Metabolomic identification of predictive and early biomarkers of cisplatin‐induced acute kidney injury in adult head and neck cancer patients

Lim, Yong Jin; Xiu, Steven G.; Kuruvilla, M. Sara; Winquist, Eric; Welch, Stephen; Black, Morgan; Faught, Lauren N.; Lee, Jasmine; Rieder, Michael J.; Blydt‐Hansen, Tom; Zappitelli, Michael; Urquhart, Bradley L.

doi:10.1111/bcp.15666

Cited by 7 publications

(5 citation statements)

References 57 publications

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“…Notably, symmetric dimethylarginine (SDMA) and tryptophan, or the 5-HIAA/5-HT ratio, were identified as potential AKI risk predictors (AUC >0.9). These findings, along with various other studies [64][65][66][67][68][69] exploring the role of metabolomics in AKI diagnosis and risk prediction, are summarized in Table 1. DKD is a specific type of kidney disease that occurs in individuals with diabetes and is a leading cause of CKD.…”

Section: Applications Of Metabolomics In Akdmentioning

confidence: 73%

Deliverables from Metabolomics in Kidney Disease: Adenine, New Insights, and Implication for Clinical Decision-Making

Ragi,

Sharma

2024

Am J Nephrol

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Background: Chronic kidney disease (CKD) presents a persistent global health challenge, characterized by complex pathophysiology and diverse progression patterns. Metabolomics has emerged as a valuable tool in unraveling the intricate molecular mechanisms driving CKD progression. Summary: This comprehensive review provides a summary of recent progress in the field of metabolomics in kidney disease with a focus on spatial metabolomics to shed important insights to enhancing our understanding of CKD progression, emphasizing its transformative potential in early disease detection, refined risk assessment, and the development of targeted interventions to improve patient outcomes. Key Message: Through an extensive analysis of metabolic pathways and small-molecule fluctuations, bulk and spatial metabolomics offers unique insights spanning the entire spectrum of CKD, from early stages to advanced disease states. Recent advances in metabolomics technology have enabled spatial identification of biomarkers to provide breakthrough discoveries in predicting CKD trajectory and enabling personalized risk assessment. Furthermore, metabolomics can help decipher the complex molecular intricacies associated with kidney diseases for exciting novel therapeutic approaches. A recent example is the identification of adenine as a key marker of kidney fibrosis for diabetic kidney disease using both untargeted and targeted bulk and spatial metabolomics. The metabolomics studies were critical to identify a new biomarker for kidney failure and to guide new therapeutics for diabetic kidney disease. Similar approaches are being pursued for acute kidney injury and other kidney diseases to enhance precision medicine decision-making.

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Section: Applications Of Metabolomics In Akdmentioning

confidence: 73%

Deliverables from Metabolomics in Kidney Disease: Adenine, New Insights, and Implication for Clinical Decision-Making

Ragi,

Sharma

2024

Am J Nephrol

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“…Metabolite biomarkers that manifest at an early stage have been identified as significant factors in assessing the severity of renal dysfunction ( Bergman et al, 2019 ; Nizioł et al, 2020 ; Lim et al, 2023a ) within diseased kidney tissues. Untargeted metabolomics employs the technique of LC-MS for analysis ( Lim et al, 2023b ), whereas MALDI MSI provides distinct ion images that reveal the distribution and localization of metabolites within complex biological samples ( Nizioł et al, 2020 ). MALDI MSI enables the spatial localization of metabolites, allowing for the visualization of the impact of drug absorption on the modulation of metabolic pathways within biological tissues.…”

Section: Resultsmentioning

confidence: 99%

Visualization of renal rotenone accumulation after oral administration and in situ detection of kidney injury biomarkers via MALDI mass spectrometry imaging

Tenebro,

Marcial,

Salcepuedes

et al. 2024

Front. Mol. Biosci.

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The examination of drug accumulation within complex biological systems offers valuable insights into the molecular aspects of drug metabolism and toxicity. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is an innovative methodology that enables the spatial visualization and quantification of biomolecules as well as drug and its metabolites in complex biological system. Hence, this method provides valuable insights into the metabolic profile and any molecular changes that may occur as a result of drug treatment. The renal system is particularly vulnerable to adverse effects of drug-induced harm and toxicity. In this study, MALDI MSI was utilized to examine the spatial distribution of drug and renal metabolites within kidney tissues subsequent to a single oral dosage of the anticancer compound rotenone. The integration of ion mobility spectrometry with MALDI MSI enhanced the data acquisition and analysis, resulting to improved mass resolution. Subsequently, the MS/MS fragment ions of rotenone reference drug were detected and characterized using MALDI HDMS/MS imaging. Notably, drug accumulation was observed in the cortical region of the representative kidney tissue sections treated with rotenone. The histological examination of treated kidney tissues did not reveal any observable changes. Differential ion intensity of renal endogenous metabolites was observed between untreated and rotenone-treated tissues. In the context of treated kidney tissues, the ion intensity level of sphingomyelin (D18:1/16:0), a sphingolipid indicator of glomerular cell injury and renal damage, was found to be elevated significantly compared to untreated kidney tissues. Conversely, the ion intensities of choline, glycero-3-phosphocholine (GPC), inosine, and a lysophosphatidylcholine LysoPC(18:0) exhibited a significant decrease. The results of this study demonstrate the potential of MALDI MSI as a novel technique for investigating the in situ spatial distribution of drugs and renal endogenous molecules while preserving the anatomical integrity of the kidney tissue. This technique can be used to study drug-induced metabolism and toxicity in a dynamic manner.

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“…The ACCENT study is a prospective observational study looking at metabolomic changes during cisplatin chemotherapy in pediatric and adult cancer patients (Jain et al, 2021). In a discovery phase of the ACCENT study, plasma and urine samples from adult head and neck cancer patients treated with cisplatin were subjected to untargeted metabolomics (Lim et al, 2023b).…”

Section: Drug Toxicitymentioning

confidence: 99%

Pharmacometabolomics in Drug Disposition, Toxicity, and Precision Medicine

Trevor,

Lim,

Urquhart

2024

Drug Metab Dispos

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The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport and pharmacokinetics is reviewed.Pharmacometabolomic approaches can help understand factors mediating drug disposition, efficacy and toxicity. While important advancements in this area have been made, their remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy. Significance StatementPharmacometabolomics has emerged as an approach to identify metabolites that allow for implementation of precision medicine approaches to pharmacotherapy. This review article provides an overview pharmacometabolomics including highlights of important examples.

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Metabolomic identification of predictive and early biomarkers of cisplatin‐induced acute kidney injury in adult head and neck cancer patients

Cited by 7 publications

References 57 publications

Deliverables from Metabolomics in Kidney Disease: Adenine, New Insights, and Implication for Clinical Decision-Making

Deliverables from Metabolomics in Kidney Disease: Adenine, New Insights, and Implication for Clinical Decision-Making

Visualization of renal rotenone accumulation after oral administration and in situ detection of kidney injury biomarkers via MALDI mass spectrometry imaging

Pharmacometabolomics in Drug Disposition, Toxicity, and Precision Medicine

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