Influence of inhibiting methemoglobin formation on erythrocyte antioxidant defense.

We aimed to study the influence of preventing methemoglobin (metHb) formation, in the roles of peroxiredoxin 2 (Prx2), glutathione peroxidase (GPx) and catalase (CAT) on the erythrocyte antioxidant defense system. We performed in vitro assays using healthy erythrocytes, with and without inhibition of autoxidation of Hb (saturation with carbon monoxide), followed by H2O2-induced oxidative stress. We assessed the enzyme activities and amounts of CAT, GPx and Prx2 in the red blood cell (RBC) cytosol and membrane and several biomarkers of oxidative stress, such as the reduced and oxidized glutathione levels, thiobarbituric acid reactive substances (TBARS) levels, membrane bound hemoglobin and total antioxidant status. When autoxidation of Hb was inhibited, no significant changes were found for GPx and CAT; Prx2 was observed only in the monomeric form in the cytosol and none bound to the membrane. Blocking the function of Hb as a pseudo-peroxidase does not seem to have an impact on the function of the RBC peroxidases.

Reticulocyte Antioxidant Enzymes mRNA Levels versus Reticulocyte Maturity Indices in Hereditary Spherocytosis, ß-Thalassemia and Sickle Cell Disease.

The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and peroxiredoxin 2 (Prx2) are particularly important in erythroid cells. Reticulocytes and other erythroid precursors may adapt their biosynthetic mechanisms to cell defects or to changes in the bone marrow environment. Our aim was to perform a comparative study of the mRNA levels of CAT, GPX1, PRDX2 and SOD1 in reticulocytes from healthy individuals and from patients with hereditary spherocytosis (HS), sickle cell disease (SCD) and ß-thalassemia (ß-thal), and to study the association between their transcript levels and the reticulocyte maturity indices. In controls, the enzyme mRNA levels were significantly correlated with reticulocyte maturity indices for all genes except for SOD1. HS, SCD and ß-thal patients showed younger reticulocytes, with higher transcript levels of all enzymes, although with different patterns. ß-thal and HS showed similar reticulocyte maturity, with different enzyme mRNA levels; SCD and HS, with different reticulocyte maturity, presented similar enzyme mRNA levels. Our data suggest that the transcript profile for these antioxidant enzymes is not entirely related to reticulocyte maturity; it appears to also reflect adaptive mechanisms to abnormal erythropoiesis and/or to altered erythropoietic environments, leading to reticulocytes with distinct antioxidant potential according to each anemia.

Toxicity Mechanisms of Gadolinium and Gadolinium-Based Contrast Agents-A Review.

Gadolinium-based contrast agents (GBCAs) have been used for more than 30 years to improve magnetic resonance imaging, a crucial tool for medical diagnosis and treatment monitoring across multiple clinical settings. Studies have shown that exposure to GBCAs is associated with gadolinium release and tissue deposition that may cause short- and long-term toxicity in several organs, including the kidney, the main excretion organ of most GBCAs. Considering the increasing prevalence of chronic kidney disease worldwide and that most of the complications following GBCA exposure are associated with renal dysfunction, the mechanisms underlying GBCA toxicity, especially renal toxicity, are particularly important. A better understanding of the gadolinium mechanisms of toxicity may contribute to clarify the safety and/or potential risks associated with the use of GBCAs. In this work, a review of the recent literature concerning gadolinium and GBCA mechanisms of toxicity was performed.

Age-Related Changes in Clinical and Analytical Variables in Chronic Hemodialyzed Patients.

Worldwide, the number of elderly individuals receiving chronic hemodialysis is rising. The aim of our study was to evaluate several clinical and analytical biomarkers in chronically dialyzed patients and analyze how they change with age. A cross-sectional study was performed by evaluating 289 end-stage renal disease patients undergoing dialysis. We evaluated the hemogram, adipokines, the lipid profile, and several markers related to inflammation, endothelial function/fibrinolysis, nutrition, iron metabolism, and cardiac and renal fibrosis. Clinical data and dialysis efficacy parameters were obtained from all patients. The relationships between studied biomarkers and age were assessed by a statistical comparison between younger (adults with age < 65 years) and older (age ≥ 65 years) patients and by performing regression analysis. Participants presented a mean age of 68.7 years (±13.6), with 66.8% (n = 193) being classified as older. Compared to younger patients, older patients presented the following: (a) significantly lower values of diastolic blood pressure (DBP) and ultrafiltration volume; (b) lower levels of phosphorus, uric acid, creatinine, and albumin; and (c) higher circulating concentrations of tissue-type plasminogen activator (tPA), D-dimer, interleukin-6, leptin, N-terminal pro B-type natriuretic peptide, and tissue inhibitor of metalloproteinase-1. In the multiple linear regression analysis, DBP values, tPA, phosphorus, and D-dimer levels were independently associated with the age of patients (standardized betas: -0.407, 0.272, -0.230, and 0.197, respectively; p < 0.001 for all), demonstrating relevant changes in biomarkers with increasing age at cardiovascular and nutritional levels. These findings seem to result from crosstalk mechanisms between aging and chronic kidney disease.

Inhibition of erythrocyte's catalase, glutathione peroxidase or peroxiredoxin 2 - Impact on cytosol and membrane.

Catalase (CAT), glutathione peroxidase (GPx) and Prx2 (peroxiredoxin 2) are the main antioxidant enzymatic defenses of erythrocytes. They prevent and minimize oxidative injuries in red blood cell (RBC) components, which are continuously exposed to oxidative stress (OS). The crosstalk between CAT, GPx and Prx2 is still not fully disclosed, as well as why these typically cytoplasmic enzymes bind to the RBC membrane. Our aim was to understand the interplay between CAT, GPx and Prx2 in the erythrocyte's cytosol and membrane. Under specific (partial) inhibition of each enzyme and increasing H2O2-induced OS conditions, we evaluated the enzyme activities and amounts, the binding of CAT, GPx and Prx2 to RBC membrane, and biomarkers of OS, such as the reduced and oxidized glutathione levels, thiobarbituric acid reactive substances (TBARS) levels, membrane bound hemoglobin and total antioxidant status. Our results support the hypothesis that when high levels of H2O2 get within the erythrocyte, CAT is the main player in the antioxidant protection of the cell, while Prx2 and GPx have a less striking role. Moreover, we found that CAT, appears to have more importance in the antioxidant protection of cytoplasm than of the membrane components, since when the activity of CAT is disturbed, GPx and Prx2 are both activated in the cytosol and mobilized to the membrane. In more severe OS conditions, the antioxidant activity of GPx is more significant at the membrane, as we found that GPx moves from the cytosol to the membrane, probably to protect it from lipid peroxidation.

Bile acids profile and redox status in healthy infants.

BACKGROUND: At birth, human neonates are more likely to develop cholestasis and oxidative stress due to immaturity or other causes. We aimed to search for a potential association between bile acids profile, redox status, and type of diet in healthy infants. METHODS: A cross-sectional, exploratory study enrolled 2-month-old full-term infants (n = 32). We measured plasma bile acids (total and conjugated), and red blood cell (RBC) oxidative stress biomarkers. The type of diet (breastfeeding, mixed, formula) was used as an independent variable. RESULTS: Plasma total bile acids medium value was 14.80 µmol/L (IQR: 9.25-18.00). The plasma-conjugated chenodeoxycholic acid percentage (CDCA%) correlated significantly and negatively with RBCs membrane-bound hemoglobin percentage (MBH%) (r = -0.635, p < 0.01) and with RBC-oxidized glutathione (r = -0.403, p < 0.05) levels. RBC oxidative stress biomarkers (especially MBH%) were predictors of conjugated CDCA%, and this predictive ability was enhanced when adjusted for the type of diet (MBH, r = 0.452, p < 0.001). CONCLUSIONS: Our data suggest that the bile acid profile might play a role in the regulation of redox status (or vice versa) in early postnatal life. Eventually, the type of diet may have some impact on this process. IMPACT: The conjugated CDCA% in plasma is negatively correlated with biomarkers of RBC oxidative stress in healthy infants. Specific biomarkers of RBC oxidative stress (e.g. MBH, GSH, GSSG) may be promising predictors of conjugated CDCA% in plasma. The type of diet may influence the predictive ability of hit RBC oxidative stress biomarkers (e.g. MBH, GSH, GSSG). Our findings suggest a link between plasma bile acids profile and the RBC redox status in healthy infants, eventually modulated by the type of diet. The recognition of this link may contribute to the development of preventive and therapeutic strategies for neonatal cholestasis.

Inflammatory biomarkers in staging of chronic kidney disease: elevated TNFR2 levels accompanies renal function decline.

BACKGROUND: Inflammation is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the disease cause. Our aim was to evaluate the potential of several inflammatory biomarkers in CKD diagnosis and staging. METHODS: A total of 24 healthy controls and 92 pre-dialysis CKD patients with diverse etiologies, were enrolled in this study and grouped according to their CKD stage. We analysed the circulating levels of inflammatory molecules, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 2 (TNFR2), pentraxin 3 (PTX3) and leptin, as well as the hemogram. We studied their association with parameters of kidney function and kidney injury, to evaluate their potential as early markers of the disease and/or of its worsening, as well as their interplay. RESULTS: Compared to controls, patients in CKD stages 1-2 presented significantly higher IL-6 and TNFR2 levels, and higher neutrophil-to-lymphocyte ratio. All inflammatory cytokines and acute-phase proteins showed a trend to increase up to stage 3, stabilizing or declining thereafter, save for TNFR2, which steadily increased from stage to stage. All inflammatory molecules, apart from PTX3, were negatively and significantly correlated with eGFR, with a remarkable value for TNFR2 (r = - 0.732, p < 0.001). CONCLUSION: TNFR2 might be useful for an early detection of CKD, as well as for disease staging/worsening. Still, the potential value of this biomarker in disease progression warrants further investigation.

The Signaling Pathway of TNF Receptors: Linking Animal Models of Renal Disease to Human CKD.

Chronic kidney disease (CKD) has been recognized as a global public health problem. Despite the current advances in medicine, CKD-associated morbidity and mortality remain unacceptably high. Several studies have highlighted the contribution of inflammation and inflammatory mediators to the development and/or progression of CKD, such as tumor necrosis factor (TNF)-related biomarkers. The inflammation pathway driven by TNF-α, through TNF receptors 1 (TNFR1) and 2 (TNFR2), involves important mediators in the pathogenesis of CKD. Circulating levels of TNFRs were associated with changes in other biomarkers of kidney function and injury, and were described as predictors of disease progression, cardiovascular morbidity, and mortality in several cohorts of patients. Experimental studies describe the possible downstream signaling pathways induced upon TNFR activation and the resulting biological responses. This review will focus on the available data on TNFR1 and TNFR2, and illustrates their contributions to the pathophysiology of kidney diseases, their cellular and molecular roles, as well as their potential as CKD biomarkers. The emerging evidence shows that TNF receptors could act as biomarkers of renal damage and as mediators of the disease. Furthermore, it has been suggested that these biomarkers could significantly improve the discrimination of clinical CKD prognostic models.

Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models.

Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773-0.912].Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model. What Is Known • The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia. • Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools. What Is New • This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC. • A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.

New Potential Biomarkers for Chronic Kidney Disease Management-A Review of the Literature.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and the mortality rate continues to be unacceptably high. The biomarkers currently used in clinical practice are considered relevant when there is already significant renal impairment compromising the early use of potentially successful therapeutic interventions. More sensitive and specific biomarkers to detect CKD earlier on and improve patients' prognoses are an important unmet medical need. The aim of this review is to summarize the recent literature on new promising early CKD biomarkers of renal function, tubular lesions, endothelial dysfunction and inflammation, and on the auspicious findings from metabolomic studies in this field. Most of the studied biomarkers require further validation in large studies and in a broad range of populations in order to be implemented into routine CKD management. A panel of biomarkers, including earlier biomarkers of renal damage, seems to be a reasonable approach to be applied in clinical practice to allow earlier diagnosis and better disease characterization based on the underlying etiologic process.

Long Pentraxin 3 as a Broader Biomarker for Multiple Risk Factors in End-Stage Renal Disease: Association with All-Cause Mortality.

Persistent inflammation in end-stage renal disease (ESRD) patients is known to underlie the progression of chronic kidney disease and to be associated with multiple risk factors including malnutrition, atherosclerosis, and cardiovascular disease (CVD). The acute-phase protein pentraxin 3 (PTX3) has a proven potential as a local inflammatory biomarker, but its clinical utility in ESRD remains unclear. Circulating levels of PTX3 and classical inflammatory mediators, including the clinical prototypical C-reactive protein (CRP), were assessed in 246 ESRD patients on dialysis and analysed in relation to the lipid profile, adipokine levels, and nutritional, cardiac, and renal fibrosis markers. Occurrence of deaths was recorded for the following year. Contrarily to the classical inflammatory markers, PTX3 levels were negatively correlated with nutritional markers and associated with a less atherogenic lipid profile. Levels of the cardiac and renal fibrosis markers and of the oxidized LDL/LDL-C ratio were found to be independent determinants of PTX3 concentration. When comparing inflammatory mediators, the increase in the PTX3 levels was the only predictor of all-cause mortality in dialysis patients in a survival model adjusted to all markers under study, other than the inflammatory ones, besides common confounding factors in dialysis. Data support the clinical applicability of PTX3 as a broader inflammatory biomarker than the classical ones, presenting a close association with inflammation, malnutrition, CVD, and renal fibrosis and a great potential to predict all-cause mortality in dialysis patients. The pleiotropic character of PTX3 may be of clinical relevance, and it could be targeted to ameliorate the high morbidity and mortality associated with ESRD.

The biocompatibility and bioactivity of hemodialysis membranes: their impact in end-stage renal disease.

End-stage renal disease is a growing health problem with increasing prevalence and high health care costs. Patients suffering from end-stage renal disease exhibit higher morbidity and mortality rates compared to the general population. These patients, who are treated using hemodialysis, typically suffer from anemia, inflammation, and oxidative stress. Inadequate dialyzer membrane biocompatibility exacerbates these negative side effects. Modifications of the composition of hemodialysis membranes have improved their biocompatibility and improve the patients' quality of life. Recently, the use of dialyzer membranes coated with bioactive compounds has also been proposed to further ameliorate dialysis-associated problems. Based on a survey of the current literature, application of bioactive membranes decreases the inflammation and oxidative stress of patients treated with hemodialysis.

Hepcidin and diabetes are independently related with soluble transferrin receptor levels in chronic dialysis patients.

Background: Soluble transferrin receptor (sTfR) is a biomarker of erythropoiesis, which is often impaired in dialysis patients. The aim of our study was to evaluate sTfR levels in chronically dialyzed patients and assess potential determinants of its levels. Methods: We performed a cross-sectional study by evaluating 246 end-stage renal disease patients undergoing dialysis and 32 healthy controls. Circulating levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, hepcidin, sTfR, growth differentiation factor 15 (GDF15), and traditional iron metabolism markers were measured, as well as hemogram parameters. Clinical data was obtained from all patients. Results: Compared to controls, patients presented similar values of sTfR, reticulocytes and reticulocyte production index (RPI), and significantly higher levels of IL-6, CRP, ferritin, hepcidin, TNF-α, and GDF15. Iron, transferrin, hemoglobin levels, erythrocyte count, mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) values were significantly lower in dialysis group. Within patients, sTfR values were higher in diabetic patients and were positively and significantly correlated with reticulocytes and erythrocytes, RPI, and therapeutic doses of erythropoiesis stimulating agents (ESA) and intravenous iron; and inversely and significantly correlated with circulating iron, ferritin, transferrin saturation, hepcidin, MCH, and MCHC. In multiple linear regression analysis, ESA dose, RPI, serum iron, diabetes, and hepcidin levels were independently associated with sTfR levels in dialysis patients and, thus, with erythropoiesis. Conclusion: Our data suggest that, besides RPI and ESA dose, diabetes and hepcidin are closely related to erythropoiesis in dialysis patients. The influence of diabetes on sTfR levels deserves further investigation.

Influence of the 6-month physical activity programs on renal function in obese boys.

BackgroundWe intended to evaluate the effects of physical activity (PA) programs on renal function in obese boys.MethodsThirty-nine boys participated in one of the following three groups: soccer (SG, n=13), traditional PA (AG, n=13), and sedentary control (CG, n=13). SG and AG were involved in 6-month PA programs, involving three sessions/week for 60-90 min. Anthropometric measurements, body composition, creatinine and cystatin C plasmatic levels, and estimated glomerular filtration rate (eGFR) were evaluated.ResultsAt baseline (n=39), age and lean mass index (LMI) were positively correlated with creatinine levels. After 6 months, both intervention groups decreased the BMI z-score and waist circumference, while the CG increased the body fat percentage (BFP). LMI increased in all the groups. SG presented a small increment in plasma creatinine and a decrease in the eGFR values, using the Schwartz formula. Concerning the cystatin C levels and eGFR values using Filler (cystatin C-based) or Combined Zappitelli (creatinine/cystatin C-based) formulas, no significant changes were observed in any group.ConclusionThe combined Zappitelli formula showed no significant impact of PA on eGFR in obese boys. Although plasma creatinine is significantly influenced by lean body mass, cystatin C is likely to be a more accurate marker of renal function in this population.

Vascular biosafety of commercial hydroxyapatite particles: discrepancy between blood compatibility assays and endothelial cell behavior.

BACKGROUND: Vascular homeostasis is ensured by a dynamic interplay involving the endothelium, the platelets and the coagulation system. Thus, the vascular safety of particulate materials must address this integrated system, an approach that has been largely neglected. This work analysed the effects of commercial hydroxyapatite (HA) particles in blood compatibility and in endothelial cell behavior, due to their clinical relevance and scarcity of data on their vascular biosafety. RESULTS: Particles with similar chemical composition and distinct size and morphology were tested, i.e. rod-like, nano dimensions and low aspect ratio (HAp1) and needle-shape with wider size and aspect ratio (HAp2). HAp1 and HAp2, at 1 to 10 mg/mL, did not affect haemolysis, platelet adhesion, aggregation and activation, or the coagulation system (intrinsic and extrinsic pathways), although HAp2 exhibited a slight thrombogenic potential at 10 mg/mL. Notwithstanding, significantly lower levels presented dose-dependent toxicity on endothelial cells' behavior. HAp1 and HAp2 decreased cell viability at levels ≥ 250 and ≥ 50 µg/mL, respectively. At 10 and 50 µg/mL, HAp1 did not interfere with the F-actin cytoskeleton, apoptotic index, cell cycle progression, expression of vWF, VECad and CD31, and the ability to form a network of tubular-like structures. Comparatively, HAp2 caused dose-dependent toxic effects in these parameters in the same concentration range. CONCLUSION: The most relevant observation is the great discrepancy of HA particles' levels that interfere with the routine blood compatibility assays and the endothelial cell behavior. Further, this difference was also found to be dependent on the particles' size, morphology and aspect ratio, emphasizing the need of a complementary biological characterization, taking into consideration the endothelial cells' functionality, to establish the vascular safety of particulate HA.

Physical exercise intervention at school improved hepcidin, inflammation, and iron metabolism in overweight and obese children and adolescents.

BackgroundObesity is often associated with iron deficiency in children and adolescents. We aimed to study the effect of an 8-month physical exercise (PE) intervention on hepcidin and other markers of inflammation and on iron status in overweight/obese children and adolescents.MethodsSeventy-three overweight/obese children and adolescents participated in the 8-month-long longitudinal study. They were divided into two groups according to their participation in an after-school PE program: the PE group (n=44) and the control group (n=29). Hepcidin, interleukin (IL)-6, C-reactive protein (CRP), iron, ferritin, transferrin, and soluble transferrin receptor (sTfR) were evaluated.ResultsAt baseline, IL-6 correlated positively with hepcidin and negatively with iron and transferrin saturation, suggesting that increasing adiposity associates with increasing IL-6 and hepcidin synthesis, reducing iron availability. After 8 months, the PE group showed a decrease in BMI z-score (P=0.003), body fat mass (P=0.012), CRP (P=0.002), IL-6 (P=0.048), ferritin (P=0.013), hepcidin (P=0.040), and sTfR (P=0.010), and an increase in iron concentration (P=0.002). Moreover, the PE group, when compared with the control group, showed lower weight (P=0.026), BMI (P=0.040), waist circumference (P=0.010), and waist-to-height ratio (P=0.046).ConclusionWe showed that an 8-month-long intervention at school allowed a reduction in BMI z-score and an improvement in inflammation, reducing hepcidin levels and the disturbances in iron status.

Physical inactivity among older adults across Europe based on the SHARE database.

Background: Regular physical activity is one of the key components of a healthy lifestyle. It is associated with better physical and cognitive functioning in later life and with increased life expectancy. The purpose of this study was to evaluate the prevalence of, and factors related to, physical inactivity among older adults across Europe. Methods: In this cross-sectional analysis, we used data from participants aged 55 or older in Wave 4 of the Survey of Health, Ageing, and Retirement in Europe (SHARE) database, a multidisciplinary and cross-national panel database covering health, socioeconomic status, and social and family networks. Individuals included in this study were classified as physically active or physically inactive. Clinical, psychosocial and sociodemographic variables were evaluated for their association with physical inactivity. Results: From the total of 58,489 individuals in SHARE, we selected 19,298 people age 55 or older (mean age 67.8 ± 8.9 years; 11,430 (59.2%) female). The overall prevalence of inactivity among individuals age 55 or older in the 16 included countries was 12.5%. The prevalence of physical inactivity varied between countries, ranging from 4.9% (Sweden) to 29% (Portugal). Increasing age, depression, physical limitations, poor sense of meaning in life, social support and memory loss were significant variables associated with physical inactivity. Conclusions: Physical inactivity can be explained by physical, cognitive and psychological conditions. Interventions aimed at promoting physical activity among older people are needed to address this diversity of factors.

Recombinant human erythropoietin-induced erythropoiesis regulates hepcidin expression over iron status in the rat.

The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis.

Risk factors for mortality in end-stage kidney disease patients under online-hemodiafiltration: three-year follow-up study.

The aim of this work was to evaluate the predictors of mortality in a group of end-stage kidney disease (ESRD) patients under dialysis, by performing a three-year follow-up study. From the 236 patients included in this study, 54 patients died during the three-year follow-up period. Our data showed that the risk of death was higher in patients presenting lower levels of mean cell hemoglobin concentration, transferrin, and albumin. Our study showed that poor nutritional status and an inflammatory-induced iron depleted erythropoiesis are important factors for mortality in these patients.

Renal risk-benefit determinants of recombinant human erythropoietin therapy in the remnant kidney rat model - hypertension, anaemia, inflammation and drug dose.

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.