Course of vascular access and relationship with treatment of anemia

Producción CientíficaBackground and objectives: Maintenance of the vascular access is a crucial factor in hemodialysis, but large studies of factors that are predictive of thrombosis are lacking. Design, setting, participants, & measurements: This prospective, multicenter study investigated a cohort to describe the management of vascular access and establish the influence of anemia as a risk factor. The cohort included 1710 patients (aged 64.4 yr; 60% men) who were followed every 3 mo at 119 centers during 12 mo. On inclusion, 9.6% had a catheter, 80.3% had a native arteriovenous fistula, and 10.1% had a polytetrafluoroethylene graft. Results: Low baseline hemoglobin increased the risk for vascular access events. The risk was higher with a polytetrafluoroethylene graft and a catheter versus arteriovenous fistula. The multivariate model included type of vascular access, previous cardiovascular events, and noncorrected anemia. The likelihood of remaining free of vascular access events 12 mo later was 0.727 (baseline hemoglobin 12.0 g/dl), figures similar to those obtained with hemoglobin from the trimester before the event. The Cox model included type of vascular access. Conclusions: Correcting anemia did not increase the risk for vascular access–related events, and anemia that was resistant to treatment identified a subgroup of patients with higher comorbidity and higher likelihood of a vascular access event

The impact of donor age on the results of renal transplantation

Producción CientíficaBackground. The use of elderly donors is becoming more frequent. An increase in the donor’s age is associated with a greater incidence of delayed graft function (DGF), chronic allograft nephropathy (CAN) and worse graft survival. Poor renal graft function is a risk factor for cardiovascular (CV) complications and, finally, for mortality of the patients. Methods. A total of 3365 adult patients transplanted in 1990 (n¼824), 1994 (n¼1075) and 1998 (n¼1466) with a functioning graft after the first year were included. The impact of donor age on renal function, DGF, acute rejection and other clinical factors was evaluated according to two donor and recipient age categories: young (60 years old). Additionally, donor age was categorized by decades for the analysis of patient and graft survival, acute rejection and CV mortality. Results. Donor mean age significantly increased during the three transplantation periods. A total of 478 out of 3365 donors were older than 60 years. Elderly donors showed an increased risk of DGF (38.9 vs 28.8%) and CAN (56.8 vs 46.2%). Mean serum creatinine at 3 and 12 months and proteinuria were significantly higher in the old donor group. Incidence and severity of acute rejection were similar in both groups. Graft and patient survival were significantly lower in the old donor group. Also, risk of mortality due to CV events was also significantly higher. A linear increase in risk of graft loss, patient death or CV mortality was observed when donor age was divided into 10 year increase subsets. Conclusions. Donor age is a strong predictor of CAN and graft loss. Patient survival is also affected by donor age, particularly by a higher risk of CV mortality

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

Influence of Tunneled Hemodialysis-Catheters on Inflammation and Mortality in Dialyzed Patients

Older age and comorbidities in hemodialysis patients determines the use of tunneled catheters as vascular access despite their reported clinical and mortality disadvantages. This prospective matched study analyzes the impact of permanent catheters on inflammation and mortality in hemodialysis patients; We studied 108 patients, 54 with AV-fistula (AVF) and 54 with indwelling hemodialysis catheters (HDC) matched by sex, age, diabetes and time under renal-replacement therapy comparing dialysis efficacy, inflammation and micro-inflammation parameters as well as mortality. Cox-regression analysis was applied to determine predictors of mortality, HDC patients presented higher C-reactive-protein (CRP) blood levels and percentage of pro-inflammatory lymphocytes CD14+/CD16+ with worse dialysis-efficacy parameters. Thirty-six-months mortality appeared higher in the HDC group although statistical significance was not reached. Age with a Hazard Ratio (HR) = 1.06, hypoalbuminemia (HR = 0.43), hypophosphatemia (HR = 0.75) and the increase in CD14+/CD16+ monocyte count (HR = 1.02) were predictors of mortality; elder patients dialyzing through HDC show increased inflammation parameters as compared with nAVF bearing patients, although they do not present a significant increase in mortality when matched by covariates. Increasing age and percentage of pro-inflammatory monocytes as well as decreased phosphate and serum-albumin were predictors of mortality and indicate the main conclusions or interpretations

Pancreatic autoantibodies and CD14+CD16+ monocytes subset are associated with the impairment of ß-cell function after simultaneous pancreas-kidney transplantation

Pancreatic autoantibodies (AAb) has been associated with a worse pancreas graft survival after simultaneous pancreas-kidney transplantation (SPK). However, due to the variable time for AAb to become positive and the lack of early biomarkers suggesting such autoimmune activation, the mechanisms leading ß-cell destruction remain uncertain. The present study aimed to evaluate the association between post-transplant AAb and the functional impairment of the pancreatic ß-cell and also the association of such AAb with inflammation after SPK. In a longitudinal study, we analyzed the impact of post-transplant glutamic acid decarboxylase (GAD-65) and the insulinoma-associated autoantigen 2 (IA-2) AAb on pancreas graft function. Serum Hb1Ac and C-peptide (C-pep) were longitudinally compared between a group with positive posttransplant AAb (AAb+; n = 40) and another matched group with negative AAb (AAb-; n = 40) until the fifth year following seroconversion. In the cross-sectional analysis, we further evaluated the systemic signatures of inflammation by measuring pro-inflammatory CD14+CD16+ monocytes by flow-cytometry and interleukin 17-A serum levels in 38 SPK recipients and ten healthy controls. In the longitudinal study, patients with AAb+ showed higher levels of Hb1Ac (p<0.001) and lower C-pep levels (p<0.001) compared to those who remained AAb- throughout the follow-up. In the cross-sectional study, AAb+ patients showed a higher percentage of CD14+CD16+ monocytes compared with those with AAb- and the healthy controls (6.70±4.19% versus 4.0±1.84% and 3.44±0.93%; p = 0.026 and 0.009 respectively). Also, CD14+CD16+ monocytes correlated with Hb1Ac and C-pep serum levels. Multivariate logistic regression showed that posttransplant AAb+ was independently associated with a higher percentage of pro-inflammatory monocytes (adjusted-OR 1.59, 95%CI 1.05–2.40, p = 0.027). The group of patients with positive AAb also showed higher levels of IL17A as compared with the other groups (either healthy control or the negative AAb subjects). In conclusion, pancreatic AAb+ after SPK were not only associated with higher Hb1Ac and lower c-peptide serum levels but also with an increased percentage of CD14+CD16+ monocytes and higher levels of circulating IL17-A

Eculizumab in secondary atypical haemolytic uraemic syndrome

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing conditionWork in this report was funded by the Instituto de Salud Carlos III: REDinREN (RD 016/009 Feder Funds), the Fondo de Investigaciones Sanitarias (13/02502 and ICI14/00350), the Ministerio de Economia y Competitividad (SAF2015-66287R) and the Autonomous Region of Madrid (S2010/BMD-2316; Grupo de Investigación Complemento-CM). SRdeC is funded by the Seventh Framework Programme European Union Project EURenOmics (305608

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

Microvesicles Derived from Indoxyl Sulfate Treated Endothelial Cells Induce Endothelial Progenitor Cells Dysfunction

Cardiovascular disease is a major cause of mortality in chronic kidney disease patients. Indoxyl sulfate (IS) is a typical protein-bound uremic toxin that cannot be effectively cleared by conventional dialysis. Increased IS is associated with the progression of chronic kidney disease and development of cardiovascular disease. After endothelial activation by IS, cells release endothelial microvesicles (EMV) that can induce endothelial dysfunction. We developed an in vitro model of endothelial damage mediated by IS to evaluate the functional effect of EMV on the endothelial repair process developed by endothelial progenitor cells (EPCs). EMV derived from IS-treated endothelial cells were isolated by ultracentrifugation and characterized for miRNAs content. The effects of EMV on healthy EPCs in culture were studied. We observed that IS activates endothelial cells and the generated microvesicles (IsEMV) can modulate the classic endothelial roles of progenitor cells as colony forming units and form new vessels in vitro. Moreover, 23 miRNAs were contained in IsEMV including four (miR-181a-5p, miR-4454, miR-150-5p, and hsa-let-7i-5p) that were upregulated in IsEMV compared with control endothelial microvesicles. Other authors have found that miR-181a-5p, miR-4454, and miR-150-5p are involved in promoting inflammation, apoptosis, and cellular senescence. Interestingly, we observed an increase in NFκB and p53, and a decrease in IκBα in EPCs treated with IsEMV. Our data suggest that IS is capable of inducing endothelial vesiculation with different membrane characteristics, miRNAs and other molecules, which makes maintaining of vascular homeostasis of EPCs not fully functional. These specific characteristics of EMV could be used as novel biomarkers for diagnosis and prognosis of vascular disease