CCL18 y su implantación en esclerosis peritoneal: validación clínica de un nuevo marcador diagnóstico y pronóstico de alteraciones de la función peritoneal

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 13-12-2016Esta tesis tiene embargado el acceso al texto completo hasta el 13-06-2018El 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 (<2.2ng/ml) se asocian con la ausencia de presentación posterior de PMF o EPS. Incrementos de CCL18 se asociaron significativamente con desarrollo de PMF. Valores de CCL18 en efluente <3.15ng/ml en el tercer año de DP presentaron un valor predictivo negativo del 89.5% y superiores a dicho umbral un riesgo mayor de PMF. La asociación de CCL18 en efluente y el desarrollo posterior de PMF se mostró independiente del abordaje clásico de transporte peritoneal. CCL18 en PE se confirma como agente fisiopatogénico de fibrosis peritoneal y fallo funcional asociado. CCL18 y PAI-1 en efluente se correlacionaron entre sí. Paricalcitol inhibe CCL18 en efluente. Conclusiones: Nuestro estudio muestra CCL18 en efluente como un marcador de riesgo de desarrollo de PMF con implicación fisiopatogénica en el modelo de fibrosis peritoneal en situación basal y en modelos inflamatorios como el de la PE, proporcionando además una potencial nueva diana terapéutica. Palabras clave: Diálisis peritoneal, efluente peritoneal, CCL18, función peritoneal, fallo de membrana peritoneal, esclerosis peritoneal encapsulante.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

Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study

Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA). Methods: This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (b-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded. Results: Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with b-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression. Conclusion: In patients with PCa and bone metastases treated with ZA, b-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially importantThis study was supported by Novartis Oncology Spai

The Effect of Nutritional Interventions on Long-Term Patient Survival in Advanced Chronic Kidney Disease

Patients with end-stage kidney disease (ESKD) are at high risk of malnutrition and subsequent related mortality when starting dialysis. However, there have been few clinical studies on the effect of nutritional interventions on long-term patient survival. A 2-year longitudinal study was conducted from January 2012 to December 2016. A total of 186 patients with non-dialysis ESKD started the nutritional education program (NEP), and 169 completed it. A total of 128 patients participated in a NEP over 6 months (personalized diet, education and oral supplementation, if needed). The control group (n = 45) underwent no specific nutritional intervention. The hospitalization rate was significantly lower for the patients with NEP (13.7%) compared with the control patients (26.7%) (p = 0.004). The mortality odds ratio for the patients who did not receive NEP was 2.883 (95% CI 0.993–8.3365, p = 0.051). The multivariate analysis showed an independent association between mortality and age (OR, 1.103; 95% CI 1.041–1.169; p = 0.001) and between mortality and the female sex (OR, 3.332; 95% CI 1.054–10.535; p = 0.040) but not between mortality and those with NEP (p = 0.051). Individualized nutrition education has long-term positive effects on nutritional status, reduces hospital admissions and increases survival among patients with advanced CKD who are starting dialysis programs

Seasonal variability of plankton blooms in the Ria de Ferrol (NW Spain): II. Plankton abundance, composition and biomass.

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NUTRITIONAL STATUS AND INTAKE PATTERN IN A GROUP OF ESRD SPANISH PATIENTS

IntroductionThe nutritional status of the ESRD patients is a crucial issue in the disease progression, that´s the reason why the patient nutritional education is so important.Our objective is to evaluate the change in the nutritional status in a group of ESRD patients after a personalized nutritional education program. Method Longitudinal case study of 103 patients who took part in a nutritional educational program over six months (personalized diet, education and oral supplementation).Results: See below Table 1.Table 1WELL-NOURISHEDUNDERNOURISHEDBeforeAfterBeforeAfterN(%)58,3%79,6%41,7%20,4%Albumin (g/dl)3,79±0,23,79±0,33,3±0,53,5±0,4⁎Prealbumin (mg/dl)32,86±5,233,85±5,628,1±5,228,6±3,3Potassium4,8±0,74,6±0,4*4,8±0.674,6±0,5Cholesterol (mg/dl)181,6±50,72167,02±41,02*177,37±38,8175,1±37,1Energy intake (kcal)1859,0±324,11571,5±219**1794,1±482,11797,7±414,3Protein intake(g)69,7±15,355,6±12,8, **69,7±18,354,26±10,6, **Weight (kg)77,5±12,374,2±11, **65,7±13,965,6±12,4BMI29,3±4,528,1±4,1, **25,76±5,1725,75±4,6ConclusionThe undernourished patients percentage (reflected by the albumin and prealbumin increase) decrease after the nutritional program. The well-nourished patients drop his weight and protein intak