Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates: A Secondary Analysis of the PENUT Randomized Clinical Trial.

JAMA Netw Open. 2023 Aug 1;6(8):e2328182. doi: 10.1001/jamanetworkopen.2023.28182 PMID: 37561461; PMCID: PMC10415963.

Starr MC, Griffin RL, Harer MW, Soranno DE, Gist KM, Segar JL, Menon S, Gordon L, Askenazi DJ, Selewski DT

Reviewed by: Jonathan R. Burris


Fluid balance plays a significant role in the morbidity and mortality of extremely low gestational age neonates (ELGANS). Acute kidney injury (AKI) diagnosis based primarily on serum creatinine can be misleading due body fluid changes postnatally.  Creatinine measures are impacted by intracellular and extracellular fluid composition. Serum creatinine is diluted with positive fluid balance and it is concentrated with negative fluid balance. Correcting serum creatinine for fluid balance allows for more accurate representation of kidney function, and may provide for more timely AKI diagnosis and earlier implementation of management and therapy.


To evaluate the epidemiology and impact of correcting fluid balance in relation to creatinine in extremely low gestational age neonates. The study had three AIMS. 1. Describe fluid-corrected serum creatinine curves in ELGANS during the first 2 postnatal weeks. 2. Describe the prevalence of AKI before and after fluid correction. 3. Evaluate the associations with short-term and long-term outcomes of AKI before and after fluid correction.

The primary hypothesis was that correction of serum creatinine for fluid balance would identify previously undiagnosed AKI episodes, and the secondary hypothesis was that fluid-corrected AKI would clarify the association of AKI with clinical outcomes.

Study design:

Post hoc cohort analysis of the PENUT Trial in extremely premature neonates born less than 28 weeks gestation. Inclusion criteria were: gestational age of 24 weeks 0 days to  27 weeks 6/7 days at birth, enrollment within first 24 hours of life, and arterial or venous access. Exclusion criteria were: major life-threatening anomalies, hematologic crises, hematocrit greater than 65%, hydrops fetalis, and congenital infection.

Daily weights and serial creatinine values from the first 14 days of life were utilized.  Fluid balanced was calculated based on the following equation: [(daily weight - birth weight)/ birthweight] x 100. Fluid corrected serum creatinine was calculated based on the equation: serum creatinine x [ 1+ (fluid balance / total body water)]. Total body water was defined at 80% of birth weight.

Each serum creatinine was fluid adjusted from a trough serum creatinine used to define the baseline and peak serum creatinine used for AKI diagnosis for the first 14 days of life. AKI was defined using neonatal modified KDIGO criteria. True AKI was based on uncorrected serum creatinine and unveiled AKI was based on fluid corrected creatinine.

Maternal and neonatal characteristics were compared based on fluid corrected AKI status. The primary outcome measure was the need for invasive mechanical ventilation on postnatal day 14. Secondary outcomes were BPD, length of stay, and mortality.


There were 923 neonates included in the cohort analysis. Correcting for fluid balance significantly altered the serum creatinine curve in the first two weeks of life. Regarding AKI incidence, 23.3% had an AKI diagnosis based on uncorrected serum creatinine.  When creatinine was corrected for fluid balance 33.9% had an AKI diagnosis. Those with primary AKI diagnosis and those with unveiled AKI diagnosis had similar clinical characteristics. When comparing against those without AKI, the unveiled AKI group had higher rates of mechanical ventilation at day of life 14.There was no difference in hospital stay and mortality between the groups. In those with AKI diagnosis, correcting for fluid had significant increased odds ratio for mechanical ventilation and grade 3 BPD.


Correcting serum creatinine for fluid balance in premature neonates increased the incidence of neonates with a diagnosis of AKI. There was an associated increased odds ratio on morbidity with higher rates of ventilation and bronchopulmonary dysplasia.


Limited to assessing fluid balance only within the first two postnatal weeks. Clinical conditions and management may result in changes in weight not reflected in the analysis. Total body water based on birthweight was a static value with changing physiology postnatally.


Correcting serum creatinine for fluid balance provides a clearer evaluation of true changes in kidney function independent of fluctuations in fluid balance alone and provides a timelier diagnosis for management.