Renal Precision Medicine in Neonates and Acute Kidney Injury: How to Convert a Cloud of Creatinine Observations to Support Clinical Decisions

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 (S cr ). However, there is extensive variability in S cr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for S cr , 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 S cr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile S cr 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.

Creatinine at Birth Correlates with Gestational Age and Birth Weight: Another Factor of the Imbroglio in Early Neonatal Life

“…Similar to the findings by Go et al [4], we observed a positive correlation of S cr at birth with GA (week, in the absence of data on days) in a large, pooled, and heterogeneous cohort (882 S cr observations, GA range 23–42 weeks) of neonates [4, 6, 7]. Although statistically significant, the clinical impact of this positive correlation is rather limited (24–40 weeks, 54.5–60.2 μmol/L, +10%).…”

“… Individual S cr values at birth (Cr birth ) in a pooled dataset in neonates (GA range 23–42 weeks) display a significant correlation (rank correlation) with GA [6, 7]. S cr , serum creatinine; GA, gestational age.…”

“… Median S cr values ( n = 4,509) in the first week of life in cohorts, based on GA (≤32 weeks [black], 32–36 weeks [dark gray], and ≥37 weeks [light gray]) [6, 7]. S cr , serum creatinine; GA, gestational age.…”

“…The pooled analysis was based on 2 separate published cohorts. The available covariates in the pooled dataset were limited to GA, postnatal age (day 1 = day of birth), and birth weight [6, 7]. In both datasets, S cr was quantified by an enzymatic assay (Roche Diagnostics, isotope dilution mass spectrometry, Cobas c702 module).…”

Amikacin or Vancomycin Exposure Alters the Postnatal Serum Creatinine Dynamics in ELBW Neonates

“…In essence, the definition is based on trends (increase) in serum creatinine concentrations and in urine output to result in AKI staging (stage 0-3) ( Table 1). However, as the dynamics in serum creatinine are most pronounced in ELBW neonates with an initial physiological increase up to day 3 and a subsequent progressive decrease over the next weeks, these trends are difficult to capture within a 'fixed or proportional increase to former creatinine observation' approach, and perhaps does not provide the granularity needed to detect 'minor changes' [25].…”