Neonatal nephrotoxic medication exposure and early acute kidney injury: results from the AWAKEN study.

BACKGROUND: We aimed to describe nephrotoxic medication exposure and investigate associations between exposure and acute kidney injury (AKI) in the neonatal intensive care unit during the first postnatal week. DESIGN/METHODS: Secondary analysis of the AWAKEN cohort. We evaluated nephrotoxic medication exposure during the first postnatal week and associations with AKI using time-varying Cox proportional hazard regressions models. Nephrotoxic medication exposure categories were defined as: no nephrotoxic medication, nephrotoxic medications excluding aminoglycosides, aminoglycoside alone, and aminoglycoside and another nephrotoxic medication. RESULTS: Of 2162 neonates, 1616 (74.7%) received ≥1 nephrotoxic medication. Aminoglycoside receipt was most common (72%). AKI developed in 211(9.8%) neonates and was associated with a nephrotoxic medication exposure (p < 0.01). Nephrotoxic medication exposures including a nephrotoxic medication excluding aminoglycoside (aHR 3.14, 95% CI 1.31-7.55) and aminoglycoside and  another nephrotoxic medication (aHR 4.79, 95% CI 2.19-10.50) were independently associated with AKI and severe AKI (stage 2/3), respectively. CONCLUSIONS: Nephrotoxic medication exposure in critically ill infants is common during the first postnatal week. Specific nephrotoxic medication exposure, principally aminoglycosides with another nephrotoxic medication, are independently associated with early AKI.

The nephrologist of tomorrow: towards a kidney-omic future.

Omics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called "Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment" (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function.

Renal injury in neonates: use of "omics" for developing precision medicine in neonatology.

Preterm birth is associated with increased risks of morbidity and mortality along with increased healthcare costs. Advances in medicine have enhanced survival for preterm infants but the overall incidence of major morbidities has changed very little. Abnormal renal development is an important consequence of premature birth. Acute kidney injury (AKI) in the neonatal period is multifactorial and may increase lifetime risk of chronic kidney disease.Traditional biomarkers in newborns suffer from considerable confounders, limiting their use for early identification of AKI. There is a need to develop novel biomarkers that can identify, in real time, the evolution of renal dysfunction in an early diagnostic, monitoring and prognostic fashion. Use of "omics", particularly metabolomics, may provide valuable information regarding functional pathways underlying AKI and prediction of clinical outcomes.The emerging knowledge generated by the application of "omics" (genomics, proteomics, metabolomics) in neonatology provides new insights that can help to identify markers of early diagnosis, disease progression, and identify new therapeutic targets. Additionally, omics will have major implications in the field of personalized healthcare in the future. Here, we will review the current knowledge of different omics technologies in neonatal-perinatal medicine including biomarker discovery, defining as yet unrecognized biologic therapeutic targets, and linking of omics to relevant standard indices and long-term outcomes.

Drug-induced acute kidney injury in neonates.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is an independent risk factor for morbidity and mortality in critically ill neonates. Nephrotoxic medication exposure is common in neonates. Nephrotoxicity represents the most potentially avoidable cause of AKI in this population. RECENT FINDINGS: Recent studies in critically ill children revealed the importance of recognizing AKI and potentially modifiable risk factors for the development of AKI such as nephrotoxic medication exposures. Data from critically ill children who have AKI suggest that survivors are at risk for the development of chronic kidney disease. Premature infants are born with incomplete nephrogenesis and are at risk for chronic kidney disease. The use of nephrotoxic medications in the neonatal intensive care unit is very common; yet the effects of medication nephrotoxicity on the short and long-term outcomes remains highly understudied. SUMMARY: The neonatal kidney is predisposed to nephrotoxic AKI. Our ability to improve outcomes for this vulnerable group depends on a heightened awareness of this issue. It is important for clinicians to develop methods to minimize and prevent nephrotoxic AKI in neonates through a multidisciplinary approach aiming at earlier recognition and close monitoring of nephrotoxin-induced AKI.

Metabolomics in pediatric nephrology: emerging concepts.

Metabolomics, the latest of the "omics" sciences, refers to the systematic study of metabolites and their changes in biological samples due to physiological stimuli and/or genetic modification. Because metabolites represent the downstream expression of genome, transcriptome, and proteome, they can closely reflect the phenotype of an organism at a specific time. As an emerging field in analytical biochemistry, metabolomics has the potential to play a major role in monitoring real-time kidney function and detecting adverse renal events. Additionally, small molecule metabolites can provide mechanistic insights into novel biomarkers of kidney diseases, given the limitations of the current traditional markers. The clinical utility of metabolomics in the field of pediatric nephrology includes biomarker discovery, defining as yet unrecognized biological therapeutic targets, linking of metabolites to relevant standard indices and clinical outcomes, and providing a window of opportunity to investigate the intricacies of environment/genetic interplay in specific disease states.

Urinary metabolomic markers of aminoglycoside nephrotoxicity in newborn rats.

BACKGROUND: Aminoglycoside exposure is a common cause of acute kidney injury (AKI). Delay in the diagnosis of AKI using conventional biomarkers has been one of the important obstacles in applying early effective interventions. We tested the hypothesis that urinary metabolomics could identify novel early biomarkers for toxic renal injury. METHODS: Three-day-old rats were divided into three groups; they received a single daily injection of vehicle (0.9% NaCl solution) or gentamicin at a dose of 10 or 20 mg/kg/d for 7 d. Urine and blood were collected after 3 and 7 d of injections. Urinary metabolites were evaluated using high-performance liquid chromatography and gas chromatography/mass spectrometry. RESULTS: A distinct urinary metabolic profile characterized by glucosuria, phosphaturia, and aminoaciduria was identified preceding changes in serum creatinine. At both the gentamicin doses, urinary tryptophan was significantly (P < 0.05) increased (fold change: 1.91 and 2.31 after 3 d; 1.81 and 1.93 after 7 d). Similarly, kynurenic acid, a tryptophan metabolite, showed a significant (P < 0.05) decrease (fold change: 0.26 and 0.24 after 3 d; 0.21 and 0.52 after 7 d), suggesting an interruption of the normal tryptophan metabolism pathway. CONCLUSION: We conclude that urinary metabolomic profiling provides a robust approach for identifying early and novel markers of gentamicin-induced AKI.