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Creatinine Assays in Early Infancy: How to Aim for a Moving Target

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Biomarkers in Kidney Disease

Abstract

Glomerular filtration rate (GFR) in neonates is very low and can only be maintained due to a delicate balance between both vasodilatory effects at the afferent and vasoconstrictor effects at the efferent glomerular arteriole. Despite this low clearance capacity, interindividual variability is already extensive and can be predicted by covariates (gestational age, birth weight, postnatal age, drugs, growth restriction, or peripartal asphyxia).

We still commonly used creatinine as a proxy for renal clearance capacity. However, before creatinine values can be used to estimate renal elimination capacity, there are some issues that need to be considered related to physiology and methodology. Creatinine at birth does not yet reflect neonatal but maternal creatinine clearance, and because of passive tubular back leak instead of active secretion, creatinine clearance does not yet fully reflect GFR. Trends will be described. Moreover, absolute creatinine values also depend on the technique. The move toward harmonization through isotope dilution mass spectrometry (IDMS) traceability has helped but has not completely solved this problem. In line with recent observations in adults, more research is needed to document the potential add on the benefit of advanced biomarkers (e.g., cystatin C). In the meanwhile, IDMS-traceable creatinine observations, compared to age-dependent, assay-specific reference values, should be used to support clinical decisions.

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Abbreviations

95 % CI:

95 % confidence intervals

AKI:

Acute kidney injury

CALIPER:

Canadian laboratory initiative on pediatric reference intervals

cGFR:

Calculated glomerular filtration rate

CLcrea :

Creatinine clearance

CLSI:

Clinical and laboratory standards institute

Cr-EDTA:

51Chrome ethylene diamine tetra acetic acid

CysC:

Cystatin C

eGFR:

Estimated glomerular filtration rate

ELBW:

Extreme low birth weight infants (i.e., <1,000 g at birth)

ELISA:

Enzyme linked immunosorbent assay

GFR:

Glomerular filtration rate

IDMS:

Isotope dilution mass spectrometry

IgG:

Immunoglobulin G

kDa:

Kilodalton

NKDEP:

National Kidney Disease Education Program

PENIA:

Particle-enhanced nephelometric immunoassay

PETIA:

Particle-enhanced turbidimetric immunoassay

pRIFLE:

Pediatric risk, injury, failure, loss, end-stage (renal risk score)

Scr :

Serum creatinine

SD:

Standard deviation

Tc-DTPA:

99mTechnecium diethylene triamine penta acetic acid

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Acknowledgement

Karel Allegaert is supported by the Fund for Scientific Research, Flanders (Fundamental Clinical Investigatorship 1800214N), and by an IWT-SBO project (130033).

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Authors and Affiliations

  1. Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000, Leuven, Belgium

    Karel Allegaert

  2. Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Karel Allegaert

  3. Intensive Care and Surgery, Erasmus MC, Sophia Children’s Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands

    Karel Allegaert

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  1. Karel Allegaert
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Correspondence to Karel Allegaert .

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Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

Definitions of Words and Terms

Newborn

Any child in the first 28 days of postnatal life. This time interval is commonly further subdivided in early neonatal (<day 8) and late neonatal life (day 8–28).

Infant

Any child beyond the first 28 days of postnatal life but not yet 365 days old (<1 year).

Preterm

Newborn born too soon; normal pregnancy takes 40 weeks of gestational age until delivery. Preterm delivery is any delivery before 37 weeks of gestational age.

ELBW

Within the preterm neonates, there is a further subdivision, either based on gestational age or on weight. Extreme low birth weight infants have a birth weight below 1,000 g at delivery.

Creatinine

Creatinine is a degradation product from creatine and is produced at a fairly constant rate, reflecting muscle mass. It is commonly measured as a reflection of renal function.

Creatinine assays

The Jaffe quantification is a colorimetric reaction method using alkaline picrate. Jaffe assays suffer from interference by endogenous (e.g., pseudo-creatinines, hemoglobin F, bilirubin) and exogenous (e.g., cephalosporins). More recently, enzymatic methods were introduced. These assays are less prone to such interference-related errors and thus seem more suitable. Nevertheless, enzymatic assays can also be affected by interferences. It is generally accepted that uncompensated Jaffe overestimates Scr and fixed corrections (e.g., 0.2 or 0.3 mg/dl), or adaptations in the analytical procedure (e.g., rate blanking) have been suggested to adapt Jaffe assays observations.

Matrix effect

This term refers to the change or the measurement bias of a given quantification method caused by (differences) in the non-analyte matrix. This may be of specific relevance in human biology since the matrix in neonates (e.g., blood) commonly differs (e.g., albumin, bilirubin, hemoglobin F) from other populations. These differences may affect measurement results and/or accuracy.

Clearance

Clearance is defined as the volume of fluid that – for a given time interval – is completely cleared of a specific compound. Creatinine clearance hereby reflects the renal elimination capacity or the glomerular filtration rate.

IDMS traceability

Isotope dilution mass spectrometry traceability. This has been introduced to adapt for the differences between different creatinine assays and serves as a golden standard to all currently marketed creatinine assays. This became even more important, since estimated glomerular filtration (eGFR) values are extrapolated from single-serum creatinine (Scr) measurements.

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Allegaert, K. (2015). Creatinine Assays in Early Infancy: How to Aim for a Moving Target. In: Patel, V. (eds) Biomarkers in Kidney Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7743-9_1-1

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  • DOI: https://doi.org/10.1007/978-94-007-7743-9_1-1

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