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Background: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr value of the age- and sex-specific reference population. We explored if this Pottel method can detect drug-related nephrotoxicity in ELBW neonates., Methods: A previously reported dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin, or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used previously published postnatal age-specific 50 th centile values in an ELBW population. Linear mixed models were applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model., Results: Serum creatinine (n = 3231) observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068-1.145, p < 0.001) was observed, corrected for effect of antibiotics. Antibiotic administrations showed a small but statistically significant difference up to postnatal day 5., Conclusions: As rescaled Scr biomarker, the Pottel method showed a clear association with ibuprofen-exposed ELBW neonates, suggesting its applicability as a pragmatic bedside alternative tool to assess nephrotoxicity., (© 2024. The Author(s).)

Background: Serum creatinine (Scr) in early neonatal life (first week of life) displays extensive variability; hence, a better understanding is needed to use Scr as a diagnostic biomarker for acute kidney injury (AKI)., Objective: The objective of this study was to explore Scr trends and its covariates in early neonatal life., Methods: Analysis of a rich, pooled Scr dataset (enzymatic assay) of 4,509 Scr observations in 1,181 neonates in the first week of life with birth weight, gestational age (GA), and postnatal age as covariates was conducted. Descriptive data were summarized as median and range. The Spearman rank correlation test was used to examine Scr, while the Mann-Whitney U test was used to determine the differences between the different GA (≤32, 33-36, or ≥37 weeks) categories., Results: The median Scr at delivery was 55.7 (range 28.3-194.5) µmol/L, correlating with birth weight (r = 0.088) or GA (r = 0.183) for the full dataset. At birth, the median Scr was highest in term (≥37-week) neonates. In early neonatal life (median Scr values), there was a gradual increase to attain a peak Scr by day 2-3, highest and most delayed in neonates ≤32 weeks GA. This is followed by a blunted decrease when ≤32-week neonates were compared to those of 33-36 or ≥37 weeks GA., Conclusions: The Scr pattern in early neonatal life is complex, with the highest Scr at birth in full-term neonates, while those ≤32 weeks GA displayed the highest and delayed peak Scr with a subsequent blunted decrease. Knowledge of these patterns is crucial to explore the utility of Scr as an AKI biomarker., (© 2020 S. Karger AG, Basel.)

Introduction: The lowest serum creatinine (nadir Scr, cut-off 1 mg/dl) during infancy predicts subsequent renal outcome in posterior urethral valve (PUV) infants, but early, neonatal values may be useful to guide care. We aimed to explore correlations between neonatal Scr values and long-term renal outcome., Methods: Retrospective evaluation of records of 39 PUV patients, treated in the University Hospitals Leuven (2001-2011). Scr measurements were collected and associations (Mann-Whitney U, Spearman) to predict unfavorable renal outcome [GFR <60 ml/min/1.73 m(2) at 2 years] were explored., Results: Unfavorable renal outcome at the last follow-up was observed in 7/36 patients (19%). Besides the nadir Scr at a median age of 5 months, also the peak Scr and Scr between days 9 and 42 correlated significantly with renal outcome. By introducing "centiles" for neonatal Scr values in this PUV cohort, the 75th Scr percentile in this PUV cohort was highly predictive for unfavorable renal outcome., Conclusions: Besides the nadir Scr, early neonatal Scr values (peak, days 9-42, PUV cohort-specific 75th centile) also predicted unfavorable renal outcome. The introduction of PUV disease specific reference Scr centiles may be helpful to facilitate earlier prediction and guide counseling, but necessitates external validation.

Background: Urinary creatinine can be quantified by Jaffe or enzymatic assays and is commonly used as denominator of urinary excretion of electrolytes or protein. Paired analysis in pediatric and adult samples documented inter-assay differences (up to 80%). We verified the interchangeability of two IDMS-traceable assays (Jaffe and enzymatic) for neonatal urine and report on neonatal urinary creatinine values using these IDMS-traceable methods., Methods: Creatinine was measured in 84 neonatal urine samples from 46 neonates by an IDMS traceable Jaffe and enzymatic assay (Roche Diagnostics, Cobas c702 module). Creatinine values, differences in urinary creatinine and clinical characteristics were described and covariates of between assay difference were explored (Wilcoxon, Bland-Altman, correlation, multiple regression)., Results: Median Jaffe and enzymatic urinary creatinine concentrations were 9.25 (range 3.7-42.2) and 9.15 (range 3.8-42.9) mg/dL respectively, resulting in a median difference of 0.08 (SD 0.6, range -2.4 to 0.96) mg/dL. In a multiple regression model, urinary enzymatic creatinine concentration (r = 0.45) and postnatal age (r = -0.59) remained independent variables of the difference between both assays (r2 adj = 0.45)., Conclusions: The tested IDMS-traceable assays showed interchangeable in heterogeneous neonatal urine samples. Using these assays, neonatal urinary creatinine showed 5-20 fold lower values than those observed in children or adults with a significant negative correlation with postnatal age.

Objective: Serum creatinine (Scr) reflects to a certain extent glomerular filtration rate in neonates, but postnatal observations also depends on the technique used to quantify Scr (Jaffe colorimetry or enzymatic quantification)., Methods: In an attempt to quantify differences between these techniques, we compared postnatal Scr trends in two consecutive cohorts of extremely low birth-weight (ELBW) neonates before and following a switch from uncompensated Jaffe to enzymatic Scr quantification. Postnatal Scr (Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 21, 28, and 42) in 151 ELBW neonates (uncompensated Jaffe) was compared to 116 more recently admitted ELBW neonates (enzymatic)., Results: Although clinical characteristics were similar between both cohorts, median postnatal Jaffe Scr values were significantly higher compared to enzymatic quantification (all days, at least p < 0.001) throughout postnatal life. While both cohorts displayed a similar trend with an initial increase with a Scr peak on Days 3 and 4 and a subsequent decrease, the difference in within-day median values fluctuated between 11 and 24 mmol.L(-1). There is neither fixed nor relative difference in Scr between both techniques., Conclusions: When using Scr to estimate renal function in ELBW neonates, clinicians should in addition to the postnatal changes and other covariates of renal function, also consider the technique applied. We provide reference values and comparison between both techniques.

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis. [ABSTRACT FROM AUTHOR]

Introduction: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postnatal age (PNA) may provide more valuable information in TH neonates. Methods: Data from seven TH neonates and one non-TH-treated, non-NE control cohorts were pooled in a retrospective study. SCr centiles over PNA, and AKI incidence (definition: SCr ↑≥0.3 mg/dL within 48 h, or ↑ ≥1.5 fold vs. the lowest prior SCr within 7 days) and mortality were calculated. Repeated measurement linear models were applied to SCr trends, modeling SCr on PNA, birth weight or gestational age (GA), using heterogeneous autoregressive residual covariance structure and maximum likelihood methods. Findings were compared to patterns in the control cohort. Results: Among 1,136 TH neonates, representing 4,724 SCr observations, SCr (10th–25th–50th–75th–90th–95th) PNA centiles (day 1–10) were generated. In TH neonates, the AKI incidence was 132/1,136 (11.6%), mortality 193/1,136 (17%). AKI neonates had a higher mortality (37.2–14.3%, p < 0.001). Median SCr patterns over PNA were significantly higher in nonsurvivors (p < 0.01) or AKI neonates (p < 0.001). In TH-treated neonates, PNA and GA or birth weight explained SCr variability. Patterns over PNA were significantly higher in TH neonates to controls (801 neonates, 2,779 SCr). Conclusions: SCr patterns in TH-treated NE neonates are specific. Knowing PNA-related patterns enable clinicians to better assess kidney function and tailor pharmacotherapy, fluids, or kidney supportive therapies. [ABSTRACT FROM AUTHOR]

Background: Cardiac surgery-associated acute kidney injury (AKI) is associated with increased morbidity and mortality in both adults and children. Objectives: This study aimed to identify clinical risk factors for AKI following cardiac surgery in the pediatric population. Data sources: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for studies published by August 2020. Study eligibility criteria: Studies were included if (1) the population consisted of pediatric patients (< 18 years old), (2) patients underwent cardiac surgery, (3) risk factors were compared between patients who developed AKI and those who did not, and (4) studies were prospective or retrospective observational studies or randomized controlled trials. Participants and interventions: Children undergoing pediatric cardiac surgery. Study appraisal and synthesis methods: Random-effects meta-analysis was performed, comparing potential risk factors between pediatric patients who developed CS-AKI and those who did not. Results: Sixty-one publications including a total of 19,680 participants (AKI: 7257 participants; no AKI: 12,423 participants) were included from studies published between 2008 and 2020. The pooled estimated incidence of AKI was 34.3% (95% confidence interval 30.0–38.8%, I2 = 96.8%). Binary risk factors that were significantly and consistently associated with AKI were the presence of pulmonary hypertension, cyanotic heart disease, univentricular heart, risk adjustment for congenital heart surgery 1 (RACHS-1) score ≥ 3, vasopressor use, cardiopulmonary bypass use, reoperation, and sepsis. Significant continuous risk factors included younger age, lower body weight, lower preoperative creatinine, higher preoperative estimated glomerular filtration rate (eGFR), higher RACHS-1 score, longer surgery time, longer cardiopulmonary bypass time, longer aortic cross-clamp time, and higher red blood cell transfusion volume. Limitations: Results are limited by heterogeneity and potential residual confounding. Conclusions and implications of key findings: Our meta-analysis identified clinical risk factors that are associated with AKI in children undergoing cardiac surgery. This might help clinicians anticipate and manage more carefully this population and implement standardized preventive strategies. Systematic review registration number: CRD42021262699. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Dear Editor, We thank Manzar for the questions raised on the applicability of centile approaches for serum creatinine (SCr) in neonates treated with therapeutic hypothermia (TH) for neonatal encephalopathy, as this enables us to further explain the potential relevance and use of centile approaches [[1]]. Based on the centiles (10th, 25th, 50th, 75th, and 90th) SCr values over PNA (day 1-day 7) previously reported in the TH (1,136 cases, 4,724 SCr values) and the control (801 cases, 2,779 SCr values) group, the SCrTH/SCrcontrols ratio has been calculated [[2], [5]]. Therefore, a given SCr can be at the 10th, 50th, or 90th centile, while the same SCr concentration may be at a different centile when collected at different time points, and the absence of an expected SCr decrease may reflect impaired GFR compared to the reference postnatal trend. [Extracted from the article]

Background: Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ELBW) neonates remains challenging. Methods: We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated. Results: A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth. Conclusions: We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Objective: Neonatologists still commonly use creatinine as a proxy for renal clearance, despite issues related to neonatal (patho)physiology and methodology (assay variability). Cystatin C (CysC) has been suggested to be a more reliable biomarker, but assay related differences have also been reported in children and adults. We are unaware of any review on the assay related impact on CysC reference values in newborns. Methods: A structured literature search was performed on published CysC values in (pre)term neonates. Results: The extensive range (>5-fold) in serum CysC observations in neonates in part relates to the fact that CysC concentrations are higher at birth with subsequent decrease and that CysC concentrations are higher in preterm compared to term neonates. The CysC assay matters while disease characteristics also affect CysC values, but not always in the predicted direction. Conclusions: Similar to creatinine, the extensive CysC range in neonates is only in part explained by renal (patho)physiology. Its applicability in neonatal medicine can be further improved by use of assay specific reference values, adapted to neonatal renal physiology (e.g. weight, age) and should be compared to a gold standard such as inulin clearance. [ABSTRACT FROM AUTHOR]

Background Urinary creatinine can be quantified by Jaffe or enzymatic assays and is commonly used as denominator of urinary excretion of electrolytes or protein. Paired analysis in pediatric and adult samples documented inter-assay differences (up to 80%). We verified the interchangeability of two IDMS-traceable assays (Jaffe and enzymatic) for neonatal urine and report on neonatal urinary creatinine values using these IDMS-traceable methods. Methods Creatinine was measured in 84 neonatal urine samples from 46 neonates by an IDMS traceable Jaffe and enzymatic assay (Roche Diagnostics, Cobas c702 module). Creatinine values, differences in urinary creatinine and clinical characteristics were described and covariates of between assay difference were explored (Wilcoxon, Bland-Altman, correlation, multiple regression). Results Median Jaffe and enzymatic urinary creatinine concentrations were 9.25 (range 3.7-42.2) and 9.15 (range 3.8-42.9) mg/dL respectively, resulting in a median difference of 0.08 (SD 0.6, range -2.4 to 0.96) mg/dL. In a multiple regression model, urinary enzymatic creatinine concentration (r = 0.45) and postnatal age (r = -0.59) remained independent variables of the difference between both assays (r2 adj = 0.45). Conclusions The tested IDMS-traceable assays showed interchangeable in heterogeneous neonatal urine samples. Using these assays, neonatal urinary creatinine showed 5-20 fold lower values than those observed in children or adults with a significant negative correlation with postnatal age. [ABSTRACT FROM AUTHOR]

To document trends and covariates of creatinemia (Scr) in extremely low birth weight (ELBW, < 1,000 g) neonates, maternal characteristics [betamethasone, premature preterm rupture of membranes (PPROM), pre-eclampsia, maternal Scr], characteristics at delivery [gestational age (GA), birth weight (BW), small for GA (SGA), Apgar, intubation] and during neonatal stay [ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, intraventricular hemorrhage, retinopathy of prematurity (ROP), phototherapy] were linked with Scr observations. Data were reported by median and range or incidence. Characteristics in ELBW neonates with raised peak Scr (>P75) were compared to controls (P75 (112.3 μmol/l), Scr remained elevated until day 28. Mothers of cases received less betamethasone, neonates had a lower GA, lower BW, lower Apgar, and needed more often intubation. Postnatal ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, ROP, and intraventricular hemorrhage were different. GA and ventilation or Apgar were independent factors for raised peak Scr. ELBW neonates display trends similar to heavier neonates, but peak Scr is higher, and the subsequent decrease slower. Raised creatinemia in ELBW neonates reflects immaturity (GA) and morbidity (ventilation, Apgar). [ABSTRACT FROM AUTHOR]