Article of the Month - Jun 2021

Creatinine filtration kinetics in critically ill neonates

Pediatric Research 2021 89:952-957. DOI: 10.1038/s41390-020-0977-4 PMID: 32454515; PMCID: PMC7688479

Danielle R Rios, Christopher J Rhee, Leah Elizondo, Kenneth M Brady, Craig G Rusin, Sebastian Acosta

Reviewed by Erin Rademacher

Education Committee Note: The unique creatinine physiology of neonates over the first week(s) of life poses major challenges to the recognition of kidney injury as well as the development of a valid AKI definition for this heterogeneous patient group. Large datasets are needed to help define normal creatinine trends from which abnormal occurrences can then be identified. This manuscript by Rios and colleagues presents robust creatinine curves by gestational age generated from almost 80,000 creatinine values. In addition, the authors offer a novel explanation for why we see the trends that we do. Certainly, this is a critical area for further scientific investigation and discussion as we work to fully understand the short and long-term impact of neonatal AKI.

Background

Creatinine clearance is used in adults as an estimate of glomerular filtration rate. However, a steady-state creatinine is required along with timed urine and serum collections. These conditions are not met in the NICU as even term neonate do not have stable creatinine values initially. There is no consistent data on the trajectory of creatinine values or what is the upper limit of normal for a given gestational age (GA) and at a given day of life.

What was the purpose of the study?

The study’s objective was to model the behavior of kidney function in neonates admitted to a NICU with repeated creatinine measurements throughout their hospitalization.

What were the study design and methods?

This is a retrospective cohort study in a single NICU. Data was extracted from the electronic medical record. Initial entry criteria included at least 1 serum creatinine measurement between January 1, 2013 and December 31, 2018. Subjects were grouped according to GA into 4 categories: 22-27 weeks = group 1, 27-32 weeks = group 2, 32-37 weeks = group 3, and 37-42 weeks = group 4. Subjects were excluded from further analysis of time modeling if they had fewer than 5 creatinine measurements in the first year of life, or did not have a creatinine with the first 3 days of life or after 10 days of life.

Mathematical modeling was used to describe the expected time course of creatinine filtration in the NICU subjects. The statistical model created a creatinine concentration profile that used three parameters: the kidney filtration onset delay (Td – the time after birth at which the kidney begins to clear creatinine), the creatinine half-life (ln(2)/k), and the steady-state creatinine concentration (G/k).

The effects of use of antenatal steroids, 5 minute Apgar score, indomethacin use, and gentamycin use on filtration delay, creatinine half-life, and steady state creatinine were examined by ANOVA.

What are the results?

4808 subjects (55.7 % male, 70.5% White, 21.2 % Black, 33.5% Hispanic) contributed 78,634 creatinine values which allowed the authors to generate 10th-90th percentile curves as a function of age in days for each GA group. The 50th percentile creatinine was below 1.0 for all GA groups. 1782 subjects remained after the exclusion criteria were applied for the modeling of creatinine over time. The median filtration onset delay was significantly longer in the youngest GA group (4.26 days) compared to the other 3 GA groups with no difference seen between the older 3 groups (1.89 days, 1.71 days, and 1.64 days). Gestational age and indomethacin were both found to significantly affect filtration delay by ANOVA. The creatinine filtration half-life also differed by GA. The medians by GA group were 8.69, 6.26, 4.38, and 4.05 days with groups 1, 2, and 3 being significantly different from each other. The only significant factor affecting filtration half-life by ANOVA was GA. Lastly, the authors showed that the median steady-state creatinine concentration did not differ between groups (0.28, 0.29, 0.26, and 0.27 for the 4 GA groups).

What was the conclusion?

The time to when a neonates kidneys begin to filter creatinine is proportional to their GA and affected by indomethacin. Infants less than 27 weeks have a median filtration onset delay of just over 4 days. Older GA infants have a delay of just over 1.5 days. Most neonates do not have a rise in creatinine with only the youngest group showing a rise in creatinine. However, even the 22-27 GA group had a 50th percentile creatinine below 1.0. The percentile curves for creatinine by GA and day of life may lead to easier and earlier recognition of abnormal renal function in neonates.

Why does this matter?

Defining the normal time course of decline of serum creatinine as well as normal values by GA and day of life will help clinicians recognize neonates with impaired renal function. This recognition will allow for possible changes in drug choice/dosing and fluid management as well as identifying neonates who may need long term monitoring of their kidney function.