IHDIP: a controlled randomized trial to assess the security and effectiveness of the incremental hemodialysis in incident patients.

BACKGROUND: Most people who make the transition to renal replacement therapy (RRT) are treated with a fixed dose thrice-weekly hemodialysis réegimen, without considering their residual kidney function (RKF). Recent papers inform us that incremental hemodialysis is associated with preservation of RKF, whenever compared with conventional hemodialysis. The objective of the present controlled randomized trial (RCT) is to determine if start HD with one sessions per week (1-Wk/HD), it is associated with better patient survival and other safety parameters. METHODS/DESIGN: IHDIP is a multicenter RCT experimental open trial. It is randomized in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 incident patients older than 18 years, with a RRF of ≥4 ml/min/1.73 m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with incremental HD (1-Wk/HD). The control group includes 76 patients who will start with thrice-weekly hemodialysis régimen. The primary outcome is assessing the survival rate, while the secondary outcomes are the morbidity rate, the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable to know the number of sessions a patient should receive when starting HD, depending on his RRF. The potentially important clinical and financial implications of incremental hemodialysis warrant this RCT. TRIAL REGISTRATION: U.S. National Institutes of Health, ClinicalTrials.gov . Number: NCT03239808 , completed 13/04/2017. SPONSOR: Foundation for Training and Research of Health Professionals of Extremadura.

Justificación y diseño de DiPPI: un ensayo controlado aleatorizado para evaluar la seguridad y la efectividad de la hemodiálisis progresiva en pacientes incidentes / Rationale and design of DiPPI: A randomized controlled trial to evaluate the safety and effectiveness of progressive hemodialysis in incident patients

INTRODUCCIÓN: La hemodiálisis (HD) progresiva es una modalidad de inicio del tratamiento renal sustitutivo adaptada a las necesidades individuales de cada paciente. Está condicionada fundamentalmente por la función renal residual (FRR). En ella, la frecuencia de sesiones con las que el paciente inicia HD (una o 2 sesiones por semana) es menor que en la HD convencional (3 por semana). Dicha frecuencia aumenta (de una a 2, y de 2 a 3) con el declinar de la FRR. Metodología/diseño: DiPPI es un estudio abierto, multicéntrico, experimental, aleatorizado 1:1 y controlado con procedimiento de práctica clínica habitual, de bajo nivel de intervención y no comercial. Incluye 152 pacientes mayores de 18 años, con enfermedad renal crónica estadio 5, que inician HD como tratamiento renal sustitutivo; y la FRR, medida por aclaramiento renal de urea (KrU) es ≥ 4ml/min/1,73 m2. El estudio se basa en un grupo de intervención con 76 pacientes que iniciarán HD con una sola sesión por semana (modalidad progresiva) y un grupo control con 76 pacientes que comenzarán con 3 sesiones por semana. El objetivo primario es evaluar la supervivencia y los objetivos secundarios son la morbilidad (hospitalizaciones), los parámetros clínicos habituales, la calidad de vida y la eficiencia. DISCUSIÓN: Este estudio permitirá conocer, con la máxima evidencia científica, cuántas sesiones debe recibir un paciente al inicio del tratamiento con HD, dependiendo de su FRR. Registro: Registrado en U.S. National Institutes of Health, ClinicalTrials.gov con número NCT03239808

INTRODUCTION: Progressive haemodialysis (HD) is a starting regime for renal replacement therapy (RRT) adapted to each patient's necessities. It is mainly conditioned by the residual renal function (RRF). The frequency of sessions with which patients start HD (one or two sessions per week), is lower than that for conventional HD (three times per week). Such frequency is increased (from one to two sessions, and from two to three sessions) as the RRF declines. Methodology/DESIGN: IHDIP is a multicentre randomised experimental open trial. It is randomised in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 patients older than 18 years with chronic renal disease stage 5 and start HD as RRT, with an RRF of ≥ 4 ml/min/1.73 m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with one session of HD per week (progressive HD). The control group includes 76 patients who will start with three sessions per week (conventional HD). The primary purpose is assessing the survival rate, while the secondary purposes are the morbidity rate (hospital admissions), the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable us to know, with the highest level of scientific evidence, the number of sessions a patient should receive when starting the HD treatment, depending on his/her RRF. Trial registration: Registered at the U.S. National Institutes of Health, ClinicalTrials.gov under the number NCT03239808

Rationale and design of DiPPI: A randomized controlled trial to evaluate the safety and effectiveness of progressive hemodialysis in incident patients. / Justificación y diseño de DiPPI: un ensayo controlado aleatorizado para evaluar la seguridad y la efectividad de la hemodiálisis progresiva en pacientes incidentes.

INTRODUCTION: Progressive haemodialysis (HD) is a starting regime for renal replacement therapy (RRT) adapted to each patient's necessities. It is mainly conditioned by the residual renal function (RRF). The frequency of sessions with which patients start HD (one or two sessions per week), is lower than that for conventional HD (three times per week). Such frequency is increased (from one to two sessions, and from two to three sessions) as the RRF declines. METHODOLOGY/DESIGN: IHDIP is a multicentre randomised experimental open trial. It is randomised in a 1:1 ratio and controlled through usual clinical practice, with a low intervention level and non-commercial. It includes 152 patients older than 18 years with chronic renal disease stage 5 and start HD as RRT, with an RRF of ≥4ml/min/1.73m2, measured by renal clearance of urea (KrU). The intervention group includes 76 patients who will start with one session of HD per week (progressive HD). The control group includes 76 patients who will start with three sessions per week (conventional HD). The primary purpose is assessing the survival rate, while the secondary purposes are the morbidity rate (hospital admissions), the clinical parameters, the quality of life and the efficiency. DISCUSSION: This study will enable us to know, with the highest level of scientific evidence, the number of sessions a patient should receive when starting the HD treatment, depending on his/her RRF. TRIAL REGISTRATION: Registered at the U.S. National Institutes of Health, ClinicalTrials.gov under the number NCT03239808.

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-ß, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. METHODS: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. RESULTS: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4(+)IL17(+), CD11b(+)Ly6G(+) and CD11b(+)Ly6C(+) cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. CONCLUSIONS: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.

Human decidua-derived mesenchymal stem cells differentiate into functional alveolar type II-like cells that synthesize and secrete pulmonary surfactant complexes.

Lung alveolar type II (ATII) cells are specialized in the synthesis and secretion of pulmonary surfactant, a lipid-protein complex that reduces surface tension to minimize the work of breathing. Surfactant synthesis, assembly and secretion are closely regulated and its impairment is associated with severe respiratory disorders. At present, well-established ATII cell culture models are not available. In this work, Decidua-derived Mesenchymal Stem Cells (DMSCs) have been differentiated into Alveolar Type II- Like Cells (ATII-LCs), which display membranous cytoplasmic organelles resembling lamellar bodies, the organelles involved in surfactant storage and secretion by native ATII cells, and accumulate disaturated phospholipid species, a surfactant hallmark. Expression of characteristic ATII cells markers was demonstrated in ATII-LCs at gene and protein level. Mimicking the response of ATII cells to secretagogues, ATII-LCs were able to exocytose lipid-rich assemblies, which displayed highly surface active capabilities, including faster interfacial adsorption kinetics than standard native surfactant, even in the presence of inhibitory agents. ATII-LCs could constitute a highly useful ex vivo model for the study of surfactant biogenesis and the mechanisms involved in protein processing and lipid trafficking, as well as the packing and storage of surfactant complexes.

Influence of polysulphone-derived dialysis membranes on the interaction of circulating mononuclear cells with the endothelium.

PURPOSE: Cardiovascular morbidity in hemodialysis (HD) patients may be influenced by the activation of circulating mononuclear cells (MCs) with subsequently increased endothelium interaction. The use of more biocompatible membranes would reduce this monocyte activation. We compare monocyte activation after using two different high-flux polymers, polysulphone and polyethersulphone. METHODS: The first part of the study was done with 10 patients who successively received dialysis for 2 weeks with polysulphone and polyethersulphone. The second part with 30 patients dialyzed for 3 months with polysulphone or polyethersulphone. Blood samples were taken before (pre-HD) and after (post-HD) the first HD session with each membrane to evaluate the effect of a single HD session. To assess acute and chronic effects of membranes, blood samples were taken pre-HD, after 2 weeks (first part of study) and after 3 months (second part of study). MCs were isolated from blood and then incubated with cultured human endothelial cells to evaluate MC adhesion, MC-dependent endothelial toxicity, and endothelial protein expressions of nitric oxide synthase and endothelin-converting enzyme-1 (ECE-1). RESULTS: One single HD session did not induce any changes. Dialysis for 2 weeks (first part of study) with polyethersulphone reduced MC adhesion to endothelium, cellular toxicity, and ECE-1 protein expression compared to polysulphone or basal conditions. Dialysis for 3 months (second part of study) increased MC adhesion to endothelium, whereas cellular toxicity was decreased with both dialyzers compared to the basal situation. CONCLUSIONS: Although polyethersulphone HD decreased the interaction of MC with the endothelium in short-term experiments, both membranes were comparable in the long-term.

Human decidua-derived mesenchymal stromal cells differentiate into hepatic-like cells and form functional three-dimensional structures.

BACKGROUND AIMS: Previously, we have shown that human decidua-derived mesenchymal stromal cells (DMSC) are mesenchymal stromal cells (MSC) with a clonal differentiation capacity for the three embryonic layers. The endodermal capacity of DMSC was revealed by differentiation into pulmonary cells. In this study, we examined the hepatic differentiation of DMSC. METHODS: DMSC were cultured in hepatic differentiation media or co-cultured with murine liver homogenate and analyzed with phenotypic, molecular and functional tests. RESULTS AND CONCLUSIONS: DMSC in hepatic differentiation media changed their fibroblast morphology to a hepatocyte-like morphology and later formed a 3-dimensional (3-D) structure or hepatosphere. Moreover, the hepatocyte-like cells and the hepatospheres expressed liver-specific markers such as synthesis of albumin (ALB), hepatocyte growth factor receptor (HGFR), α-fetoprotein (AFP) and cytokeratin-18 (CK-18), and exhibited hepatic functions including glycogen storage capacity and indocyanine green (ICG) uptake/secretion. Human DMSC co-cultured with murine liver tissue homogenate in a non-contact in vitro system showed hepatic differentiation, as evidenced by expression of AFP and ALB genes. The switch in the expression of these two genes resembled liver development. Indeed, the decrease in AFP and increase in ALB expression throughout the co-culture were consistent with the expression pattern observed during normal liver organogenesis in the embryo. Interestingly, AFP and ALB expression was significantly higher when DMSC were co-cultured with injured liver tissue, indicating that DMSC respond differently under normal and pathologic micro-environmental conditions. In conclusion, DMSC-derived hepatospheres and DMSC co-cultured with liver homogenate could be suitable in vitro models for toxicologic, developmental and pre-clinical hepatic regeneration studies.

Isolation and characterization of true mesenchymal stem cells derived from human term decidua capable of multilineage differentiation into all 3 embryonic layers.

OBJECTIVE: The objective of the study was to isolate and characterize a population of mesenchymal stem cells (MSCs) from human term placental membranes. STUDY DESIGN: We isolated an adherent cell population from extraembryonic membranes. Morphology, phenotype, growth characteristics, karyotype, and immunological and differentiation properties were analyzed. RESULTS: The isolated placental MSCs were from maternal origin and named as decidua-derived mesenchymal stem cells (DMSCs). DMSCs differentiated into derivatives of all germ layers. It is the first report about placental MSC differentiation into alveolar type II cells. Clonally expanded DMSCs differentiated into all embryonic layers, including pulmonary cells. DMSCs showed higher life span than placental cells from fetal origin and proliferated without genomic instability. CONCLUSION: The data suggest that DMSCs are true multipotent MSCs, distinguishing them from other placental MSCs. DMSCs could be safely used in the mother as a potential source of MSCs for pelvic floor dysfunctions and immunological diseases. Additionally, frozen DMSCs can be stored for both autologous and allogeneic tissue regeneration.

Effect of different antihypertensive treatments on Ras, MAPK and Akt activation in hypertension and diabetes.

Ras GTPases function as transducers of extracellular signals regulating many cell functions, and they appear to be involved in the development of hypertension. In the present study, we have investigated whether antihypertensive treatment with ARBs (angiotensin II receptor blockers), ACEi (angiotensin-converting enzyme inhibitors) and diuretics induce changes in Ras activation and in some of its effectors [ERK (extracellular-signal-regulated kinase) and Akt] in lymphocytes from patients with hypertension without or with diabetes. ACEi treatment transiently reduced Ras activation in the first month of treatment, but diuretics induced a sustained increase in Ras activation throughout the 3 months of the study. In patients with hypertension and diabetes, ARB, ACEi and diuretic treatment increased Ras activation only during the first week. ACEi treatment increased phospho-ERK expression during the first week and also in the last 2 months of the study; however, diuretic treatment reduced phospho-ERK expression during the last 2 months of the study. In patients with hypertension and diabetes, antihypertensive treatments did not induce changes in phospho-ERK expression in lymphocytes. ACEi treatment reduced phospho-Akt expression in patients with hypertension and diabetes only in the first month of treatment. In conclusion, these findings show that antihypertensive treatments with ACEi, and diuretics to a lesser extent, modify Ras activation and some of its signalling pathways, although in different directions, whereas ARBs do not appear to have any influence on Ras signalling pathways.

Verapamil reverts acute renal functional impairment induced by angiotensin II converting enzyme inhibitors.

Angiotensin converting enzyme inhibitors (ACEI) reduce blood pressure (BP) and provide end-organ protection, but may induce renal function deterioration. In these cases, serum creatinine (SCr) can be normalized by ACEI withdrawn. In some patients, it could be desirable to maintain the ACEI for the protection of the kidney and heart. The objective of the study was to evaluate the effect of Verapamil (V) on renal function added to patients with elevated SCr due to ACEI treatment. In 46 hypertensive patients without previous renal failure, in which ACEI treatment induced an acute increase in SCr (> or = 20% or 0.5 mg/dL), ACEI treatment was maintained and 180 mg/day of V was added for 12 weeks. Those patients showing further SCr increase or no BP control at four weeks were withdrawn. Patients under BP control were moved on the combination V 180 + Trandolapril 2 mg/day for eight weeks more. SCr decreased from 136 +/- 49 micromol/L at baseline to 126 +/- 49 at 12 weeks after adding V (p < 0.001) and to 111 +/- 31 micromol/L at 20 weeks (p < 0.01). Creatinine clearance increased from 62 +/- 22 mL/min at baseline to 68 +/- 28 after 12 weeks of V (p < 0.001). This article demonstrates than in patients with acute renal function impairment secondary to ACEI treatment, the addition of 180 mg/day of verapamil to ACEI reverses SCr towards previous values.

Comparative study of intravenous ascorbic acid versus low-dose desferroxamine in patients on hemodialysis with hyperferritinemia.

BACKGROUND: In patients on hemodialysis (HD), parenteral iron improves the response to recombinant human erythropoietin (rhuEPO) therapy, but in some subjects it produces an iron overload, increasing their morbidity and mortality rates. In these cases, iron administration must be discontinued. This study aimed to investigate the efficiency of treatment with ascorbic acid (AA) or desferroxamine (DFO) to mobilize and reduce iron stores, and to determine the effect of these compounds on erythropoiesis. METHODS: We performed a prospective and randomized trial over 6 months, which included 27 patients with serum ferritin levels >800 ng/mL, TSAT >30% and stabilized hemoglobin (Hb) and rhuEPO doses. All patients had previously received parenteral iron (Ferlecit). Nine patients received 200 mg of intravenous (i.v.) AA 3 times/week and nine patients received 1 mg/Kg/week of DFO; the remaining nine patients were the control group. RESULTS: There were no significant differences in iron loss or mobilization due to dialysis. When Ferlecit was discontinued, functional iron did not vary and the epoetin resistance index (rhuEPO dose/Hb) was reduced by 21% in the i.v. AA group. In the DFO and control groups, functional iron levels fell. In the DFO group the epoetin resistance index increased by 20%, with no modifications in the control group. There was a positive correlation between transaminases and serum ferritin. CONCLUSIONS: In HD patients with an iron overload, neither i.v. AA administration or low-dose DFO increased iron mobilization or iron loss due to dialysis. I.v. AA administration allows elimination of iron from stores without any drop in the functional iron produced by discontinuing parenteral maintenance iron; it also improves the response to rhuEPO. DFO did not elicit any positive effects on erythropoiesis.