Naturally occurring fragments of collagen type I alpha 1 chain (COL1A1) have been previously associated with chronic kidney disease (CKD), with some fragments showing positive and others negative associations. Using urinary peptidome data from healthy individuals (n=1131) and CKD patients (n=5585) this aspect was investigated in detail. Based on the hypothesis that many collagen peptides are derived not from the full, mature collagen molecule, but from (larger) collagen degradation products, relationships between COL1A1 peptides containing identical sequences were investigated, with the smaller (offspring) peptide being a possible degradation product of the larger (parent) one. The strongest correlations were found for relationships where the parent differed by a maximum of 3 amino acids from the offspring, indicating an exopeptidase-regulated stepwise degradation process. Regression analysis indicated that CKD affects this degradation process. Comparison of matched CKD patients and control individuals (n=612 each) showed that peptides at the start of the degradation process were consistently downregulated in CKD, indicating an attenuation of COL1A1 endopeptidase-mediated degradation. However, as these peptides undergo further degradation, likely mediated by exopeptidases, this downregulation can become less significant or even reverse, leading to an upregulation of later stage fragments and potentially explaining the inconsistencies observed in previous studies.

HM is the founder and co-owner of Mosaiques Diagnostics GmbH (Hannover, Germany). IKM and JS are employed by Mosaiques Diagnostics GmbH. ML, LF, and PP are employed at Delta4 GmbH (Vienna, Austria).

IKM was supported by a grant from European Union's Horizon Europe Marie Skłodowska-Curie Actions Doctoral Networks - Industrial Doctorates Programme (HORIZON - MSCA - 2021 - DN-ID, grant number 101072828). VJ was supported by a grant from the 'Deutsche Forschungsgemeinschaft' (DFG, German Research Foundation) through the Transregional Collaborative Research Centre (TRR 219; Project-ID 322900939, subproject S-03, INST 948/4S-1); CRU 5011 project number 445703531, Cost-Action CA 21165, IZKF Multiorgan complexity in Friedreich Ataxia and Phase Transition in Disease 1-1, ERA-PerMed (ERA-PERMED2022-202-KidneySign). HM and JS were supported by the German Federal Ministry of Education and Research (BMBF) via funding to the UPTAKE project (01EK2105B) and SIGNAL (01KU2307, under the frame of ERA PerMed) and via COST-Action PERMEDIK CA21165, supported by COST (European Cooperation in Science and Technology). PP, ML, and LF have received funding from the Austrian Research Promotion Agency (FFG) under grant agreement No. 911422 (Delta4Tech). Views and opinions expressed are those of the authors only and do not necessarily reflect those of the funders.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical review and approval were waived for this study (based on the ethics opinion received from the ethics committee of the Hannover Medical School, Germany no. 3116-2016), due to all data being fully anonymized.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.