Search Results (37)

Background: The neutrophil-to-lymphocyte ratio (NLR) has emerged as a readily available marker of systemic inflammation and immune dysregulation. In patients undergoing hemodialysis, inflammation is a known contributor to erythropoietin resistance. However, the relationship between the NLR and the erythropoietin resistance index (ERI) has not been extensively characterized. Methods: A total of 317 hemodialysis patients were retrospectively evaluated and stratified into tertiles based on NLR levels. Biochemical, inflammatory, and anthropometric variables were compared across groups. Spearman’s rank correlation was used to assess the relationship between the NLR and the ERI. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive ability of the NLR for erythropoietin resistance, defined as ERI > 10. Subsequently, linear and logistic regression models were employed to examine the independent association between the NLR and the ERI, adjusting for relevant covariates. Results: Higher NLR tertiles were significantly associated with increased CRP, lower serum iron, and elevated ERI (p = 0.002). Spearman’s analysis revealed a modest but significant correlation between the NLR and the ERI (ρ = 0.31, p < 0.0001). ROC analysis identified an NLR threshold of 4.4 for detecting ERI > 10. In multivariable analysis, the NLR was independently associated with the ERI both as a continuous variable (β = 0.848, p = 0.046) and as a binary outcome (OR = 1.22, 95% CI: 0.95–1.24, p = 0.0021), while serum iron and hemoglobin also emerged as significant predictors. Conclusions: In this cohort of hemodialysis patients, a higher NLR was independently associated with increased erythropoietin resistance, suggesting its potential utility as an accessible inflammatory biomarker in anemia management. These findings add to the limited but growing body of evidence supporting the prognostic role of the NLR in dialysis populations and warrant further validation in prospective studies. Full article

Background: Although erythropoiesis-stimulating agent (ESA) therapy is fundamental for correcting anemia, excessive ESA administration is associated with increased risks. This study aimed to investigate the impact of the erythropoietin resistance index (ERI) on clinical outcomes in a population-based cohort of hemodialysis (HD) patients. Methods: This retrospective study analyzed datasets from patients who underwent periodic HD quality assessments and their claims data. Overall, we included 35,913 patients. Participants were divided into quartiles based on the ERI during the 6-month assessment period: Q1, Q2, Q3, and Q4 groups. Results: The 5-year survival rates were 68.8% (Q1), 67.8% (Q2), 66.9% (Q3), and 60.2% (Q4) (p < 0.001). Multivariable analysis showed the same trends as the univariable analysis. Additionally, a spline curve using the multivariable model indicated that the increased ERI was linked to all-cause mortality. However, cardiovascular events were not associated with ERI quartiles in Cox regression analyses. Subgroup analysis revealed that in most subgroups, the all-cause mortality was significantly higher in those with a high ERI than in those with a low ERI. Further analysis using the balanced cohort, which attenuated baseline characteristic differences, confirmed that the high mortality in those with a high ERI was maintained. Conclusions: Our population-based cohort study reveals an association between the ERI and all-cause mortality in HD patients. Full article

The relationship between telomere shortening and patients with chronic kidney disease (CKD) has recently been investigated. Although most patients respond adequately to erythropoiesis-stimulating agents (ESAs), approximately 10% do not, and this is referred to as ESA resistance. The aim of our study was to investigate the relationship between telomere shortening and erythropoietin resistance in patients with CKD on hemodialysis. This cross-sectional, comparative, analytical, and observational study was conducted in patients of both sexes over 18 years of age diagnosed with CKD. Two groups of patients were identified. The first group consisted of 40 patients receiving erythropoiesis-stimulating agents with erythropoietin resistance. The second group consisted of 40 patients with the same characteristics but without erythropoietin resistance. Telomere length was measured by real-time PCR. Eighty patients were included in the study. Mean hemoglobin levels were lower in the erythropoietin resistance group (8.8 ± 1.67 vs. 11.95 ± 1.81, p = 0.001). Differences were observed in hematocrit and albumin levels, which were lower in patients with erythropoietin resistance, while PTH levels were higher in this group (788 ± 538.47 vs. 535.65 ± 603.06, p = 0.001). A significant difference in telomere length (T/S) was observed between the two groups, with shorter telomere length in the erythropoietin resistance group (0.45 ± 0.04 vs. 0.56 ± 0.03, p = 0.01). Telomere shortening may be associated with anemia and erythropoietin resistance in patients with CKD undergoing hemodialysis. This relationship suggests the need to explore whether telomere length recovery improves the response to ESAs. Full article

Background: Removal of large uraemic toxins is still a challenge. Haemodiafiltration (HDF) has produced some results, although large convective volume, optimal vascular access to increase the blood flow rate and strict water quality management are required. Medium cut-off, high-retention-onset membranes have been recently developed, introducing the concept therapy called expanded haemodialysis (HDx). Furthermore, vitamin E-coated membrane has potential beneficial effects on inflammation and oxidative stress. Methods: A prospective longitudinal multicentre study was conducted for 3 months among 24 chronic haemodialysis patients. Patients were randomly assigned into either HDF with high-flux membrane or HDx with Theranova or ViE-X membrane. The primary goal was to assess albumin loss among the three types of dialyzers. Secondary goals included assessment of depurative efficacy for uraemic toxins and clinical outcomes. Results: Mean albumin loss was significantly higher in patients undergoing HDx with Theranova membrane, without any difference in serum albumin concentration among the three groups. Instantaneous clearance of small and middle molecules was significantly higher in patients undergoing HDF, but we did not find differences in removal ratio and Kt/V. Reduction in the erythropoietin resistance index was observed in patients treated with ViE-X membrane due to their lower dialysis vintage. Conclusions: The higher albumin loss during HDx has no effects on pre-dialysis serum albumin. HDx with Theranova in the presence of lower session length, lower Qb, lower convective dose, and lower instantaneous clearance reached the same dialysis efficacy compared to HDF. Full article

Background/Objectives: Hemodialysis (HD) patients with advanced chronic kidney disease (CKD) are highly vulnerable to complications from SARS-CoV-2 infection. Anemia management in this population is complex, particularly due to erythropoietin resistance, which may be exacerbated by COVID-19-related inflammation. To this aim, in this small-scale retrospective study, we investigated trends in the erythropoietin resistance index (ERI) over time in patients with and without SARS-CoV-2 infection. Methods: This single-center retrospective study included 25 HD patients, divided into two groups: 15 with a history of SARS-CoV-2 infection (CoV2 group) and 10 without (nonCoV2 group). The ERI was assessed over four visits, with 70–100-day intervals between them. Linear mixed models were used to evaluate factors associated with ERI changes. Results: Patients in the CoV2 group exhibited significantly higher ERI increases between T1 (baseline) and T2 (post-infection) compared to the nonCoV2 group (median ΔERI: +4.65 vs. −0.27, p < 0.001). During the T2–T4 recovery period, CoV2 patients demonstrated a delayed but substantial decline in the ERI, converging to baseline levels by T4. Male sex and hemoglobin levels were negatively associated with the ERI. Conclusions: SARS-CoV-2 infection induces transient but significant erythropoietin resistance in HD patients, likely due to inflammation and disrupted erythropoiesis. Tailored anemia management strategies, including the potential use of hypoxia-inducible factor stabilizers, are warranted. Larger, multicenter studies are needed to validate these findings and improve treatment protocols. Full article

Background/Objectives: Renal anemia is one of the major complications associated with chronic kidney disease (CKD). Erythropoietin-stimulating agents (ESAs) are commonly used; however, some patients exhibit resistance. Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) have emerged as a novel treatment for renal anemia, enhancing erythropoiesis and iron metabolism. Methods: We retrospectively analyzed laboratory data related to erythropoiesis from 105 patients with CKD before and after treatment with HIF-PHI or ESA. The dialysis initiation and mortality rates were also assessed over a median follow-up of 614 days. Results: HIF-PHI and ESA significantly increased the hemoglobin levels within 6 months of treatment (9.5 ± 1.0 to 10.7 ± 1.1, p < 0.01, and 9.9 ± 1.5 to 10.7 ± 1.2 g/dL, p < 0.01, respectively). The HIF-PHI group demonstrated a significant decrease in red cell distribution width (14.5 ± 1.9% to 13.8 ± 1.4%, p < 0.01), suggesting improved erythropoiesis, and exhibited a lower cumulative incidence of outcomes. The aged-adjusted multivariate analysis confirmed the independent association between HIF-PHI treatment and reduced risk of cumulative outcome (p = 0.042). Conclusions: HIF-PHIs can serve as an alternative to ESA for managing renal anemia in CKD, improving both hematological parameters and long-term outcomes. Full article

Background/Objectives: The barrier properties of the human small intestine play a crucial role in regulating digestion, nutrient absorption and drug metabolism. Current in vitro organotypic models consist only of an epithelium, which does not take into account the possible role of stromal cells such as fibroblasts or the extracellular matrix (ECM) which could contribute to epithelial barrier properties. Therefore, the aim of this study was to determine whether these stromal cells or ECM were beneficial or detrimental to barrier function when incorporated into an organotypic human small intestine model. Methods: Intestinal epithelial cell lines or primary cell organoids derived from the epithelial stem cells of the small intestine were cultivated either on a porous Transwell membrane (epithelial model) or on a primary small intestinal stromal cell-populated collagen-fibrin hydrogel (full thickness model). Results: Both models expressed villin (enterocytes), lysozyme (Paneth cells), Ki67 (proliferative cells) and zonula occludens-1 (tight junctions). The polarized epithelial barriers of the full thickness models demonstrated a significant decrease in transepithelial electrical resistance (TEER) with values comparable to that found in the native small intestine in contrast to the higher TEER values observed in the epithelial models. This correlated to an increase in secreted zonulin, a regulator of intestine permeability, in the full thickness models. The decreased TEER values were due to both the stromal cells and the choice of the hydrogel versus the Transwell membrane. Moreover, erythropoietin and epithelial growth factor secretion, which have roles in regulating barrier integrity, directly correlated with the changes in TEER and permeability. Conclusions: This study emphasizes the importance of different cell types being incorporated into small intestine models and, also, the influence of the scaffold or matrix used. Full article

Background/Objectives: Lipid metabolism and adiponectin modulate erythropoiesis in vitro and in general population studies and may also affect responsiveness to erythropoietin in patients undergoing haemodialysis (HD). However, little is known about the impact of lipid-associated biomarkers on reticulocyte production and erythropoietin resistance index (ERI) in patients undergoing HD. Therefore, we aimed to investigate their impacts in 167 stable patients undergoing HD. Methods: Pre-dialysis blood samples were collected and analysed for reticulocyte counts and serum lipid profiles by routine analyses and serum carnitine profiles (C0–C18) by LC-MS/MS. ERI was calculated as erythropoietin dose/kg/week normalized for haemoglobin levels. Results: The independent positive determinants of reticulocyte count were log [Triglyceride (TG)] and logC18:1. A large proportion of longer-chain acylcarnitines was positively correlated with reticulocyte counts, possibly resulting from the accumulation of acylcarnitines in mitochondria undergoing fateful exocytosis from reticulocytes. These results indicate a possible association between reticulocyte formation and reduced β-oxidation, which occurs during the peripheral phase of erythroblast enucleation. Total cholesterol (TC) and log [C2/(C16 + C18:1)] as a putative marker of β-oxidation efficiency were negative independent determinants of ERI. Moreover, acyl chain length had a significantly positive impact on the correlation coefficients of individual acylcarnitines with ERI, suggesting that enhanced β-oxidation may be associated with reduced ERI. Finally, adiponectin had no independent association with reticulocyte counts or ERI despite its negative association with HDL-C levels. Conclusions: Enhanced fatty acid β-oxidation and higher TC levels may be associated with lower ERI, whereas higher TG levels and longer acylcarnitines may be related to the latest production of reticulocytes in stable patients undergoing HD. Full article

Background/Objectives: The present study examined the effect of 12-week combined exercise training in normobaric hypoxia on arterial stiffness, inflammatory biomarkers, and red blood cell (RBC) hemorheological function in 24 obese older women (mean age: 67.96 ± 0.96 years). Methods: Subjects were randomly divided into two groups (normoxia (NMX; n = 12) and hypoxia (HPX; n = 12)). Both groups performed aerobic and resistance exercise training programs three times per week for 12 weeks, and the HPX group performed exercise programs in hypoxic environment chambers during the intervention period. Body composition was estimated using bioelectrical impedance analysis equipment. Arterial stiffness was measured using an automatic waveform analyzer. Biomarkers of inflammation and oxygen transport (tumor necrosis factor alpha, interleukin 6 (IL-6), erythropoietin (EPO), and vascular endothelial growth factor (VEGF)), and RBC hemorheological parameters (RBC deformability and aggregation) were analyzed. Results: All variables showed significantly more beneficial changes in the HPX group than in the NMX group during the intervention. The combined exercise training in normobaric hypoxia significantly reduced blood pressure (systolic blood pressure: p < 0.001, diastolic blood pressure: p < 0.001, mean arterial pressure: p < 0.001, pulse pressure: p < 0.05) and brachial–ankle pulse wave velocity (p < 0.001). IL-6 was significantly lower in the HPX group than in the NMX group post-test (p < 0.001). Also, EPO (p < 0.01) and VEGF (p < 0.01) were significantly higher in the HPX group than in the NMX group post-test. Both groups showed significantly improved RBC deformability (RBC EI_3Pa) (p < 0.001) and aggregation (RBC AI_3Pa) (p < 0.001). Conclusions: The present study suggests that combined exercise training in normobaric hypoxia can improve inflammatory biomarkers and RBC hemorheological parameters in obese older women and may help prevent cardiovascular diseases. Full article

Expression of microRNAs, such as miR-365, is known to be dysregulated in many tumors, including oral cancers, although little is known about their role or functions. The objective of this project is to evaluate the downstream targets of miR-365 to determine any potential pathways or effects. Downstream targets for miR-365 (miRdatabase target scores > 90) were used for qPCR screening of oral cancer cell lines (SCC4, SCC9, SCC15, SCC25, CAL27). Each oral cancer cell line expressed miR-365 downstream targets molybdenum cofactor synthesis-2 (MOCS2), erythropoietin receptor (EPOR), IQ motif containing-K (IQCK), carboxypeptidase A3 (CPA3), solute carrier family 24 member-3 (SLC24A3), and coiled-coil domain containing 47 (CCDC47)—although the expression levels varied somewhat. However, differential results were observed with ubiquitin protein ligase E3 component n-recognin-3 (UBR3), nudix hydrolase-12 (NUDT12), zinc finger CCHC-type containing-14 (ZCCHC14), and homeobox and leucine zipper encoding (HOMEZ). These data suggest that many of the miR-365 targets are expressed in the oral cancers screened, with the differential expression of UBR3, ZCCHC14, HOMEZ, and NUDT12, which may be correlated with chemoresistance among two specific oral cancer cell lines (SCC25, SCC9). These results suggest this differential expression may signal potential targets for patient treatment with tumors exhibiting miR-365 and chemotherapeutic resistance. Full article

Anemia is a common hematological disorder that affects 12% of the community-dwelling population, 40% of hospitalized patients, and 47% of nursing home residents. Our understanding of the impact of inflammation on iron metabolism and erythropoiesis is still lacking. In older adults, anemia can be divided into nutritional deficiency anemia, bleeding anemia, and unexplained anemia. The last type of anemia might be caused by reduced erythropoietin (EPO) activity, progressive EPO resistance of bone marrow erythroid progenitors, and the chronic subclinical pro-inflammatory state. Overall, one-third of older patients with anemia demonstrate a nutritional deficiency, one-third have a chronic subclinical pro-inflammatory state and chronic kidney disease, and one-third suffer from anemia of unknown etiology. Understanding anemia’s pathophysiology in people aged 65 and over is crucial because it contributes to frailty, falls, cognitive decline, decreased functional ability, and higher mortality risk. Inflammation produces adverse effects on the cells of the hematological system. These effects include iron deficiency (hypoferremia), reduced EPO production, and the elevated phagocytosis of erythrocytes by hepatic and splenic macrophages. Additionally, inflammation causes enhanced eryptosis due to oxidative stress in the circulation. Identifying mechanisms behind age-related inflammation is essential for a better understanding and preventing anemia in older adults. Full article

Breast cancer (BCA) remains the leading cause of cancer-related mortality among women worldwide. This review delves into the therapeutic challenges of BCA, emphasizing the roles of interleukin-13 receptor α2 (IL-13Rα2) and erythropoietin-producing hepatocellular receptor A2 (EphA2) in tumor progression and resistance. Highlighting their overexpression in BCA, particularly in aggressive subtypes, such as Her-2-enriched and triple-negative breast cancer (TNBC), we discuss the potential of these receptors as targets for chimeric antigen receptor T-cell (CAR-T) therapies. We examine the structural and functional roles of IL-13Rα2 and EphA2, their pathological significance in BCA, and the promising therapeutic avenues their targeting presents. With an in-depth analysis of current immunotherapeutic strategies, including the limitations of existing treatments and the potential of dual antigen-targeting CAR T-cell therapies, this review aims to summarize potential future novel, more effective therapeutic interventions for BCA. Through a thorough examination of preclinical and clinical studies, it underlines the urgent need for targeted therapies in combating the high mortality rates associated with Her-2-enriched and TNBC subtypes and discusses the potential role of IL-13Rα2 and EphA2 as promising candidates for the development of CAR T-cell therapies. Full article

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors’ progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors. Full article

The study of anaemia is a well-developed discipline where the concepts of precision medicine have, in part, been researched extensively. This review discusses the treatment of erythropoietin (EPO) deficiency anaemia and resistance in cases of chronic kidney disease (CKD). Traditionally, erythropoietin-stimulating agents (ESAs) and iron supplementation have been used to manage anaemia in cases of CKD. However, these treatments pose potential risks, including cardiovascular and thromboembolic events. Newer treatments have emerged to address these risks, such as slow-release and low-dosage intravenous iron, oral iron supplementation, and erythropoietin–iron combination therapy. Another novel approach is the use of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). This review highlights the need for precision medicine targeting the genetic components of EPO deficiency anaemia in CKD and discusses individual variability in genes such as the erythropoietin gene (EPO), the interleukin-β gene (IL-β), and the hypoxia-inducible factor gene (HIF). Pharmacogenetic testing aims to provide targeted therapies and interventions that are tailored to the specific characteristics of an individual, thus optimising treatment outcomes and minimising resistance and adverse effects. This article concludes by suggesting that receptor modification has the potential to revolutionise the treatment outcomes of patients with erythropoietin deficiency anaemia through the integration of the mentioned approach. Full article

Background and Objectives: Iron deficiency and anemia characterize patients on chronic hemodialysis (HD). Available intravenous iron agents, such as ferric gluconate (FG) and ferric carboxymaltose (FCM), vary in dosing regimens and safety profiles. The aim of the present study was to analyze the modification of the iron status, the correction of anemia, and the economic implications after the shift from FG to FCM therapy in chronic HD patients. We evaluated, during the study, the variations in iron metabolism, assessing ferritin and transferrin saturation, erythropoietin-stimulating agent (ESA) doses and the number of administrations, the effects on anemic status, and consequent costs. Materials and Methods: A retrospective study was performed with a follow-up period of 24 months, enrolling forty-two HD patients. The enrolment phase started in January 2015, when patients were treated with iv FG, and continued until December 2015, when FG was discontinued, and, after a wash-out period, the same patients were treated with FCM. Results: The iron switch reduced the administered dose of ESA by 1610.500 UI (31% of reduction; p < 0.001) during the entire study period and reduced the erythropoietin resistance index (ERI) (10.1 ± 0.4 vs. 14.8 ± 0.5; p < 0.0001). The FCM group had the highest percentage of patients who did not require ESA treatment during the study period. The FCM patients were characterized by higher levels of iron (p = 0.04), ferritin (p < 0.001), and TSAT levels (p < 0.001) compared to the FG patients. The annual cost during FG infusion was estimated at EUR 105,390.2, while one year of treatment with FCM had a total cost of EUR 84,180.7 (a difference of EUR 21,209.51 (20%), saving EUR 42.1 per patient/month (p < 0.0001). Conclusions: FCM was a more effective treatment option than FG, reducing ESA dose requirements, increasing Hb levels, and improving iron status. The reduced ESA doses and the decreased number of patients needing ESA were the main factors for reducing overall costs. Full article