IMODE-CKD · Clinical and system –omics for the identification of the MOlecular DEterminants of established Chronic Kidney Disease

Clinical and system –omics for the identification of the MOlecular DEterminants of established Chronic Kidney Disease

Publishable Summary iMODE-CKD integrated multi-disciplinary expertise in proteomics, metabolomics, transcriptomics, bioinformatics, pathology, and clinical science from leading academic and industrial investigators, establishing a unique training platform on biomarker research and Systems Biology. This educational scope was placed in the context of a significant research objective: to improve quality of life of patients with chronic kidney disease (CKD) and diminish the severe health and economic burden imposed by this disease, by providing better diagnostic and prognostic means for CKD progression. The main objectives of iMODE-CKD were: - Training young scientists to become the next generation of true translational multidisciplinary researchers exploiting multiple -omics technologies to their full extent. - Training young scientists in Systems Biology approaches to decipher molecular pathology and understanding clinical phenotypes. - Identifying and validating molecules involved in progression of renal complications through clinical –omics in established CKD. - Understanding the molecular determinants of established CKD through integrative Systems Biology. Summary of main results In the context of iMODE-CKD, 10 PhD students (6 male-4 female) and 1 experienced researcher (female) were recruited, originating from 9 different countries. An intensive training program was implemented including workshops on chronic kidney disease, -omics technologies and systems biology, training courses on renal histopathology and biomarker measurements through state of the art technologies, courses on various complimentary skills (entrepreneurship, manuscript writing) enhanced by a series of lectures on relevant topics (including time and project management, grant writing, career development, ethics in science), secondments incorporating inter-sectoral (academia-industry) mobility, regular network meetings (6 in total) as well as regular communication and management and scientific presentations through weekly webseminars. At the time of the report, all ESRs have completed or are in the process of submitting their PhD thesis, with four ESRs having already defended and been awarded their PhD diploma with high honors. Significant outputs of iMODE-CKD include: 1) Following receiving all required ethics approvals, inclusion of existing (UZ Ghent biobank, NT-CVD, Prediction) and prospective (CKD-Bio) CKD cohorts in the iMODE-CKD study was performed and a respective unified database was developed. The clinical core parameters, including all relevant formulas for calculating eGFR (estimated Glomerular filtration rate), were defined targeting better determination of the CKD stages. 2) Databases integrating literature multi-source data relevant to CKD were generated, and disseminated to the scientific community and general public via respective publications (Fernandes M and Husi H Sci Rep. 2017 Jan 12;7:40367; Krochmal et al., Database (Oxford). 2016 Sep 1;2016. pii: baw128) and open access platforms (http://peptickddb.com/; http://www.padb.org/ckddb) 3) High quality –omics data (transcriptomics, peptidomics, proteomics, metabolomics) in relation to CKD progression were generated, statistically analyzed and validated, giving rise to markers associated with the disease. Respective data have been in cases already published in high impact publications (Pontillo et al, Kidney International Reports in press, https://doi.org/10.1016/j.ekir.2017.06.004; Smith A et al, Proteomics. 2016 Jun;16(11-12):1759-6; Pontillo C et al, Nephrol Dial Transplant. 2016 Jul 6. pii: gfw239; Smith A et al, Biochim Biophys Acta. 2016 Nov 23. pii: S1570-9639(16)30250-3) or have been submitted for publication. 4) Using the developed database resources in combination with the newly collected -omics data, workflows for data integration were refined and models for IgA nephropathy (IgAN) and CKD progression were generated and disseminated via respective publications (Krochmal et al, Sci Rep. 2017 Aug 22;7(1):9091) 5) Based on these models, targets for CKD progression and IgAN were predicted and the first ones for IgAN were experimentally verified. These included adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP), all verified for their overexpression in the kidney tissue of IgAN patients in comparison to controls, via immunohistochemistry (Krochmal et al, Sci Rep. 2017 Aug 22;7(1):9091). 6) Based in part on collected data within the iMODE-CKD, a letter of support for the application of the urinary CKD273 peptide classifier in early diagnosis of Diabetic Nephropathy was provided to partner MOS by the US Food and Drug Administration (https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508790.pdf ). 7) In total thirty-eight manuscripts that were already cited over 200 times were published to date as a result of the project, and additional have been submitted for publication, in multiple cases, representing inter-sectoral collaborations (SME-academic co-authorship). In addition a book on systems biology was edited by iMODE-CKD supervisors with contributions from all ESRs and ER and is in final stages of production. 8) A training platform on renal histology was established (http://nefropatologia.hsgerardo.org/) to serve the scientific community and general public. 9) Extensive activities including the use of a combination of different dissemination routes (internet, personal contacts, presentations to scientific meetings, brochures, video, social media, open days, -summarized briefly below), enabled widespread dissemination of the iMODE-CKD activities, fruitful feedback by the scientific community, increased awareness of the general public on CKD and research activities in the field, maximizing the impact of the program (described below-section A). Impact iMODE-CKD is expected to have major impact on all research and social-economic levels: Research a) The multi-source data integrative resources (the aforementioned literature databases) established in the course of iMODE-CKD are expected to largely facilitate future biomarker and/or systems biology research in the field. b) Existing resources were optimized and important know-how on multiple aspects of -omics analysis was established (such as optimized workflows for high resolution -omics data generation from small amounts of clinical specimens (eg; Filip et al PLoS One. 2015 Jul 24;10(7):e0133773; Gil RB et al, Anal Bioanal Chem. 2016 Jul;408(17):4683-91; Papadopoulos T et al BMC Syst Biol. 2017 Mar 1;11(1):31) and optimized workflows for multi-source data integration (Krochmal et al, Sci Rep. 2017 Aug 22;7(1):9091) expected to assist clinical –omics as well as systems biology approaches in this (CKD) and other research fields. c) The findings open up multiple research avenues and form the basis of a series of new investigations: these include further validation of selected findings (such as the observed association of various urine peptides with degree of tissue fibrosis; association of citric acid metabolites and certain osmolytes in association to CKD progression) and potential IgAN and Diabetic nephropathy targets predicted by the developed models. d) The results of iMODE-CKD form the basis for novel scientific projects and marketable products by the partners building upon the established collaborations but also expanding to include new partners as identified via the extensive dissemination and networking activities carried out during the project Social-economic a) iMODE-CKD increased the competitiveness of the trained ESRs in their future professional endeavors; it should be noted that five of the ESRs have already embarked on job settlements of their top choices in Europe and USA. d) Through the implementation of the urinary CKD273 peptide classifier in clinical trials, as supported by the FDA, better patient stratification at clinical trial entry, hence improvement in the treatment efficacy and eventually patient outcome are foreseen. c) The established urine markers for CKD progression (such as the peptide CKD 273 and metabolic profiles currently being validated) are expected to facilitate drug development in the field by serving as surrogate markers /endpoints indicative of disease progression. d) Besides the positive impact on patient quality of life, considering the heavy financial burden imposed to current societies by the treatment of end stage renal disease, the established urinary markers for renal disease progression are expected to confer a financial benefit; this is supported by respective health economic calculations, recently published (Cristelis E et al, Nephrol Dial Transplant (2017) 1–9 ; doi: 10.1093/ndt/gfx068). e) iMODE-CKD findings can support drug development efforts in the field; contacts of iMODE-CKD partners with pharmaceutical companies have been established to define avenues for future collaborative studies. In conclusion, iMODE-CKD delivered significant and important outputs expected to impact positively on the future career of the trained young scientists, the competitiveness of involved partners, future scientific endeavors in the CKD and systems biology fields and importantly, the management of CKD patients.

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