Cell apoptosis and hemodialysis-induced inflammation

Cell apoptosis and hemodialysis-induced inflammation. Hemodialysis patients exhibit a defective immune response leading to an increased susceptibility of infections and neoplasms. Far from being helpful, dialytic therapy per se also may be responsible for this acquired immunodeficiency. Dialysis membranes and bacterial products present in dialysis water may trigger and even perpetuate an abnormal mononuclear cell activation. Upon contact with cellulosic dialysis membranes, monocytes display an increased expression of surface markers of cell activation, such as adhesion molecules CD18, CD49, CD54 and the lipopolysaccharide (LPS) ligand (CD14). Moreover, proinflammatory cytokines as IL-1β and TNF-α are released both in vivo and in vitro when monocytes are exposed to cellulosic membranes. Of special interest is the fact that end-stage renal disease patients undergoing hemodialysis exhibit an increased mononuclear cell apoptosis. This apoptosis is directly related to the degree of biocompatibility of the dialysis membrane. Apoptosis is activated when monocytes enter in contact with the cellulosic dialysis membrane through cell surface receptors linked to G-proteins. In early steps of apoptosis signaling, pertussis toxin-sensitive G proteins are coupled to protein kinase C (PKC)-dependent phosphorylative mechanisms. Furthermore, recent evidence support that the execution phase of apoptosis is mediated by a caspase-3 dependent pathway. Finally, very recent available data support that monocytes subjected to repeated activation suffer a process of accelerated senescence, as demonstrated by the senescent phenotype (CD14 and CD32) expressed and their shortened telomeric length. This senescent profile may generage a defective cellular response in acute stress situations, explaining (at least in part) the altered immune response observed in hemodialysis patients

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications

Evaluación de los diferentes tipos de membranas de hemodiálisis

La pluralidad de membranas utilizadas en la fabricación de dializadores, contribuye a que se presente en el mercado gran número de ellos, más de 400 en el ámbito de la EDTA, con características muy diferentes, tanto en lo relativo a sus prestaciones funcionales como a su "biocompatibilidad" y su precio. La trascendencia clínica y económica del uso de uno u otro tipo de dializador ha sido objeto de multitud de publicaciones y considerable debate que no ha llegado a materializarse en un cuerpo de doctrina universalmente aceptado, que sitúe con precisión la contribución relativa de cada tipo de dializador al resultado clínico del tratamiento en diálisis de la insuficiencia renal; y, consecuentemente, la efectividad y eficiencia de este elemento, fundamental en dicho tratamiento. El objeto del presente informe es proporcionar información respecto de dichas cuestiones, desde una perspectiva global, ponderando el valor relativo de los diferentes criterios en juego que afectan a: efectividad clínica, funcionalidad, biocompatibilidad y precio.Presentación, Abreviaturas, Informe de síntesis, Tratamiento de IRCT: Desarrollo actual y resultados, Objetivos y fundamentos de la técnica, Biocompatibilidad, Clasificación de membranas. Criterios y parámetros, Diálisis adecuada, Morbi-mortalidad asociada a diálisis Uso de las diferentes categorías de membranas, Consideraciones económicas, Conclusiones, Hemodiálisis: Evolución histórica y consideraciones generales, Morbilidad asociada a la diálisis Evolución de la técnica y diálisis adecuada, Criterios de clasificación de las membranas, Valoración clínica de las diferentes categorías de membranas, Extensión del uso de las diferentes categorías de membranas Aspectos económicos del tratamiento, Anexos

Impact of targeting Kt instead of Kt/V

Producción CientíficaBackground. Patients must receive an adequate dialysis dose in each hemodialysis (HD) session. Ionic dialysance (ID) enables the dialysis dose to be monitored in each session. The aim of this study was to compare the achievement of Kt versus eKt/V values and to analyse the main impediments to reaching the dialysis dose. Methods. Of 5316 patients from 54 Fresenius Medical Care centers in Spain undergoing their usual HD regime, 3275 received ID and were included in the study. Results. The minimum prescribed dose of eKt/V was reached in 91.2% of the patients, while the minimum recommended dose of Kt was reached in only 66.8%. Patients not receiving the minimum Kt dose were older, had spent 7 months less on dialysis, had a dialysis duration of 6 min less, had 5.7 kg more of body weight and Qb was 47 mL/min lower. The target Kt was not reached by 62% of patients with catheters and by 37% of women. With each quintile increase of body weight, eKt/V decreased and Kt increased. Of patients with a body weight >80 kg, 1.4%, mostly men, reached the target Kt but not prescribed eKt/V. Conclusions. The impact of monitoring the dose with Kt instead of Kt/V is that identifies 25.8% of patients who did not reach the minimum Kt while achieving Kt/V. The main impediments to achieving an adequate dialysis dose were catheter use, female sex, advanced age, greater body weight, shorter dialysis time and lower Qb

Survival with low- and high-flux dialysis

FUNDING COSMOS is sponsored by the Bone and Mineral Research Unit (Hospital Universitario Central de Asturias), SAFIM (Sociedad Asturiana Fomento Investigaciones O´ seas), the European Renal Association–European Dialysis and Transplant Association, the National Program of I þ D þ I 2008–2011 and Instituto de Salud Carlos III (ISCIII), the ISCIII Retic REDinREN (RD06/0016/1013, RD12/0021/0023 and RD16/ 0009/0017), the ISCIII (ICI14/00107, PI17/00384 and PI20/ 00633), Fondo Europeo de Desarrollo Regional (FEDER), Plan Estatal de I þ D þ I 2013–2016, Plan de Ciencia, Tecnologia e Innovacion 2013–2017 y 2018–2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), Fundacio´n Renal I ´nigo A ~ ´ lvarez de Toledo (FRIAT) and the Spanish Society of Nephrology (Estudio Estrate´gico de la SEN). Logistics (meetings, secretarial help, printing of materials, development of website for data entry, etc.) have been financially supported by AMGEN Europe and FRIAT. The authors are not aware of any additional relationships, funding or financial holdings that might be perceived as affecting the objectivity of this study. COSMOS participating centres: see Supplementary Appendix.Background. Besides advances in haemodialysis (HD), mortality rates are still high. The effect of the different types of HD membranes on survival is still a controversial issue. The aim of this COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis was to survey, in HD patients, the relationship between the use of conventional low- or high-flux membranes and all-cause and cardiovascular mortality. Methods. COSMOS is a multicentre, open-cohort, 3-year prospective study, designed to evaluate mineral and bone disorders in the European HD population. The present analysis included 5138 HD patients from 20 European countries, 3502 randomly selected at baseline (68.2%), plus 1636 new patients with <1 year on HD (31.8%) recruited to replace patients who died, were transplanted, switched to peritoneal dialysis or lost to follow-up by other reasons. Cox-regression analysis with timedependent variables, propensity score matching and the use of an instrumental variable (facility-level analysis) were used. Results. After adjustments using three different multivariate models, patients treated with high-flux membranes showed a lower all-cause and cardiovascular mortality risks fhazard ratio (HR) = 0.76 [95% confidence interval (CI) 0.61-0.96] and HR = 0.61 (95% CI 0.42-0.87), respectivelyg, that remained significant after matching by propensity score for all-cause mortality (HR = 0.69, 95% CI 0.52-0.93). However, a facility-level analysis showed no association between the case-mix-adjusted facility percentage of patients dialysed with high-flux membranes and all-cause and cardiovascular mortality. Conclusions. High-flux dialysis was associated with a lower relative risk of all-cause and cardiovascular mortality. However, dialysis facilities using these dialysis membranes to a greater extent did not show better survival.publishersversionpublishe

Renal Function After Dopamine and Fluid Administration in Patients with Malignant Obstructive Jaundice. A Prospective Randomized Study

Abstract Background and Aims: Acute renal failure is a relevant complication in obstructive jaundice (OJ). The extracellular water volume (ECW) depletion and myocardial dysfunction affects haemodynamic and renal disturbance in patients with OJ. Methods: A prospective open randomised study was conducted to evaluate the effect of peridrainage saline infusion associated with dopamine administration on hormonal and renal function derangements in 102 patients with malignant OJ. Patients were randomly distributed according to whether (n=64) or not (n=38) received dopamine with saline solution before endoscopic biliary drainage. Furthermore, patients receiving dopamine were randomly distributed whether (n=31) or not (n=33) received additional dopamine administration during the postdrainage phase. Different parameters such as ECW, serum levels of aldosterone, renin, atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), endothelin-1 (ET-1), urine PGE2 and creatinine clearance (CrCl) were analyzed. Results: Fluid administration was accompanied by an increase in the ECW (p=0.01) and an improvement in the CrCl (p=0.01). Dopamine increased CrCl by 11% (p=0.04) and reduced urinary PGE2 concentration (p=0.02). After drainage, a transient worsening of CrCl was seen in patients on i.v. fluid infusion alone but not in dopamine groups (p=0.001). Improvement of CrCl after dopamine administration was found in patients with serum bilirubin &gt; 16 mg/dl and sodium urine excretion &lt;145 mEq/l. Conclusions: The administration of dopamine associated with appropriate i.v. fluid infusion in the peridrainage period has an impact on renal function only in selected patients with malignant biliary obstruction. This effect is more relevant in patients with higher marked cholestasis

Markers of endothelial damage in patients with chronic kidney disease on hemodialysis

Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/µl) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM.Support for this work was provided by Plan Nacional de IDi Proyectos de Investigación en Salud of Instituto de Salud Carlos III (ISCIII)–Subdirección General de Evaluación, Fondos de desarrollo regional (FEDER; PI11/01536, PI12/01489, PI14/00806, PI15/01785); Junta de Andalucía grants (P010-CTS-6337, P11-CTS-7352); and Fundación Nefrológica. P. Buendía, A. Carmona, and C. Luna-Ruiz are fellows from Consejería de Innovacion, Ciencia y Empresa, Junta de Andalucía

The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function

[Background] In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype.[Methods] This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2–3 studying a relationship between FGF23 and vascular dysfunction.[Results] In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2–3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222.[Conclusion] In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.This work was supported by a Spanish government grant from the Programa Nacional I+D+I 2013–2016 and Instituto de Salud Carlos III (ISCIII) grants PI18/0138 and PI21/0654 co-financing from European Funds (FEDER), Consejería de Salud (grants PI-0136 and PI-0169-2020) from the Junta de Andalucía, Framework Programme 7 Syskid UE grant FP7-241544, and EUTOX and REDinREN from the ISCIII. N.V. and J.M.D.-T. were supported by Consejería de Economía, Innovación, Ciencia y Empleo (grant CVI-7925) from the Junta de Andalucía. Y.A. and J.R.M.-C. are senior researchers supported by the Nicolás Monardes Programme, Consejería de Salud-Servicio Andaluz de Salud (Junta de Andalucía).Peer reviewe

Supplemental Material The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function

3 pages. -- Figure S1. Supplemental Material. Effects of anti-miR-221 and miR-222. -- Figure S1. Supplemental Material: A) Anti-miR-221 and B) anti-miR-222 transfection for 48 h decreased not significantly the expression of miR-221 and miR-222 in VSMC. -- Figure S2. Supplemental Material. Recombinant Klotho administration did not modify the expression of contractile markers of VSMC. -- Figure S3. Histological quantifications in thoracic aortas of rats of synthetic markers of VSMC.Peer reviewe