Periodic Reporting for period 1 - STRATEGY-CKD (System omics to unravel the gut-kidney axis in Chronic Kidney Disease.)
Berichtszeitraum: 2020-02-01 bis 2022-01-31
Chronic kidney disease (CKD) remains a major public health problem. The global prevalence of CKD is estimated between 11 to 13%. Although women have a greater prevalence of CKD compared to men [12.1% vs 8.1%], men are 1.5 times more likely to develop end-stage kidney disease (ESKD). Cardiovascular disease (CVD) is the major cause of death in CKD patients accounting for nearly 50% of all deaths compared to 26% in the population with normal kidney function. The global burden of CKD-associated diseases is alarmingly high, accounting for nearly 9% of the total health care cost. Traditional risk factors like old age, gender, smoking, … insufficiently explain the high risk for CVD in CKD, while non-traditional risk factors (accumulation of uraemic toxins, inflammation, endothelial dysfunction,…) seem to play a far more important role in vascular disease than in the general population. Accumulation of uraemic toxins is associated with the increased risk for CVD in CKD and depends on the balance between elimination by the kidneys, which progressively decreases during the course of CKD, and generation of the toxins. A substantial part of this generation occurs in the intestine by bacterial metabolisation of dietary products. In spite of its importance, the gut-kidney axis in the context of uraemic toxicity and/or in the development/optimisation of therapies, has long be neglected. Addressing the gut microbial metabolism trying to decrease levels of these metabolites and so their toxicity with the aim to improve the (CV) outcome of CKD patients could be a cost effective alternative/supporting therapeutic approach with limited invasiveness, which needs further exploration.
The objective of STRATEGY-CKD is to train a new generation of scientist to enable them to translate knowledge and ideas in the field of the gut-kidney axis into innovative research and therapeutic approaches for CKD patients.
The objective of STRATEGY-CKD is to train a new generation of scientist to enable them to translate knowledge and ideas in the field of the gut-kidney axis into innovative research and therapeutic approaches for CKD patients.
We are training early-stage researchers (ESRs) to gain excellent scientific and transferable skills with exposure to both academic and nonacademic environments. This will allow them to build bridges between researchers and entrepreneurs and to support the future translation of research findings in innovative therapies. Different training activities were organised in cooperation with complementary research consortia to synergistically improve structural training on European level.
On research level, we are working towards the identification of novel targets related to the gut-kidney axis to improve outcome of patients with CKD. For this aim patient samples are used and cell culture set-ups and animal models are established. State-of-the-art omic approaches are trained and applied and bioinformatics and systems biology support is available. ESR1 and ESR6 are building on the intestinal bacterial metagenome data of CKD patients in different stages of the disease to explore bacterial metabolisation pathways contributing to increased levels of uremic toxins with potential cardiovascular toxicity. ESR2 already significantly advanced in the peptidomic analysis of plasma of the same CKD patient cohort, to be integrated with the intestinal microbiome in collaboration with ESR4. ESR5 performed a literature search on the role of microbiota in CKD as revealed by various -omics (proteomics, metabolomics and transcriptomics) technologies and ESR3 and ESR5 now are and will further focus on the urinary and fecal suspension proteome of the CKD patients. ESR4 established a cell-cell communication framework, the statistical approaches from which are to be extended to multi-omics data and CKD/CVD-associated compounds. ESR8 focuses on role of the uraemic toxin, lanthionine, in the development of vessel lesions endothelial dysfunction. In addition, samples (blood and fecal) from CKD patients have been collected offering an independent patient cohort for analysis. ESR7 explored the interaction between microbiota and kidney disease at several levels: (a) In cultured tubular cells and in (b) in a mice model, focusing on the microbiota-related inflammasome on kidney injury. ESR9 setup new experiments using CKD rat models in order to study further effects of microbiome-derived metabolites on different organs. ESR10 focuses on the functional evaluation of kidney proximal tubule cells upon exposure to gut-derived metabolites and the intestinal epithelial barrier function in CKD as first experiments towards evaluation the gut-kidney-axis on chip. ESR11 studied the intestinal microbiota-derived metabolites in CKD related to vascular calcification in a rat model and ESR12 worked on the response of mice to indoxyl sulfate as microbial metabolite taking into account sex-related differences. Finally, ESR13 validated and optimized a 3D-transwell co-culture model to study future potential interventions.
All combined, the ESRs have joined efforts to set-up the technical methods and to establish the experimental models and are well on their way to study the gut-kidney axis, which in the end will open new opportunities to find novel therapeutic targets and strategies to improve cardiovascular outcome of CKD patients.
On research level, we are working towards the identification of novel targets related to the gut-kidney axis to improve outcome of patients with CKD. For this aim patient samples are used and cell culture set-ups and animal models are established. State-of-the-art omic approaches are trained and applied and bioinformatics and systems biology support is available. ESR1 and ESR6 are building on the intestinal bacterial metagenome data of CKD patients in different stages of the disease to explore bacterial metabolisation pathways contributing to increased levels of uremic toxins with potential cardiovascular toxicity. ESR2 already significantly advanced in the peptidomic analysis of plasma of the same CKD patient cohort, to be integrated with the intestinal microbiome in collaboration with ESR4. ESR5 performed a literature search on the role of microbiota in CKD as revealed by various -omics (proteomics, metabolomics and transcriptomics) technologies and ESR3 and ESR5 now are and will further focus on the urinary and fecal suspension proteome of the CKD patients. ESR4 established a cell-cell communication framework, the statistical approaches from which are to be extended to multi-omics data and CKD/CVD-associated compounds. ESR8 focuses on role of the uraemic toxin, lanthionine, in the development of vessel lesions endothelial dysfunction. In addition, samples (blood and fecal) from CKD patients have been collected offering an independent patient cohort for analysis. ESR7 explored the interaction between microbiota and kidney disease at several levels: (a) In cultured tubular cells and in (b) in a mice model, focusing on the microbiota-related inflammasome on kidney injury. ESR9 setup new experiments using CKD rat models in order to study further effects of microbiome-derived metabolites on different organs. ESR10 focuses on the functional evaluation of kidney proximal tubule cells upon exposure to gut-derived metabolites and the intestinal epithelial barrier function in CKD as first experiments towards evaluation the gut-kidney-axis on chip. ESR11 studied the intestinal microbiota-derived metabolites in CKD related to vascular calcification in a rat model and ESR12 worked on the response of mice to indoxyl sulfate as microbial metabolite taking into account sex-related differences. Finally, ESR13 validated and optimized a 3D-transwell co-culture model to study future potential interventions.
All combined, the ESRs have joined efforts to set-up the technical methods and to establish the experimental models and are well on their way to study the gut-kidney axis, which in the end will open new opportunities to find novel therapeutic targets and strategies to improve cardiovascular outcome of CKD patients.
Chronic kidney disease forms a major socio-economic problem. Its high and still increasing prevalence (will) impact(s) the lives of millions of people worldwide. Dialysis required at end-stage kidney disease comes at a high societal cost. Ideally preventive therapeutic measures which could help to decrease comorbidities and delay disease progression are urgently needed.
Within the STRATEGY-CKD project we are putting strong efforts in optimal dissemination of the scientific results to increase public awareness of the large socio-economic burden of CKD. Identification of the pathological mechanisms involved and of novel therapeutic targets related to the gut-kidney axis could improve outcome of CKD patients in a less invasive and cost effective manner.
In relation to training, STRATEGY-CKD is providing technological, mechanistic and data analysis covering the whole gut kidney axis and the development of potential therapeutic interventions. This also includes complementary skill training essential for personal and career development; business and ethical training. Also, the ESRs are being integrated with SME partners and the industry associated partner, being important stakeholders in the therapeutic implementation process. Together, this will enable the generation of multidisciplinary researchers skilled to combat complex diseases and successfully build bridges between clinicians, researchers and companies. Furthermore, this multi-disciplinary training program will ensure that the ESRs will graduate as scientists trained in facing current scientific challenges using advanced technological tools that are widely applicable in both academia and industry, thereby substantially enhancing their research career prospects.
Also on research level, STRATEGY-CKD advances beyond the current state of art by applying a holistic approach and combining all aspects of disease research (advanced experimental models, translational studies, mechanistic insight, therapeutic interventions) . Omics analyses in diseased conditions have already been proven successful by our partners. The use of bioinformatics/systems biology integrating data and reveal potential targets to treat diseases, and translate research results into innovative health care products.
Within the STRATEGY-CKD project we are putting strong efforts in optimal dissemination of the scientific results to increase public awareness of the large socio-economic burden of CKD. Identification of the pathological mechanisms involved and of novel therapeutic targets related to the gut-kidney axis could improve outcome of CKD patients in a less invasive and cost effective manner.
In relation to training, STRATEGY-CKD is providing technological, mechanistic and data analysis covering the whole gut kidney axis and the development of potential therapeutic interventions. This also includes complementary skill training essential for personal and career development; business and ethical training. Also, the ESRs are being integrated with SME partners and the industry associated partner, being important stakeholders in the therapeutic implementation process. Together, this will enable the generation of multidisciplinary researchers skilled to combat complex diseases and successfully build bridges between clinicians, researchers and companies. Furthermore, this multi-disciplinary training program will ensure that the ESRs will graduate as scientists trained in facing current scientific challenges using advanced technological tools that are widely applicable in both academia and industry, thereby substantially enhancing their research career prospects.
Also on research level, STRATEGY-CKD advances beyond the current state of art by applying a holistic approach and combining all aspects of disease research (advanced experimental models, translational studies, mechanistic insight, therapeutic interventions) . Omics analyses in diseased conditions have already been proven successful by our partners. The use of bioinformatics/systems biology integrating data and reveal potential targets to treat diseases, and translate research results into innovative health care products.