerulonephritis, interstitial nephritis, or estimated by modified Jaffe method, was repeated on days
hemolytic uremic syndrome), known chronic kidney disease 2, 4, and 6/7 after FST. Kidney support therapy (KST), in
(CKD), or hypersensitivity to furosemide were excluded the form of continuous kidney replacement therapy (CKRT),
from the study. Hemodynamic instability was defined as the peritoneal dialysis (PD), intermittent hemodialysis (IHD), or
presence of any of the following: capillary refill time > 3 s, sustained low-efficiency daily dialysis (SLEDD), was initi-
cold extremities with or without skin mottling or require- ated in eligible patients as per the standard ICU protocol
ment of > 2 vasopressors (dopamine, adrenaline, noradrena- after one-to-one discussion involving the affected family,
line, or vasopressin) to maintain blood pressure > 5th centile intensive care, and nephrology teams. Ventilation and shock
for age, sex, and height. AKI was defined and staged as per were managed as per standard guidelines. Outcome data,
KDIGO 2012 criteria [19]. Patients needed to fulfill either including need for KST and mortality, were collected and
the urine output or serum creatinine criteria (whichever was recorded in the proforma.
higher if both were met) for staging the severity of AKI. Statistical analysis was done using Stata software, version
CKD was defined and staged as per standard criteria [20]. 14.2 (Stata Corp., College Station, TX). Continuous data
Estimated glomerular filtration rate (eGFR) was calculated were expressed as mean ± standard deviation (SD) or median
using the modified Schwartz formula [21]. The lowest serum (interquartile range, IQR), and analyzed by Student’s “t” test
creatinine value within the preceding 3 months was taken as or Mann–Whitney “U” test, as appropriate. Categorical data
the baseline creatinine; if no serum creatinine was available, were expressed as percentage or proportion and analyzed
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