Summary of Study ST003924

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002457. The data can be accessed directly via it's Project DOI: 10.21228/M81Z64 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003924
Study TitleNMR-based Urinary Biomarkers in Pediatric Primary Mitochondrial Disorders and Chronic Kidney Disease: Shared Mitochondrial Dysfunction, Diverging Biosignatures
Study TypeProspective
Study SummaryBackground: Renal involvement is a frequent manifestation of primary mitochondrial disorders (PMD), either as a presenting feature or during the disease course. Simultaneously, the metabolomic profile of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD. Methods: We performed untargeted 1H-NMR metabolomic profiling of 76 urine samples from 61 paediatric patients. Outlier samples and patients undergoing acute decompensation were excluded from the main analyses. Final comparisons included genetically confirmed PMD without CKD (n = 13);, SMD (n = 10), non-mitochondrial CKD (n = 28; 17 at stages 1–2 and 9 at stages 3–5), and healthy controls (n = 10). Spectral data was analysed using multivariate (PCA, PLS-DA) and univariate approaches after normalization to urinary creatinine or total spectral area. Results: Correlations between normalization strategies varied across metabolites (Pearson r ranging from –0.32 to 0.98), underscoring the need for cautious interpretation of normalization-dependent findings. PMD patients exhibited distinct urinary metabolic profiles compared to controls (high predictive value, Q² = 0.52), with significantly elevated levels of several metabolites, including 4-aminohippurate, homovanillic acid (HVA), cis-aconitate, and fumarate were significantly elevated in PMD patients and remained discriminative compared to both CKD and control groups. A multimetabolite panel comprising 4-aminohippurate, HVA, histidine, and cis-aconitate achieved high diagnostic accuracy for distinguishing PMD from CKD stage 3–5 (AUC = 0.944), integrating complementary metabolic pathways related to energy metabolism, amino acid handling, and tubular function. Conclusion: Urinary metabolomic profiling by 1H-NMR revealed a distinct biosignature in paediatric PMD patients without renal involvement, characterized by elevated levels of 4-aminohippurate, HVA, and TCA cycle intermediates. The consistent increase in 4-aminohippurate and HVA—both reliant on energy-dependent proximal tubular excretion—points to impaired mitochondrial modulation of tubular function, even in the absence of overt renal disease. These findings support the use of urinary 1H-NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.
Institute
University of Aveiro
DepartmentReference Center for Inherited Metabolic Disorders, Centro Hospitalar Universitario de Santo António
LaboratoryDepartment of Chemistry and CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
Last NamePaiva Coelho
First NameMargarida
AddressLargo da Maternindade, S/N 4050 Porto
Emailmmargaridacoelho.dca@chporto.min-saude.pt
Phone+351913448849
Submit Date2025-05-19
Num Groups6
Total Subjects60
Num Males35
Num Females25
Study CommentsRaw NMR data (.fid, acqus, pdata/1) and processed spectral matrices included. Spectra acquired using Bruker AVANCE III 500 MHz spectrometer and normalized to total area. Ocasional urine samples irrespective of fasting period
Publicationsto be submitted
Raw Data AvailableYes
Raw Data File Type(s)fid
Analysis Type DetailNMR
Release Date2025-11-19
Release Version1
Margarida Paiva Coelho Margarida Paiva Coelho
https://dx.doi.org/10.21228/M81Z64
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002457
Project DOI:doi: 10.21228/M81Z64
Project Title:Urinary metabolomic profiling in pediatric primary mitochondrial disease (PMD) and chronic kidney disease (CKD)
Project Type:Prospective
Project Summary:Untargeted ¹H-NMR metabolomics analysis of urine samples from pediatric patients with primary mitochondrial disease (PMD), secondary mitochondrial dysfunction (SMD), chronic kidney disease (CKD), patients with PMD and CKD, and healthy controls. Spectra were normalized to total spectral area and 60 samples were included after quality control.
Institute:University of Aveiro
Department:Reference Center for Inherited Metabolic Disorders, Centro Hospitalar Universitario de Santo António, Unidade Local de Saúde de Santo António
Laboratory:Chemistry Department - Universidade de Aveiro
Last Name:Paiva Coelho
First Name:Margarida
Address:Largo da Maternidade S/N, 4050 Porto
Email:mmargaridacoelho.dca@chporto.min-saudept
Phone:+351913448849
Funding Source:This study was funded by a grant from Pfizer Vaccines / SPP 2019. This work was developed within the scope of the CICECO-Aveiro Institute of Materials, UIDB/50011/2020 project (doi: 10.54499/UIDB/50011/2020), UIDP/50011/2020 (doi: 10.54499/UIDP/50011/2020) and LA/P/0006/2020 (doi:10.54499/LA/P/0006/2020), financed by national funds through the FCT/MCTES (PIDDAC). We also acknowledge funds from the Foundation for Science and Technology through the BetterBone project (2022.04286.PTDC, doi: 10.54499/2022.04286.PTDC), the Portuguese National NMR Network (RNRMN), supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).
Project Comments:This project includes ¹H-NMR-based untargeted metabolomic profiling of urine in mitochondrial disorders. Data includes raw Bruker spectra and processed bin-integrated matrices.
Publications:to be submitted
Contributors:Margarida Paiva Coelho, Teresa Costa, Aureliano Dias, Inês C.R. Graça, Hugo Rocha, Laura Vilarinho, Esmeralda Martins, João E. Rodrigues, Ana M. Gil

Subject:

Subject ID:SU004059
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:1-18
Gender:Male and female
Human Medications:Recorded
Human Smoking Status:Not applicable (pediatric cohort)
Human Alcohol Drug Use:Not applicable (pediatric cohort)
Human Nutrition:Not controlled
Human Inclusion Criteria:Children and adolescents (1–18 years) followed in the metabolic or nephrology clinics. Groups included: (i) genetically confirmed primary mitochondrial disease (PMD), (ii) clinical suspicion of mitochondrial disease without molecular confirmation (SMD), (iii) chronic kidney disease (CKD), and (iv) controls with normal renal function and no suspicion of mitochondrial disease.
Human Exclusion Criteria:Age <1 month, post-renal transplant status, acute illness or metabolic decompensation at sampling, and known secondary causes of mitochondrial dysfunction.

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Disease Sample source
SA444353P40CKD1_2 Urine
SA444354P50CKD1_2 Urine
SA444355P49CKD1_2 Urine
SA444356P48CKD1_2 Urine
SA444357P47CKD1_2 Urine
SA444358P46CKD1_2 Urine
SA444359P45CKD1_2 Urine
SA444360P44CKD1_2 Urine
SA444361P43CKD1_2 Urine
SA444362P42CKD1_2 Urine
SA444363P41CKD1_2 Urine
SA444364P39CKD1_2 Urine
SA444365P52CKD1_2 Urine
SA444366P38CKD1_2 Urine
SA444367P37CKD1_2 Urine
SA444368P53CKD1_2 Urine
SA444369P51CKD1_2 Urine
SA444370P54CKD3_5 Urine
SA444371P55CKD3_5 Urine
SA444372P56CKD3_5 Urine
SA444373P57CKD3_5 Urine
SA444374P58CKD3_5 Urine
SA444375P60CKD3_5 Urine
SA444376P61CKD3_5 Urine
SA444377P62CKD3_5 Urine
SA444378P59CKD3_5 Urine
SA444379P36Control Urine
SA444380P30Control Urine
SA444381P35Control Urine
SA444382P28Control Urine
SA444383P29Control Urine
SA444384P26Control Urine
SA444385P27Control Urine
SA444386P34Control Urine
SA444387P32Control Urine
SA444388P33Control Urine
SA444389P31Control Urine
SA444390P25PMD+CKD Urine
SA444391P15ePMD+CKD Urine
SA444392P15dPMD+CKD Urine
SA444393P15cPMD+CKD Urine
SA444394P15bPMD+CKD Urine
SA444395P15aPMD+CKD Urine
SA444396P13PMD Urine
SA444397P12PMD Urine
SA444398P14PMD Urine
SA444399P10PMD Urine
SA444400P04PMD Urine
SA444401P09PMD Urine
SA444402P02PMD Urine
SA444403P03PMD Urine
SA444404P11PMD Urine
SA444405P05PMD Urine
SA444406P06PMD Urine
SA444407P07PMD Urine
SA444408P08PMD Urine
SA444409P17SMD Urine
SA444410P18SMD Urine
SA444411P19SMD Urine
SA444412P20SMD Urine
SA444413P21SMD Urine
SA444414P22SMD Urine
SA444415P23SMD Urine
SA444416P24SMD Urine
SA444417P16SMD Urine
Showing results 1 to 65 of 65

Collection:

Collection ID:CO004052
Collection Summary:Urine samples from pediatric patients with mitochondrial disease, chronic kidney disease, or healthy controls. We recruited children and adolescents into four groups: (i) patients with genetically confirmed primary mitochondrial disorders (PMD, n = 15); (ii) individuals with clinical suspicion of mitochondrial disease but no established molecular diagnosis (SMD, n = 10); (iii) patients with chronic kidney disease (CKD, any stage, n = 29); and (iv) an opportunistic control group (n = 10) comprising otherwise healthy individuals followed in the Nephrology outpatient clinic, with no evidence of kidney or metabolic disease (e.g., mild vesicoureteral reflux or post-infectious follow-up). . CKD patients were stratified into two main groups: CKD stages 1-2 and stages 3-5, according to KDIGO 2024 guidelines staging
Collection Protocol Filename:MP_Methods.txt
Collection Protocol Comments:Random urine samples
Sample Type:Urine
Collection Method:Ocasional sample
Collection Location:Porto
Collection Frequency:undetermined
Collection Duration:2 years
Volumeoramount Collected:1 ml
Storage Conditions:-80℃

Treatment:

Treatment ID:TR004068
Treatment Summary:None

Sample Preparation:

Sampleprep ID:SP004065
Sampleprep Summary:Urine samples were centrifuged, buffered with phosphate buffer containing TSP, and transferred to NMR tubes.
Sampleprep Protocol Filename:MP_Methods.txt
Processing Method:Centrifugation, buffering
Processing Storage Conditions:-80℃
Extraction Method:None
Extract Enrichment:None
Extract Cleanup:None
Extract Storage:-80℃
Sample Resuspension:Not applicable
Sample Derivatization:Not applicable
Sample Spiking:TSP (as chemical shift reference)
Subcellular Location:Not applicable

Analysis:

Analysis ID:AN006442
Analysis Type:NMR
Analysis Protocol File:MP_Methods.txt
Num Factors:6
Num Metabolites:45
Results File:ST003924_AN006442_Results.txt
Units:ppm #NMR_METABOLITE_DATA NMR_METABOLITE_DATA:UNITS

NMR:

NMR ID:NM000315
Analysis ID:AN006442
Instrument Name:Bruker AVANCE III
Instrument Type:FT-NMR
NMR Experiment Type:1D-1H
Spectrometer Frequency:500 MHz
NMR Solvent:H₂O/D₂O (phosphate buffer in D₂O with TSP)
Pulse Sequence:noesygppr1d
Water Suppression:Presaturation
Chemical Shift Ref Cpd:TSP (0 ppm)
Number Of Scans:64
Dummy Scans:4
Acquisition Time:4s
Relaxation Delay:4s
Spectral Width:12 ppm
Num Data Points Acquired:65536
Real Data Points:65536
Line Broadening:0,3 Hz
Baseline Correction Method:manual
Chemical Shift Ref Std:TSP (0 ppm)
Binned Increment:0.001 ppm
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