proteomes Article Molecular Mapping of Urinary Complement Peptides in Kidney Diseases Ralph Wendt 1,† , Justyna Siwy 2,† , Tianlin He 2 , Agnieszka Latosinska 2 , Thorsten Wiech 3 , Peter F. Zipfel 4,5 , Aggeliki Tserga 6 , Antonia Vlahou 6 , Harald Rupprecht 7 , Lorenzo Catanese 7 , Harald Mischak 2 and Joachim Beige 1,8, *   Citation: Wendt, R.; Siwy, J.; He, T.; Latosinska, A.; Wiech, T.; Zipfel, P.F.; Tserga, A.; Vlahou, A.; Rupprecht, H.; Catanese, L.; et al. Molecular Mapping of Urinary Complement Peptides in Kidney Diseases. Proteomes 2021, 9, 49. https:// doi.org/10.3390/proteomes9040049 Academic Editors: J. Justin Hsuan and Piotr Widlak Received: 7 October 2021 Accepted: 8 December 2021 Published: 13 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Nephrology and Kuratorium for Dialysis and Transplantation (KfH) Renal Unit, Hospital St. Georg, 04129 Leipzig, Germany; Ralph.Wendt@sanktgeorg.de 2 Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; siwy@mosaiques-diagnostics.com (J.S.); he@mosaiques-diagnostics.com (T.H.); latosinska@mosaiques-diagnostics.com (A.L.); mischak@mosaiques-diagnostics.com (H.M.) 3 Nephropathology Section, Institute of Pathology, University Medical Center, 20246 Hamburg, Germany; t.wiech@uke.de 4 Institute of Microbiology, Friedrich-Schiller-University, 07743 Jena, Germany; peter.zipfel@hki-jena.de 5 Department of Infection Biology, Leibniz Institute for Natural Product Researach and Infection Biology, 07745 Jena, Germany 6 Biomedical Research Foundation, Academy of Athens, Department of Biotechnology, 11527 Athens, Greece; tserga@bioacademy.gr (A.T.); vlahoua@bioacademy.gr (A.V.) 7 Department of Nephrology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany; harald.rupprecht@klinikum-bayreuth.de (H.R.); lorenzoriccardo.catanese@gmail.com (L.C.) 8 Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06108 Halle (Saale), Germany * Correspondence: Joachim.Beige@sanktgeorg.de; Tel.: +49-341-909-4896 † These authors contributed equally. Abstract: Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement frag- ments. We investigated the occurrence of complement fragments in urine, their association with kidney function and disease etiology in 16,027 subjects, using mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database. Twenty-three different urinary pep- tides originating from complement proteins C3, C4 and factor B (CFB) could be identified. Most C3-derived peptides showed inverse association with estimated glomerular filtration rate (eGFR), while the majority of peptides derived from CFB demonstrated positive association with eGFR. Several peptides derived from the complement proteins C3, C4 and CFB were found significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific comple- ment activation and could serve as non-invasive biomarkers to support development of complement interventions through assessing complement activity for patients’ stratification and monitoring of drug impact. Further investigation of these complement peptides may provide additional insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors. Keywords: complement; peptide; urine; biomarker; kidney disease; proteomics; CE-MS; capillary electrophoresis 1. Introduction The urinary proteome holds information on disease and disease pathophysiology [1]. Significant association of specific urinary peptides was demonstrated in large studies that Proteomes 2021, 9, 49. https://doi.org/10.3390/proteomes9040049 https://www.mdpi.com/journal/proteomes