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Combatting the CardioRenal Syndrome: towards an integrative Analysis to reduce cardiovascular burden in chronic kidney disease

Periodic Reporting for period 2 - CaReSyAn (Combatting the CardioRenal Syndrome: towards an integrative Analysis to reduce cardiovascular burden in chronic kidney disease)

Reporting period: 2020-01-01 to 2021-12-31

Successfully combatting a complex disease requires multi-disciplinary and methodically well-trained scientists. CaReSyAn strived to accomplish exactly this: in a close cooperation between academia, SMEs and industry partners, we trained young scientists to successfully integrate proteomics, clinical, experimental and bioinformatical analyses to enhance the understanding, diagnosis and therapy of the cardiorenal syndrome. The cardiorenal syndrome comprises disorders of the heart, vessels and kidneys, including the increased development of cardiovascular disease in patients with chronic kidney disease. With ~45% of all deaths in patients with chronic kidney disease caused by cardiovascular disease, the socio-economic burden of the cardiorenal syndrome is extremely high. Key objectives were to provide: 1) Excellent scientific training on the pathology of pathological kidney-heart crosstalk, integrating clinical/mechanistic knowledge with technological skills to generate innovative insights triggering the understanding, diagnosis and treatment of the cardiorenal syndrome; 2) Excellent complementary skills in personal and career development as well as business training required to extend beyond scientific research; and 3) Exposure to both academic and non-academic environments, required to build bridges between researchers and companies and support the future translation of research findings in innovative products and services. To this end, a successful multi-disciplinary training program was established, embedded in an already established cooperation of academic and non-academic partners. This enabled our early-stage researchers to successfully perform their scientific research and reach the scientific goals of CaReSyAn: 1) We identified biomarkers of pathological kidney-heart crosstalk by proteomics/peptidomics analyses as candidates for diagnosis, prediction and treatment of the cardiorenal syndrome; 2) We generated high-dimensional network models of the cardiorenal syndrome using bioinformatics, to assess the value of biomarker candidates in diagnostic and predictive signatures; and 3) We studied the pathology of the cardiorenal syndrome as well as the role of biomarker/target candidates and novel therapeutic strategies, to reveal novel diagnostic and therapeutic options by combining preclinical and clinical analyses.
As one highlight, novel calcification-regulatory peptides were identified by our partners as candidates for novel therapeutic strategies targeting increased cardiovascular calcification in patients with chronic kidney disease, resulting in a European patent application. Furthermore, building on the successful collaborations in CaReSyAn, a new joint institute between the RWTH Aachen and the Maastricht University was created, named the Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), to ensure continuation of European training and research efforts as in CaReSyAn also beyond the borders of this consortium.
We have trained early-stage researchers to successfully integrate proteomics, clinical and experimental analyses to enhance the understanding, diagnosis and therapy of the cardiorenal syndrome. Trainings also included improvement of technological as well as complementary skills, and this with exposure to both academic and non-academic environments. Different training activities were organized in cooperation with complementary research consortia to synergistically improve structural training on European level. The different awards that were awarded to our early-stage researchers demonstrate that our training program was highly successful.
On research level, we identified biomarkers of the cardiorenal syndrome by proteomics/peptidomics analysis of patient biomaterial. This includes the identification of diagnostic biomarkers for diagnosis of increased cardiovascular risk in patients with chronic kidney disease. Furthermore, we identified and characterized biomarkers for vascular calcification in patients with chronic kidney disease, with vascular calcification highly contributing to cardiovascular morbidity in these patients. Based on these findings, high-dimensional network models of the cardiorenal syndrome were generated using bioinformatics, with the aim to provide deeper insights into the value of biomarker candidates in diagnostic and predictive signatures of the disease. Also, we studied in detail the underlying pathological processes of the cardiorenal syndrome, since such insights are required to trigger the development of novel therapeutic strategies specifically tailored to the cardiorenal patient. For example, we studied how vascular calcification is affected by the novel biomarkers or by so-called post-translational modifications of proteins that we identified to be deregulated in the cardiorenal syndrome. An additional focus was set on how vascular calcification is influenced by uremic toxins, which are substances that are highly accumulating patients with a failing kidney function. Moreover, our studies revealed novel insights into premature aging of the cardiovascular system as well as on the vulnerability of cardiomyocytes in the context of chronic kidney disease. Finally, we proceeded also to testing the potential effect of novel therapeutic strategies in reducing pathological mechanisms linked to the cardiorenal syndrome in preclinical studies. As a highlight, a novel calcification-blocking peptide was discovered and fully characterized in terms of protective effects towards vascular calcification. Also, a potential therapy interfering with one of the identified biomarkers of the cardiorenal syndrome revealed to provide protection against vascular calcification in preclinical studies. Overall, we can summarize that training as well as research within CaReSyAn covered all aspects from discovery of novel disease regulators up to deep characterization of disease mechanisms and the initiation of therapeutic translation strategies.
CaReSyAn was built on advanced technologies and established cooperations, but was fully complementary to ongoing European programs focusing solely on chronic kidney disease or cardiovascular disease. We were able to synergistically improve structural training on European level, with as training highlights the European Cardiorenal Winter/Summer schools that we yearly organized together with other national or European research consortia as well as in close collaboration with non-academic partners. Patent applications resulting from CaReSyAn highlight its impact on scientific level, as first step towards further developments in direction of clinical translation. Finally, one major exploitable outcome of CaReSyAn is the installment of a joint institute between the RWTH Aachen and the Maastricht University, an effort which impact was recently also highlighted by the EU itself: https://www.linkedin.com/feed/update/urn:li:activity:6874721337643036672/. This institute has the aim to ensure on international level a continuous close collaboration between clinicians, researchers and industrial partners for sustained delivery of high-quality training, translation-focused research and clinical translation efforts.
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