Abstract
Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (Scr). However, there is extensive variability in Scr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for Scr, but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while Scr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile Scr values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant—commonly transient—mean GFR decrease (−50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury negation has a significant impact on AKI incidence and severity. It is hereby important to realize that follow-up should not be discontinued at discharge, as there are concerns about long-term renal outcome. These illustrations suggest that integration of renal (patho)physiology into neonatal precision medicine are an important tool to improve contemporary neonatal care, not only for the short-term but also with a positive health impact throughout life.
Highlights
Precision medicine is defined as a structured approach to treat or prevent specific diseases based on the inter-individual variability in genes, physiology, and environment
This serum creatinine (Scr) variability is partly explained by maturational changes and nonmaturational changes related to pathophysiology, e.g., perinatal asphyxia, co-medication, congenital anomalies of the kidney and urinary track (CAKUT), cardiac surgery with bypass, or extra-corporeal membrane oxygenation (4, 5)
As estimated by creatinine excretion in urine, muscle mass increased from 12% of birth weight at 25 weeks to 19% at 34 GA weeks and 24% at term (11)
Summary
Precision medicine is defined as a structured approach to treat or prevent specific diseases based on the inter-individual variability in genes, physiology, and environment. This is reflected in extensive inter- and intra-individual variability in serum creatinine (Scr), resulting in a cloud instead of extractable and interpretable information for clinicians This “cloud” is illustrated, after plotting Scr observations (enzymatic assay) in (pre)term neonates collected in one Neonatal Intensive Care Unit (NICU) in the first 42 postnatal days of life (3). There is about a 4fold difference in Scr observed for all consecutive days, so that improved understanding on reference values is needed to attain precision medicine This Scr variability is partly explained by maturational changes (e.g., birth weight, gestational age [GA], postnatal age) and nonmaturational changes related to pathophysiology, e.g., perinatal asphyxia, co-medication, congenital anomalies of the kidney and urinary track (CAKUT), cardiac surgery with bypass, or extra-corporeal membrane oxygenation (4, 5). This explains the significant impact of non-steroidal anti-inflammatory drugs (NSAIDs, −20 up to −40% of the glomerular filtration rate [GFR] in ELBW neonates, depending on the type and dose) or asphyxia (up to −40 to −50% of GFR)
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