Ossorio González, Marta, Selgas Gutiérrez, Rafael (dir.), Bajo Rubio, María Auxiliadora (dir.), UAM. Departamento de Medicina, Selgas Gutiérrez, Rafael, and Bajo Rubio, María Auxiliadora
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 13-12-2016, Esta tesis tiene embargado el acceso al texto completo hasta el 13-06-2018, El proceso de remodelado de la membrana peritoneal se ve mediado por una interacción inflamatoria y profibrótica que deriva en el fallo de membrana peritoneal (PMF) y en última estancia en su complicación más grave, la EPS. Dada la implicación de los macrófagos peritoneales alternativamente activados (M2) en el proceso de fibrosis peritoneal, se plantea la implicación fisiopatogénica de su citoquina CCL18 en dicha fibrosis y sus consecuencias funcionales derivadas. Objetivos del estudio: validar los niveles de CCL18, en suero y efluente peritoneal, como marcadores de alteraciones funcionales y estructurales profibróticas de la membrana peritoneal y explorar potenciales inhibidores del sistema profibrótico M2-CCL18. Métodos: Mediante un estudio longitudinal sobre 43 pacientes durante los 3 primeros años de DP y un corte transversal sobre 61 pacientes de >3 años en DP, valoramos CCL18 en suero y efluente estableciendo su asociación con PMF, EPS y factores de riesgo peritoneal. Estudiamos la implicación de CCL18 en efluente en PE secundaria a hipersensibilidad por clorhexidina. Relacionamos CCL18 con otras moléculas asociadas a EPS como PAI-1. Evaluamos CCL18 como diana terapéutica y su respuesta a inhibidores de la fibrosis como paricalcitol. Resultados y Discusión: Valores bajos y estables de CCL18 en efluente (, The fibrotic remodeling of the peritoneal membrane is mediated by inflammatory and profibrotic interaction, resulting in the failure of peritoneal membrane (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS). Given the involvement of alternatively activated peritoneal macrophages (M2) in the process of peritoneal fibrosis, we hypostasized that its cytokine CCL18 has a physiopathogenic involvement in peritoneal fibrosis and its derived functional consequences. Objectives: validate CCL18 levels in serum and peritoneal effluent as a marker of fibrotic structural and functional alterations of the peritoneal membrane and explore potential inhibitors of profibrotic system M2 - CCL18. Methods: Through a longitudinal study of 43 patients during the first 3 years of PD and a cross section of 61 long-term PD patients (>3 years) , we analyze serum and effluent CCL18 and its association with PMF, EPS and peritoneal risk factors. We study the involvement of effluent CCL18 in chlorhexidine hypersensitivity secondary PE and CCL18 interaction with other molecules associated with EPS as PAI-1. Paricalcitol was studied as a CCL18 therapeutic agent. Results and discussion: Low and stable values of CCL18 in effluent (< 2.2ng/ml) are associated with the absence of subsequent presentation of PMF or EPS. An increase in CCL18 levels at any time was a predictive factor for PMF development. At year 3 of PD, CCL18 values in effluent under 3.15ng/ml showed an 89.5% negative predictive value, and higher levels were associated with later PMF. The association of effluent CCL18 and the subsequent development of PMF was shown independent from the classical approach of peritoneal transport. CCL18 in PE is confirmed as a physiopathogenic agent of peritoneal fibrosis and its associated membrane functional failure. Effluent CCL18 and PAI -1 correlated with each other. Paricalcitol inhibits CCL18 production by M2 macrophagues. Conclusions: Our study shows CCL18 in effluent as a marker of risk of development of PMF with physiopathogenic involvement in the model of peritoneal fibrosis at baseline and inflammatory models such as the PE, also providing a potential new therapeutic target. Key words: Peritoneal dialysis, peritoneal effluent, CCL18, peritoneal function, peritoneal membrane failure, encapsulating peritoneal sclerosis.