Novel biomarkers for acute kidney injury in high-risk pediatric populations: a systematic review
Clinical Snapshot
PICO Framework
| P — Population | High-risk pediatric patients (children) at risk of or diagnosed with acute kidney injury across multiple clinical contexts (e.g., post-cardiac surgery, critically ill, nephrotoxic drug exposure, sepsis, congenital anomalies) |
| I — Intervention | Novel diagnostic biomarkers for AKI (including NGAL, KIM-1, cystatin-C, TIMP-2×IGFBP-7, IL-18, and others) |
| C — Comparator | Traditional biomarker (serum creatinine) as the reference standard for AKI diagnosis |
| O — Outcomes | Diagnostic accuracy outcomes: area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and other performance measures for early detection or prediction of AKI |
Bottom Line
This systematic review synthesises evidence from 53 studies on novel biomarkers for early AKI detection in high-risk paediatric populations, identifying NGAL, KIM-1, and cystatin-C as the most studied and promising candidates, with TIMP-2×IGFBP-7 and IL-18 showing early predictive potential. The review is methodologically grounded through PROSPERO registration and QUADAS-2 risk of bias assessment. However, the absence of meta-analytic pooling, formal GRADE certainty ratings, and incomplete search strategy reporting substantially limit the strength of conclusions that can be drawn. The narrative synthesis, while clinically informative, cannot resolve the considerable heterogeneity across paediatric subpopulations, biomarker assay platforms, and AKI definitions. A critical metadata concern also exists: the DOI provided does not match the listed journal, which must be resolved before citation. For Australian clinicians, these biomarkers remain investigational in the paediatric context — neither TGA-approved for this indication nor MBS-reimbursable. This review is best interpreted as a high-quality directional summary that identifies research priorities rather than a practice-changing document. Prospective multicentre validation studies with standardised paediatric cut-offs and clinically meaningful outcome endpoints are urgently needed.
Key Findings
P Value: Not reported at review level
Effect Size: No pooled effect size reported; narrative synthesis identifies NGAL, KIM-1, and cystatin-C as the most studied and most promising biomarkers; TIMP-2×IGFBP-7 and IL-18 identified as potentially predictive early markers
Primary Outcome: Diagnostic accuracy of novel biomarkers (AUC, sensitivity, specificity) for early detection or prediction of AKI in high-risk paediatric populations across 53 included studies
Nnt Or Sensitivity: Individual study-level AUC, sensitivity, and specificity values are referenced but not pooled; no summary diagnostic odds ratios or hierarchical summary ROC curves reported
Confidence Interval: Not reported (no meta-analysis performed)
Clinical Application
NGAL and cystatin-C assays are commercially available in many tertiary centres. TIMP-2×IGFBP-7 (NephroCheck) is FDA-cleared in adults but paediatric validation remains incomplete. Point-of-care urine NGAL testing is feasible in PICU environments. Widespread implementation is currently limited by lack of standardised paediatric cut-off values, assay variability, and absence of outcome-linked intervention trials. In Australia, paediatric AKI management is guided by KDIGO 2012 criteria, which remain serum creatinine-dependent. The TGA has not yet approved NephroCheck or equivalent novel biomarker assays for paediatric diagnostic use. NGAL and cystatin-C are available through major pathology providers (e.g., NSW Health Pathology, Pathology Queensland) but are not currently listed on the Medicare Benefits Schedule (MBS) as standalone AKI diagnostic tests. The RACGP and ANZPHN have not issued specific guidance on novel AKI biomarker use in children. Australian paediatric nephrology centres (e.g., The Children's Hospital at Westmead, Royal Children's Hospital Melbourne) may consider these biomarkers in research or high-risk clinical protocols, but routine implementation awaits further local validation and regulatory approval. High-risk paediatric patients including those undergoing cardiac surgery with cardiopulmonary bypass, critically ill children in PICU settings, neonates, children receiving nephrotoxic medications, and those with sepsis or haematological malignancies
Abstract
Acute Kidney Injury (AKI) is currently diagnosed in pediatric patients by measuring rises in serum creatinine. The objective of this systematic review is to determine the diagnostic accuracy of novel biomarkers for early detection or prediction of pediatric AKI across a variety of high-risk pediatric populations. Relevant studies were searched in PubMed, Cochrane Library, and Web of Science databases. Observational studies and randomized trials assessing diagnostic biomarkers for AKI in high-risk pediatric populations were included, while studies limited to traditional biomarkers, adult populations, or non-original research were excluded. Risk of bias was assessed using the QUADAS-2 tool. The review was prospectively registered in PROSPERO (CRD420261293432). Diagnostic accuracy outcomes included AUC, sensitivity, specificity, and other performance measures. 53 total studies were included and grouped into 1 of 5 categories based on the specific population of pediatric patients studied and the general etiology of their AKI. Of note, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and cystatin-C were among the most studied biomarkers and showed significant promise as reliable indicators of kidney injury. The product of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein-7, interleukin-18, and others showed some evidence of being predictive, early markers of AKI and warrant additional investigation. The review further discusses the integration of novel biomarkers within existing clinical detection frameworks, including validated risk stratification tools and emerging FDA-approved biomarker assays, to contextualize their translational potential in high-risk pediatric populations. Future advances in precision medicine may lead to earlier diagnosis and better prognosis for pediatric patients suffering from AKI. What is known: Acute kidney injury in children is associated with significant morbidity, and serum creatinine often detects kidney injury only after substantial damage has occurred.This study adds: This systematic review summarizes current evidence on emerging pediatric acute kidney injury biomarkers and highlights those with the greatest potential for earlier diagnosis across multiple high-risk populations.Potential impact: Earlier identification of acute kidney injury using novel biomarkers may enable more timely intervention and improve outcomes, although further validation is needed before widespread clinical implementation.
References
- 1.Backston, K., Buehrer, B., Ezgü, D., Sivaram, P., Tanna, S., Koka, R., Sethi, S. K., Moritz, M., & Raina, R. (2026). Novel biomarkers for acute kidney injury in high-risk pediatric populations: a systematic review. Renal Failure. https://doi.org/10.1371/journal.pone.0178091 [Note: DOI-journal mismatch identified; independent verification of this reference is strongly recommended prior to citation]
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