Metabolome-derived kidney function scores as prognostic readouts of cardiovascular-kidney-metabolic health.
Kidney disease is a rapidly growing global health concern, tightly linked to cardiovascular and metabolic disease within the recently defined cardiovascular-kidney-metabolic (CKM) syndrome. Routine clinical assessment of kidney function primarily relies on creatinine-based estimated glomerular filtration rates (eGFRcr) which can be affected by non-renal factors and declines only after substantial kidney damage. Using data from the MetaCardis study (N=1,723), we derived metabolomic kidney function gaps (mKFGs)-the difference between metabolome-predicted eGFRcr and measured eGFRcr. A physiology-guided feature-selection strategy - anchored on three cardiometabolic markers (haemoglobin, albumin and the Neutrophil-to-Lymphocyte Ratio) that associate with mKFGs but not with eGFRcr - yielded compact sex-stratified metabolite panels (40-98 out of 1,514 metabolites) that tracked cardiovascular-kidney-metabolic risk. Machine-Learning models revealed distinct metabolic signatures, including biomarkers of meat consumption and androgens, highlighting potential sex-specific pathways linked to CKM health. External validation in the general-population Canadian Longitudinal Study on Aging (N=9,958) and German Chronic Kidney Disease Study (N=5,113) cohorts revealed that mKFGs added incremental predictive value for future CKM events and all-cause mortality beyond eGFRcr and established risk equations. Our findings open new avenues for personalised risk stratification for CKM disease progression and targeted interventions based on metabolically defined kidney health.
Authors
- Sara Vieira‐Silva (ORCID: https://orcid.org/0000-0002-4616-7602)
- Jeroen Raes (ORCID: https://orcid.org/0000-0002-1337-041X)
- Marc‐Emmanuel Dumas (ORCID: https://orcid.org/0000-0001-9523-7024)
- Janis Marc Nolde (ORCID: https://orcid.org/0000-0001-6864-8514)
- Trine Nielsen (ORCID: https://orcid.org/0000-0002-2066-7895)
- Francesc Puig‐Castellví (ORCID: https://orcid.org/0000-0003-1064-9586)
- Sofia Kirke Forslund (ORCID: https://orcid.org/0000-0003-4285-6993)
- Kanta Chechi (ORCID: https://orcid.org/0000-0003-1929-4128)
- Karine Clément (ORCID: https://orcid.org/0000-0002-2489-3355)
- Romina Pacheco‐Tapia (ORCID: https://orcid.org/0000-0002-4694-3456)
- Fredrik Bäckhed (ORCID: https://orcid.org/0000-0002-4871-8818)
- Inés Castro (ORCID: https://orcid.org/0000-0003-4349-3477)
- Michael Stümvoll (ORCID: https://orcid.org/0000-0001-6225-8240)
- Eugeni Belda (ORCID: https://orcid.org/0000-0003-4307-5072)
- Jean‐Michel Oppert (ORCID: https://orcid.org/0000-0003-0324-4820)
- Henrik Vestergaard (ORCID: https://orcid.org/0000-0003-3090-269X)
- Oluf Borbye Pedersen (ORCID: https://orcid.org/0000-0002-3321-3972)
- Kai‐Uwe Eckardt (ORCID: https://orcid.org/0000-0003-3823-0920)
- Rima Chakaroun (ORCID: https://orcid.org/0000-0001-9901-1815)
- Gwen Falony (ORCID: https://orcid.org/0000-0003-2450-0782)
- Judith Aron‐Wisnewsky (ORCID: https://orcid.org/0000-0002-3104-9769)
- Peggy Sekula (ORCID: https://orcid.org/0000-0003-2263-447X)
- Julien Chilloux (ORCID: https://orcid.org/0000-0002-0384-7317)
- Matthias Blueher
- Emmanuelle Le Chatelier (ORCID: https://orcid.org/0000-0002-2724-0536)
- Jean‐Daniel Zucker (ORCID: https://orcid.org/0000-0002-5597-7922)
- Antonis Myridakis (ORCID: https://orcid.org/0000-0003-1690-6651)
- Manyi Jia (ORCID: https://orcid.org/0000-0001-9467-1494)
- Torben F. Hansen (ORCID: https://orcid.org/0000-0001-8748-3831)
- Philippe Froguel
- Petros Andrikopoulos (ORCID: https://orcid.org/0000-0002-1555-3498)
- Christine Rouault
- Parminder Raina (ORCID: https://orcid.org/0000-0002-8107-3193)
- Mark G. Lathrop (ORCID: https://orcid.org/0000-0002-2660-7105)
- Angelos Manolias (ORCID: https://orcid.org/0000-0002-3907-3755)
- Elena Butz (ORCID: https://orcid.org/0009-0006-2692-1192)
- Jens Nielsen
- Elliot Murphy
- Peer Bork
- Christine Poitou
- Lars Koeber
- Anna Koettgen
- Pierre Bel Lassen
- S. Dusko Ehrlich
Institutions
- University of Copenhagen (DK)
- University of Freiburg (DE)
- Johannes Gutenberg University Mainz (DE)
- Max Delbrück Center (DE)
- Université de Lille (FR)
- Université Paris-Saclay (FR)
- Sorbonne Université (FR)
- European Molecular Biology Laboratory (DE)
- European Molecular Biology Laboratory (DE)
- University College London (GB)
- Imperial College London (GB)
- McGill University (CA)
- Chalmers University of Technology (SE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Gothenburg (SE)
- Wageningen University & Research (NL)
- Leipzig University (DE)
- McMaster University (CA)
- KU Leuven (BE)
Publication Details
- Journal
- medRxiv
- Published
- 2026-11-10
- DOI
- https://doi.org/10.64898/2026.11.09.26367636
- Primary Topic
- Chronic Kidney Disease and Diabetes
- Type
- preprint