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Identification and Management of Patients at Risk – Outcome and Vascular Events in Peritoneal Dialysis

Periodic Reporting for period 2 - IMPROVE-PD (Identification and Management of Patients at Risk – Outcome and Vascular Events inPeritoneal Dialysis)

Reporting period: 2021-01-01 to 2023-06-30

Chronic kidney disease (CKD) afflicts 8% of the European population and increase risks of infections, cardiovascular disease (CVD) and death. It might progress to end-stage renal disease, prevalent in 250,000 people in Europe, from infants to geriatrics, that depend on a life-saving renal replacement therapy such as peritoneal dialysis (PD). During PD, a fluid is instilled into the peritoneal cavity so ultrafiltration (UF) and diffusion occur across the peritoneal membrane (PM) to eliminate waste materials and water from the body.
Although PD offers economic and performance benefits over haemodialysis (HD), both therapies accelerate atherosclerosis and CVD.
Improved understanding of the molecular mechanisms involved in inflammation, and their connection with CVD will help in the design of interventions to reduce PD-related complications. Inter-sectoral research and well-trained researchers with amultidisciplinary skills are crucial to drive improvements in PD therapy. A risk-adjusted individualized PD approach is also crucial. IMPROVE-PD consortium was born to allow close collaboration between industrial and academic sectors, working in partnership with patients and public to achieve these ambitious targets.
IMPROVE-PD aimed to reduce CVD and mortality in PD patients by enabling tailored approaches targeted to the individual characteristics of the patient. To achieve this, the consortium worked on 3 different scientific work packages (WP), aiming at:
1. “Identifying the patient at risk who will benefit from individualizing therapy”
2. “Understanding the patient at risk”
3. “Early phase studies of novel anti-inflammatory therapies in PD”
Throughout these years, the consortium has impacted on the social, economic and scientific areas, strongly contributing with a large amount of new knowledge to improve patients’ quality of life. It combined PD registries and biobanks, and innovative experimental models to delineate the role of local and systemic, metabolic and immune system-mediated responses on patient outcome. Based on predictive algorithms and pathophysiological markers signatures, therapeutic actions resulted in improvement and personalisation of PD therapy.
IMPROVE-PD offered 15 Early-Stage Researchers (ESRs) to work in a multidisciplinary pan-European PhD level training programme delivered by leading academic, clinical and industrial stakeholders. Network-wide and training activities, combined with individual projects and secondments provided key skills, preparing ESRs as highly skilled researchers. Some of the most relevant findings achieved are:
• Creation of a platform, IMPROVE-PD Finder, combining key meta-data from dialysis registries, observational and randomized prospective clinical studies, and bio-banks
• Validation of omics data and molecular mechanisms as well as junction and transcellular transporter proteins across health, CKD and PD treatments
• Test of PD supplemention with Alanyl-Glutamine, demonstrating protective actions
• Development of novel methodology to investigate the endothelial and epithelial barrier function, integrating functional measurements and junction component studies on single molecule level
• Analysis to stratify the risk of technique failure and CVD
• Creation of calculator software to predict endurance in PD
• Analysis of the mechanisms of local to systemic inflammatory communication, identifying IL17 as a cytokine involved in the PM damage induced by PD fluids, in CVD, and in the CKD-associated inflammation. Several regulatory miRNAs were identified as potential therapies in CKD. Epigenetic drugs ameliorated renal and PM damage
• Study of the role of water channels in the structure and function of the PM during PD in relation to fasting, changes in body composition and accumulation of fat
• Analysis of the effects of a peritoneal infection on the systemic inflammation state and endogenous ligands increased following peritonitis
• Establishment of a new model of vascular smooth muscle cell to calcification phenotype
• Study of cytokines elevated during PD in relationship with vascular osteogenic gene expression and calcification
• Study of Extracellular matrix components alterations in cells undergoing vascular osteogenic differentiation
• Association between inflammatory state induced by PD, CKD and obesity, with the size and vulnerability of atherosclerotic plaques
• Test of an antibody treatment, Anti-Galectin-2, to reduce atherosclerotic plaque size
• Study of the effect of an additive for PD fluid on the gut microbiome
• sequencing of human stool samples to expand the human microbiome dataset, supplemented with metabolomics of plasma and effluent
• Analysis of the levels of glucose degradation products or osmotic agents that lead stress-related responses, and how cytoprotection can attenuate it
• Set up of an In vitro system for studying signalling between mesothelial and endothelial cells. Perturbations caused by PD fluids in the cell-to-cell communication and effect of an additive to the PD fluid were studied
• Lithium addition to PD fluids showed a better preservation of the PM in mice
• New PD mouse model with CVD and an in vitro chronic exposure model of patient uremic serum to endothelial cells were developed
• Novel osmotic agents’ candidates to induce less peritoneal injury - one was patented
• Assessment of systemic effects of exposure to glucose-based fluids
• A trial was designed to assess relevant outcomes with a novel PD fluid
• A meta-analysis on transcriptomic data related to PD to create a molecular network
• Identification of drugs not prescribed yet in PD patients affecting biological processes of high significance for PD
On top of these achievements, also important for the consortium was to be able to disseminate these results in the Scientific Community and to exploit them to incorporate this knowledge to the PD field and collaborate in the improvement of patients' quality of life, as well as to communicate them to the general public and make awareness on the PD issues in the society. Several dissemination and communication actions were carried out during these years:
-A website with an access restricted for the consortium (Virtual Campus) and a public section including the results of the project to be available to the research community, stakeholders and the society
-IMPROVE-PD dedicated symposium in the 14th EuroPD Conference (the most important European forum of PD) and the joint ISPD and EuroPD congress in 2021
-Online Master Classes
-Publications in peer-reviewed journals. A consensus paper is being prepared to highlight the most relevant knowledge raised from this project regarding systemic inflammation, CVD and other outcomes related to PD treatments
-Twitter & Youtube accounts
-Professional Youtube videos
-Other activities carried out by the ESRs and the principal investigators
With the ageing European demographic, the people affected by CKD is growing. PD is an efficient and cost-effective treatment that can be performed at home without constant assistance.
This consortium stimulated the ESRs’ entrepreneurship and equipped them with a unique transferable skillset to improve employability. The training received made them aware of the real processes and challenges by which basic experimental and clinical data is translated into patient care and newly developed therapies.
IMPROVE-PD consortium, Academy in Madrid