Tese de Doutoramento Medicina 2023 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

ABSTRACT Chronic kidney disease (CKD) is a major health problem because of its high prevalence: up to 10% of the general population suffers from CKD and 30% are considered at risk of developing CKD. The mortality rates are higher than other chronic diseases, including most types of cancer. Even though there is a relative lack of innovative solutions in CKD management, which is holding CKD outcomes back. This scenario calls for new tools of risk stratification and tailored peritoneal dialysis PD prescriptions. Advances in the current knowledge might necessarily include the identification of biomarkers, potential targets and mechanisms of toxicity of uremia. Together with better knowledge on the impact of peritoneal dialysis on these mechanisms will definitely improve patient-oriented outcomes. The nravelling of reasons for the extremely high burden of cardiovascular disease in uremia is also a medical unmet need. On the other hand, it is consensual that PD negatively impacts the integrity of the peritoneal membrane, and that fibrosis is a key pathophysiological path of functional loss, menacing both patient and technique survival. However, evidence was missing the impact of uremia in membrane fibrosis and the impact of fibrosis of the peritoneal membrane before the start of PD in PD long-term outcomes. In chapter III, we hypothesized that uremia has different forms of presentation among patients and that fibrosis is already present in the peritoneal membrane in pre-PD for some patients. To follow our hypothesis, we performed a histomorphological characterization of the membrane status in pre-PD aiming to investigate if fibrosis was already present in some patients. In addition, we investigated the link between uremia and fibrosis in peritoneal membrane to identify a biopsy-free marker of the status of the peritoneal membrane (Chapter I). A clinical-mechanistic, transversal, single-center study was conducted in adult incident PD patients with baseline peritoneal biopsies: 58 biopsies were scored considering the submesothelial compact zone thickness (STM), vasculopathy and inflammation. We investigated if the membrane status could be inferred from a panel of blood proteins (TNFα, α-Klotho, Galectin-3, FGF21, FGF23, TWEAK, TNFα, hsPCR). In Chapter IV, we assumed that membrane integrity at pre-PD was a predictor of membrane survival in DP and that the combination of uremic factors, pre existent cardiovascular disease and other age-related indicators might be predictive indicators of the global cardiovascular disease during PD. For that, in a 5-year follow-up, the membrane status, aging and fibrosis related indicators (age, frailty score and panel of blood biomarkers of chapter 1) were characterized at the baseline and investigated as predictors of the endpoints: a) PD failure and time until PD failure and b) a major cardiovascular event (MACE) or time until MACE and c) all causes mortality. These studies provided evidence that support strategies for tailored prescriptions patients: 1- While there is a high person-to-person variability, fibrosis might be already present in the membrane at pre-dialysis (Chapter III). 2- Membrane fibrosis in pre-PD is related to the individual´s uremic fingerprint in the blood (Chapter III). 3- Low α-Klotho circulating levels can infer fibrosis in membrane (Chapter III). 4- Fibrosis of peritoneal membrane before the start of PD is not related to the peritoneal transport and is not an indicator of membrane survival in PD (Chapter IV). 5- Galectine-3, a key driver of the aging process is predictive of the survival of the peritoneal membrane (Chapter IV). 6- Fibrosis of peritoneal membrane before the start of PD is an indicator of cardiovascular vulnerability (Chapter IV). 7- Klotho level is related to fibrosis of the membrane and a predictive of major cardiovascular events (Chapter IV). 8- Galectine-3 and Klotho are putative minimally invasive tools guide nephrologists in PD (Chapter IV). Overall, outputs of chapter III and IV contribute to novelty in PD field: highlighted the histopathology of the peritoneal membrane in the uremic milieu and unveiled the status of the peritoneal membrane pre- PD as a window to the systemic cardiovascular risk. Two putative tools for precision PD emerged from our research: a predictor of membrane survival (galectine3) and a predictor of cardiovascular risk in PD patients (α-Klotho). Within a non-invasive assessment at the beginning of the technique and a capability to infer the longitudinal evolution and outcomes, they are candidates to support tailored prescriptions. In chapters V to VII we analyzed the repercussion of PD in different cardiovascular clinical contexts: a) demonstrating its ability to preserve residual renal function and mitigate cardiovascular disease (Chapter V and VI), b) documenting the benefits of PD in cardiovascular disease with resistance to diuretics resistance (Chapter VII) c) producing a protocol proposing the value of ultrafiltration in the Diuretic resistant heart failure ((Chapter VII) In chapters V-VII we contributed to support the reasons why PD is a better therapeutic option for patients with cardiovascular disease (Chapter IV - Chapter VII). Our data support that even patients with vulnerable phenotype of biological accelerated ageing could take advantage of this home-based modality of renal replacement therapy, with no differences in mortality and had good survival in the technique, despite a higher risk of CV events (Chapter IV). It offers gentle ultrafiltration with minimal impact on hemodynamics that results in a lower degree of neurohumoral stimulation and in slower decline of renal function, factors known to be associated with survival. Peritoneal ultrafiltration leads to effective continuous solute clearance, such as potassium, allowing better up-titration of risk-modifying pharmacological treatment (Chapter VII). This technique is also not associated with myocardial stunning and seems to achieve a reduction in inflammatory burden. These advantages are confirmed when treating patients with cardiovascular established disease (Chapter V and Chapter VII) and for congenital heart disease in children undergoing cardiac surgery (Chapter V)